DEPOD - human DEPhOsphorylation Database

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	RELA (QuickGO)	Interactive visualization of RELA structures (A quick tutorial to explore the interctive visulaization) Representative structure: 4KV1
Synonyms	RELA, NFKB3
Protein Name	RELA
Alternative Name(s)	Transcription factor p65;Nuclear factor NF-kappa-B p65 subunit;Nuclear factor of kappa light polypeptide gene enhancer in B-cells 3;
Protein Family	noSimilarity_annotations
EntrezGene ID	5970 (Comparitive Toxicogenomics)
UniProt AC (Human)	Q04206 (protein sequence)
Enzyme Class	N/A
Molecular Weight	60219 Dalton
Protein Length	551 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000173039 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree \| eggNOG - ENOG410IG8F \| eggNOG - ENOG410XT64
Phosphorylation Network	Visualize

Domain organization, Expression, Diseases

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Localization, Function, Catalytic activity and Sequence

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Localization (UniProt annotation)
Nucleus Cytoplasm Note=Nuclear, but also found in thecytoplasm in an inactive form complexed to an inhibitor (I-kappa-B) (PubMed:1493333) Colocalized with DDX1 in the nucleus uponTNF-alpha induction (PubMed:19058135) Colocalizes with GFI1 inthe nucleus after LPS stimulation (PubMed:20547752)
Function (UniProt annotation)
NF-kappa-B is a pleiotropic transcription factor presentin almost all cell types and is the endpoint of a series of signaltransduction events that are initiated by a vast array of stimulirelated to many biological processes such as inflammation,immunity, differentiation, cell growth, tumorigenesis andapoptosis NF-kappa-B is a homo- or heterodimeric complex formedby the Rel-like domain-containing proteins RELA/p65, RELB,NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 The heterodimeric RELA-NFKB1 complex appears to be most abundant one The dimers bind atkappa-B sites in the DNA of their target genes and the individualdimers have distinct preferences for different kappa-B sites thatthey can bind with distinguishable affinity and specificityDifferent dimer combinations act as transcriptional activators orrepressors, respectively The NF-kappa-B heterodimeric RELA-NFKB1and RELA-REL complexes, for instance, function as transcriptionalactivators NF-kappa-B is controlled by various mechanisms ofpost-translational modification and subcellularcompartmentalization as well as by interactions with othercofactors or corepressors NF-kappa-B complexes are held in thecytoplasm in an inactive state complexed with members of the NF-kappa-B inhibitor (I-kappa-B) family In a conventional activationpathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs)in response to different activators, subsequently degraded thusliberating the active NF-kappa-B complex which translocates to thenucleus The inhibitory effect of I-kappa-B on NF-kappa-B throughretention in the cytoplasm is exerted primarily through theinteraction with RELA RELA shows a weak DNA-binding site whichcould contribute directly to DNA binding in the NF-kappa-Bcomplex Beside its activity as a direct transcriptionalactivator, it is also able to modulate promoters accessibility totranscription factors and thereby indirectly regulate geneexpression Associates with chromatin at the NF-kappa-B promoterregion via association with DDX1 Essential for cytokine geneexpression in T-cells (PubMed:15790681) The NF-kappa-Bhomodimeric RELA-RELA complex appears to be involved in invasin-mediated activation of IL-8 expression
Catalytic Activity (UniProt annotation)
N/A
Protein Sequence
MDELFPLIFPAEPAQASGPYVEIIEQPKQRGMRFRYKCEGRSAGSIPGERSTDTTKTHPTIKINGYTGPGTVRISLVTKD PPHRPHPHELVGKDCRDGFYEAELCPDRCIHSFQNLGIQCVKKRDLEQAISQRIQTNNNPFQVPIEEQRGDYDLNAVRLC FQVTVRDPSGRPLRLPPVLSHPIFDNRAPNTAELKICRVNRNSGSCLGGDEIFLLCDKVQKEDIEVYFTGPGWEARGSFS QADVHRQVAIVFRTPPYADPSLQAPVRVSMQLRRPSDRELSEPMEFQYLPDTDDRHRIEEKRKRTYETFKSIMKKSPFSG PTDPRPPPRRIAVPSRSSASVPKPAPQPYPFTSSLSTINYDEFPTMVFPSGQISQASALAPAPPQVLPQAPAPAPAPAMV SALAQAPAPVPVLAPGPPQAVAPPAPKPTQAGEGTLSEALLQLQFDDEDLGALLGNSTDPAVFTDLASVDNSEFQQLLNQ GIPVAPHTTEPMLMEYPEAITRLVTGAQRPPDPAPAPLGAPGLPNGLLSGDEDFSSIADMDFSALLSQISS

Motif information from Eukaryotic Linear Motif atlas (ELM)

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Gene Ontology (P: Process; F: Function and C: Component terms)

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GO:0000122	P:negative regulation of transcription by RNA polymerase II
GO:0000790	C:nuclear chromatin
GO:0000977	F:RNA polymerase II regulatory region sequence-specific DNA binding
GO:0000978	F:RNA polymerase II proximal promoter sequence-specific DNA binding
GO:0000980	F:RNA polymerase II distal enhancer sequence-specific DNA binding
GO:0000981	F:RNA polymerase II transcription factor activity
GO:0000983	sequence-specific DNA binding
GO:0001077	F:transcription factor activity
GO:0001078	RNA polymerase II core promoter sequence-specific DNA binding
GO:0001205	F:transcriptional activator activity
GO:0001889	RNA polymerase II proximal promoter sequence-specific DNA binding
GO:0001942	F:transcriptional repressor activity
GO:0002223	RNA polymerase II proximal promoter sequence-specific DNA binding
GO:0003677	F:transcriptional activator activity
GO:0003682	RNA polymerase II distal enhancer sequence-specific DNA binding
GO:0003700	P:liver development
GO:0003705	P:hair follicle development
GO:0005634	P:stimulatory C-type lectin receptor signaling pathway
GO:0005654	F:DNA binding
GO:0005667	F:chromatin binding
GO:0005737	F:DNA-binding transcription factor activity
GO:0005829	F:transcription factor activity
GO:0006117	RNA polymerase II distal enhancer sequence-specific binding
GO:0006355	C:nucleus
GO:0006954	C:nucleoplasm
GO:0006968	C:transcription factor complex
GO:0007568	C:cytoplasm
GO:0008134	C:cytosol
GO:0008284	P:acetaldehyde metabolic process
GO:0009887	P:regulation of transcription
GO:0010033	DNA-templated
GO:0010224	P:inflammatory response
GO:0014040	P:cellular defense response
GO:0016032	P:aging
GO:0019221	F:transcription factor binding
GO:0019901	P:positive regulation of cell proliferation
GO:0031293	P:animal organ morphogenesis
GO:0031490	P:response to organic substance
GO:0031625	P:response to UV-B
GO:0032332	P:positive regulation of Schwann cell differentiation
GO:0032481	P:viral process
GO:0032495	P:cytokine-mediated signaling pathway
GO:0032570	F:protein kinase binding
GO:0032868	P:membrane protein intracellular domain proteolysis
GO:0033209	F:chromatin DNA binding
GO:0033234	F:ubiquitin protein ligase binding
GO:0033256	P:positive regulation of chondrocyte differentiation
GO:0033590	P:positive regulation of type I interferon production
GO:0033613	P:response to muramyl dipeptide
GO:0035525	P:response to progesterone
GO:0035729	P:response to insulin
GO:0035924	P:tumor necrosis factor-mediated signaling pathway
GO:0035994	P:negative regulation of protein sumoylation
GO:0038095	C:I-kappaB/NF-kappaB complex
GO:0042177	P:response to cobalamin
GO:0042301	F:activating transcription factor binding
GO:0042802	C:NF-kappaB p50/p65 complex
GO:0042803	P:cellular response to hepatocyte growth factor stimulus
GO:0042805	P:cellular response to vascular endothelial growth factor stimulus
GO:0042826	P:response to muscle stretch
GO:0043066	P:Fc-epsilon receptor signaling pathway
GO:0043123	P:negative regulation of protein catabolic process
GO:0043200	F:phosphate ion binding
GO:0043278	F:identical protein binding
GO:0043620	F:protein homodimerization activity
GO:0044212	F:actinin binding
GO:0044877	F:histone deacetylase binding
GO:0045084	P:negative regulation of apoptotic process
GO:0045892	P:positive regulation of I-kappaB kinase/NF-kappaB signaling
GO:0045893	P:response to amino acid
GO:0045944	P:response to morphine
GO:0046627	P:regulation of DNA-templated transcription in response to stress
GO:0046982	F:transcription regulatory region DNA binding
GO:0047485	F:protein-containing complex binding
GO:0050727	P:positive regulation of interleukin-12 biosynthetic process
GO:0050852	P:negative regulation of transcription
GO:0050862	DNA-templated
GO:0051059	P:positive regulation of transcription
GO:0051092	DNA-templated
GO:0051591	P:positive regulation of transcription by RNA polymerase II
GO:0051607	P:negative regulation of insulin receptor signaling pathway
GO:0061614	F:protein heterodimerization activity
GO:0070301	F:protein N-terminus binding
GO:0070431	P:regulation of inflammatory response
GO:0070491	P:T cell receptor signaling pathway
GO:0070498	P:positive regulation of T cell receptor signaling pathway
GO:0070555	F:NF-kappaB binding
GO:0071222	P:positive regulation of NF-kappaB transcription factor activity
GO:0071223	P:response to cAMP
GO:0071224	P:defense response to virus
GO:0071316	P:pri-miRNA transcription by RNA polymerase II
GO:0071347	P:cellular response to hydrogen peroxide
GO:0071354	P:nucleotide-binding oligomerization domain containing 2 signaling pathway
GO:0071356	F:repressing transcription factor binding
GO:0071532	P:interleukin-1-mediated signaling pathway
GO:0098978	P:response to interleukin-1
GO:0099527	P:cellular response to lipopolysaccharide
GO:1901222	P:cellular response to lipoteichoic acid
GO:1901223	P:cellular response to peptidoglycan
GO:1901224	P:cellular response to nicotine
GO:1901522	P:cellular response to interleukin-1
GO:1902894	P:cellular response to interleukin-6
GO:1902895	P:cellular response to tumor necrosis factor
GO:1904385	F:ankyrin repeat binding
GO:2000630	C:glutamatergic synapse
GO:2001237	P:postsynapse to nucleus signaling pathway

KEGG Pathway
Reactome Pathway

Pathway ID	Pathway Name	Pathway Description (KEGG)
hsa01523	Antifolate resistance	Since the 1940s, antifolates have played a pivotal role in drug treatment of malignant, microbial, parasitic and chronic inflammatory diseases. The molecular basis of the anti-proliferative activity of antifolates relies on inhibition of key enzymes in folate metabolism, which results in disruption of purine and thymidylate biosynthesis, inhibition of DNA replication and cell death. The anti-inflammatory properties of antifolate have been most strongly related to its ability to block the release of pro-inflammatory cytokines such as tumour necrosis factor (TNF)-alpha or interleukin (IL)-1beta. Cells may develop resistance to an antifolate drug by virtue of impaired drug transport into cells, augmented drug export, impaired activation of antifolates through polyglutamylation, augmented hydrolysis of antifolate polyglutamates, increased expression and mutation of target enzymes, and the augmentation of cellular tetrahydrofolate-cofactor pools in cells.
hsa04010	MAPK signaling pathway	The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli.
hsa04014	Ras signaling pathway	The Ras proteins are GTPases that function as molecular switches for signaling pathways regulating cell proliferation, survival, growth, migration, differentiation or cytoskeletal dynamism. Ras proteins transduce signals from extracellular growth factors by cycling between inactive GDP-bound and active GTP-bound states. The exchange of GTP for GDP on RAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Activated RAS (RAS-GTP) regulates multiple cellular functions through effectors including Raf, phosphatidylinositol 3-kinase (PI3K) and Ral guanine nucleotide-dissociation stimulator (RALGDS).
hsa04024	cAMP signaling pathway	cAMP is one of the most common and universal second messengers, and its formation is promoted by adenylyl cyclase (AC) activation after ligation of G protein-coupled receptors (GPCRs) by ligands including hormones, neurotransmitters, and other signaling molecules. cAMP regulates pivotal physiologic processes including metabolism, secretion, calcium homeostasis, muscle contraction, cell fate, and gene transcription. cAMP acts directly on three main targets: protein kinase A (PKA), the exchange protein activated by cAMP (Epac), and cyclic nucleotide-gated ion channels (CNGCs). PKA modulates, via phosphorylation, a number of cellular substrates, including transcription factors, ion channels, transporters, exchangers, intracellular Ca2+ -handling proteins, and the contractile machinery. Epac proteins function as guanine nucleotide exchange factors (GEFs) for both Rap1 and Rap2. Various effector proteins, including adaptor proteins implicated in modulation of the actin cytoskeleton, regulators of G proteins of the Rho family, and phospholipases, relay signaling downstream from Rap.
hsa04062	Chemokine signaling pathway	Inflammatory immune response requires the recruitment of leukocytes to the site of inflammation upon foreign insult. Chemokines are small chemoattractant peptides that provide directional cues for the cell trafficking and thus are vital for protective host response. In addition, chemokines regulate plethora of biological processes of hematopoietic cells to lead cellular activation, differentiation and survival.The chemokine signal is transduced by chemokine receptors (G-protein coupled receptors) expressed on the immune cells. After receptor activation, the alpha- and beta-gamma-subunits of G protein dissociate to activate diverse downstream pathways resulting in cellular polarization and actin reorganization. Various members of small GTPases are involved in this process. Induction of nitric oxide and production of reactive oxygen species are as well regulated by chemokine signal via calcium mobilization and diacylglycerol production.
hsa04064	NF-kappa B signaling pathway	Nuclear factor-kappa B (NF-kappa B) is the generic name of a family of transcription factors that function as dimers and regulate genes involved in immunity, inflammation and cell survival. There are several pathways leading to NF-kappa B-activation. The canonical pathway is induced by tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) or byproducts of bacterial and viral infections. This pathway relies on IKK- mediated IkappaB-alpha phosphorylation on Ser32 and 36, leading to its degradation, which allows the p50/p65 NF-kappa B dimer to enter the nucleus and activate gene transcription. Atypical pathways are IKK-independent and rely on phosphorylation of IkappaB-alpha on Tyr42 or on Ser residues in IkappaB-alpha PEST domain. The non-canonical pathway is triggered by particular members of the TNFR superfamily, such as lymphotoxin-beta (LT-beta) or BAFF. It involves NIK and IKK-alpha-mediated p100 phosphorylation and processing to p52, resulting in nuclear translocation of p52/RelB heterodimers.
hsa04066	HIF-1 signaling pathway	Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis. It consists of two subunits: an inducibly-expressed HIF-1alpha subunit and a constitutively-expressed HIF-1beta subunit. Under normoxia, HIF-1 alpha undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the subunit. In contrast, under hypoxia, HIF-1 alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Eventually, HIF-1 acts as a master regulator of numerous hypoxia-inducible genes under hypoxic conditions. The target genes of HIF-1 encode proteins that increase O2 delivery and mediate adaptive responses to O2 deprivation. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, or various growth factors.
hsa04071	Sphingolipid signaling pathway	Sphingomyelin (SM) and its metabolic products are now known to have second messenger functions in a variety of cellular signaling pathways. Particularly, the sphingolipid metabolites, ceramide (Cer) and sphingosine-1-phosphate (S1P), have emerged as a new class of potent bioactive molecules. Ceramide can be generated de novo or by hydrolysis of membrane sphingomyelin by sphingomyelinase (SMase). Ceramide is subsequently metabolized by ceramidase to generate sphingosine (Sph) which in turn produces S1P through phosphorylation by sphingosine kinases 1 and 2 (SphK1, 2). Both ceramide and S1P regulate cellular responses to stress, with generally opposing effects. S1P functions as a growth and survival factor, acting as a ligand for a family of G protein-coupled receptors, whereas ceramide activates intrinsic and extrinsic apoptotic pathways through receptor-independent mechanisms.
hsa04137	Mitophagy - animal	Mitochondria act as the energy powerhouse of the cell, and are essential for eukaryotic cells to grow and function normally. However, deleterious byproducts of oxidative phosphorylation process called reactive oxidative species (ROS) lead to mitochondrial dysfunction. If the damage is too excessive to be repaired, such mitochondria are selectively recognized and targeted for degradation by a specific mode of autophagy, termed mitophagy. The loss of the mitochondrial membrane potential can induce mitophagy, involving the kinase PINK1 and the E3 ligase Parkin. PINK1 serves as the sensor for the mitochondrial depolarization and recruits Parkin, followed by ubiquitin-dependent recruitment of mitophagy receptors. There are also several PINK1/Parkin-independent mitophagy pathways, in which a group of LIR-containing receptors are required in response to different stimuli. Mitophagy contributes to the maintenance of a healthy mitochondrial network and the prevention of programmed cell death.
hsa04151	PI3K-Akt signaling pathway	The phosphatidylinositol 3' -kinase(PI3K)-Akt signaling pathway is activated by many types of cellular stimuli or toxic insults and regulates fundamental cellular functions such as transcription, translation, proliferation, growth, and survival. The binding of growth factors to their receptor tyrosine kinase (RTK) or G protein-coupled receptors (GPCR) stimulates class Ia and Ib PI3K isoforms, respectively. PI3K catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP3) at the cell membrane. PIP3 in turn serves as a second messenger that helps to activate Akt. Once active, Akt can control key cellular processes by phosphorylating substrates involved in apoptosis, protein synthesis, metabolism, and cell cycle.
hsa04210	Apoptosis	Apoptosis is a genetically programmed process for the elimination of damaged or redundant cells by activation of caspases (aspartate-specific cysteine proteases). The onset of apoptosis is controlled by numerous interrelating processes. The 'extrinsic' pathway involves stimulation of members of the tumor necrosis factor (TNF) receptor subfamily, such as TNFRI, CD95/Fas or TRAILR (death receptors), located at the cell surface, by their specific ligands, such as TNF-alpha, FasL or TRAIL, respectively. The 'intrinsic' pathway is activated mainly by non-receptor stimuli, such as DNA damage, ER stress, metabolic stress, UV radiation or growth-factor deprivation. The central event in the 'intrinsic' pathway is the mitochondrial outer membrane permeabilization (MOMP), which leads to the release of cytochrome c. These two pathways converge at the level of effector caspases, such as caspase-3 and caspase-7. The third major pathway is initiated by the constituents of cytotoxic granules (e.g. Perforin and Granzyme B) that are released by CTLs (cytotoxic T-cells) and NK (natural killer) cells. Granzyme B, similarly to the caspases, cleaves its substrates after aspartic acid residues, suggesting that this protease has the ability to activate members of the caspase family directly. It is the balance between the pro-apoptotic and anti-apoptotic signals that eventually determines whether cells will undergo apoptosis, survive or proliferate. TNF family of ligands activates anti-apoptotic or cell-survival signals as well as apoptotic signals. NGF and Interleukin-3 promotes the survival, proliferation and differentiation of neurons or hematopoietic cells, respectively. Withdrawal of these growth factors leads to cell death, as described above.
hsa04211	Longevity regulating pathway	Regulation of longevity depends on genetic and environmental factors. Caloric restriction (CR), that is limiting food intake, is recognized in mammals as the best characterized and most reproducible strategy for extending lifespan. Four pathways have been implicated in mediating the CR effect. These are the insulin like growth factor (IGF-1)/insulin signaling pathway, the sirtuin pathway, the adenosine monophosphate (AMP) activated protein kinase (AMPK) pathway and the target of rapamycin (TOR) pathway. The collective response of these pathways to CR is believed to promote cellular fitness and ultimately longevity via activation of autophagy, stress defense mechanisms, and survival pathways while attenuating proinflammatory mediators and cellular growth. Furthermore, there is evidence supporting that life span extension can be achieved with pharmacologic agents that mimic the effects of caloric restriction, such as rapamycin, via mTOR signaling blockade, resveratrol, by activating SIRT1 activity, and metformin, which seems to be a robust stimulator of AMPK activity. As an aging suppressor, Klotho is an important molecule in aging processes and its overexpression results in longevity.
hsa04218	Cellular senescence	Cellular senescence is a state of irreversible cellular arrest and can be triggered by a number of factors, such as telomere shortening, oncogene activation, irradiation, DNA damage and oxidative stress. It is characterized by enlarged flattened morphology, senescence-associated beta-galactosidase (SA-b-gal) activity, secretion of inflammatory cytokines, growth factors and matrix metalloproteinases, as part of the senescence-associated secretory phenotype (SASP). Cellular senescence is functionally associated with many biological processes including aging, tumor suppression, placental biology, embryonic development, and wound healing.
hsa04380	Osteoclast differentiation	The osteoclasts, multinucleared cells originating from the hematopoietic monocyte-macrophage lineage, are responsible for bone resorption. Osteoclastogenesis is mainly regulated by signaling pathways activated by RANK and immune receptors, whose ligands are expressed on the surface of osteoblasts. Signaling from RANK changes gene expression patterns through transcription factors like NFATc1 and characterizes the active osteoclast.
hsa04620	Toll-like receptor signaling pathway	Specific families of pattern recognition receptors are responsible for detecting microbial pathogens and generating innate immune responses. Toll-like receptors (TLRs) are membrane-bound receptors identified as homologs of Toll in Drosophila. Mammalian TLRs are expressed on innate immune cells, such as macrophages and dendritic cells, and respond to the membrane components of Gram-positive or Gram-negative bacteria. Pathogen recognition by TLRs provokes rapid activation of innate immunity by inducing production of proinflammatory cytokines and upregulation of costimulatory molecules. TLR signaling pathways are separated into two groups: a MyD88-dependent pathway that leads to the production of proinflammatory cytokines with quick activation of NF-{kappa}B and MAPK, and a MyD88-independent pathway associated with the induction of IFN-beta and IFN-inducible genes, and maturation of dendritic cells with slow activation of NF-{kappa}B and MAPK.
hsa04621	NOD-like receptor signaling pathway	Specific families of pattern recognition receptors are responsible for detecting various pathogens and generating innate immune responses. The intracellular NOD-like receptor (NLR) family contains more than 20 members in mammals and plays a pivotal role in the recognition of intracellular ligands. NOD1 and NOD2, two prototypic NLRs, sense the cytosolic presence of the bacterial peptidoglycan fragments that escaped from endosomal compartments, driving the activation of NF-{kappa}B and MAPK, cytokine production and apoptosis. On the other hand, a different set of NLRs induces caspase-1 activation through the assembly of multiprotein complexes called inflammasomes. The activated of caspase-1 regulates maturation of the pro-inflammatory cytokines IL-1B, IL-18 and drives pyroptosis.
hsa04622	RIG-I-like receptor signaling pathway	Specific families of pattern recognition receptors are responsible for detecting viral pathogens and generating innate immune responses. Non-self RNA appearing in a cell as a result of intracellular viral replication is recognized by a family of cytosolic RNA helicases termed RIG-I-like receptors (RLRs). The RLR proteins include RIG-I, MDA5, and LGP2 and are expressed in both immune and nonimmune cells. Upon recognition of viral nucleic acids, RLRs recruit specific intracellular adaptor proteins to initiate signaling pathways that lead to the synthesis of type I interferon and other inflammatory cytokines, which are important for eliminating viruses.
hsa04623	Cytosolic DNA-sensing pathway	Specific families of pattern recognition receptors are responsible for detecting foreign DNA from invading microbes or host cells and generating innate immune responses. DAI is the first identified sensor of cytosolic DNA which activates the IRF and NF-{kappa}B transcription factors, leading to production of type I interferon and other cytokines. The second type of cytoplasmic DNA sensor is AIM2. Upon sensing DNA, AIM2 triggers the assembly of the inflammasome, culminating in interleukin maturation. In addition to these receptors, there is a mechanism to sense foreign DNA, with the host RNA polymerase III converting the DNA into RNA for recognition by the RNA sensor RIG-I. These pathways provide various means to alert the cell.
hsa04625	C-type lectin receptor signaling pathway	C-type lectin receptors (CLRs) are a large superfamily of proteins characterized by the presence of one or more C-type lectin-like domains (CTLDs). CLRs function as pattern-recognition receptors (PRRs) for pathogen-derived ligands in dendric cells, macrophages, neutrophils, etc., such as Dectin-1 and Dectin-2 for recognition of fungi-derived B-glucan and high mannose-type carbohydrates. Upon ligand binding, CLRs stimulate intracellular signaling cascades that induce the production of inflammatory cytokines and chemokines, consequently triggering innate and adaptive immunity to pathogens.
hsa04657	IL-17 signaling pathway	The interleukin 17 (IL-17) family, a subset of cytokines consisting of IL-17A-F, plays crucial roles in both acute and chronic inflammatory responses. IL-17A, the hallmark cytokine of the newly defined T helper 17 (TH17) cell subset, has important roles in protecting the host against extracellular pathogens, but also promotes inflammatory pathology in autoimmune disease, whereas IL-17F is mainly involved in mucosal host defense mechanisms. IL-17E (IL-25) is an amplifier of Th2 immune responses. IL-17C has biological functions similar to those of IL-17A. The functions of IL-17B and IL-17D remain largely elusive. The IL-17 family signals via their correspondent receptors and activates downstream pathways that include NF-kappaB, MAPKs and C/EBPs to induce the expression of antimicrobial peptides, cytokines and chemokines. The receptor proximal adaptor Act1 (an NF-kappaB activator 1) is considered as the master mediator in IL-17A signaling. It is likely that Act1 is a common signal adaptor also shared by other members mediated signalings in this family.
hsa04658	Th1 and Th2 cell differentiation	Immunity to different classes of microorganisms is orchestrated by separate lineages of effector T helper (TH)-cells, which differentiate from naive CD4+ precursor cells in response to cues provided by antigen presenting cells (APC) and include T helper type 1 (Th1) and Th2. Th1 cells are characterized by the transcription factor T-bet and signal transducer and activator of transcription (STAT) 4, and the production of IFN-gamma. These cells stimulate strong cell-mediated immune responses, particularly against intracellular pathogens. On the other hand, transcription factors like GATA-3 and STAT6 drive the generation of Th2 cells that produce IL-4, IL-5 and IL-13 and are necessary for inducing the humoral response to combat parasitic helminths (type 2 immunity) and isotype switching to IgG1 and IgE. The balance between Th1/Th2 subsets determines the susceptibility to disease states, where the improper development of Th2 cells can lead to allergy, while an overactive Th1 response can lead to autoimmunity.
hsa04659	Th17 cell differentiation	Interleukin (IL)-17-producing helper T (Th17) cells serve as a subset of CD4+ T cells involved in epithelial cell- and neutrophil mediated immune responses against extracellular microbes and in the pathogenesis of autoimmune diseases. In vivo, Th17 differentiation requires antigen presentation and co-stimulation, and activation of antigen presenting-cells (APCs) to produce TGF-beta, IL-6, IL-1, IL-23 and IL-21. This initial activation results in the activation and up-regulation of STAT3, ROR(gamma)t and other transcriptional factors in CD4+ T cells, which bind to the promoter regions of the IL-17, IL-21 and IL-22 genes and induce IL-17, IL-21 and IL-22. In contrast, the differentiation of Th17 cells and their IL-17 expression are negatively regulated by IL-2, Th2 cytokine IL-4, IL-27 and Th1 cytokine IFN-gamma through STAT5, STAT6 and STAT1 activation, respectively. Retinoid acid and the combination of IL-2 and TGF-beta upregulate Foxp3, which also downregulates cytokines like IL-17 and IL-21. The inhibition of Th17 differentiation may serve as a protective strategy to 'fine-tune' the expression IL-17 so it does not cause excessive inflammation. Thus, balanced differentiation of Th cells is crucial for immunity and host protection.
hsa04660	T cell receptor signaling pathway	Activation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. Engagement of these receptors through the interaction with a foreign antigen associated with major histocompatibility complex molecules and CD28 counter-receptors B7.1/B7.2, respectively, results in a series of signaling cascades. These cascades comprise an array of protein-tyrosine kinases, phosphatases, GTP-binding proteins and adaptor proteins that regulate generic and specialised functions, leading to T-cell proliferation, cytokine production and differentiation into effector cells.
hsa04662	B cell receptor signaling pathway	B cells are an important component of adaptive immunity. They produce and secrete millions of different antibody molecules, each of which recognizes a different (foreign) antigen. The B cell receptor (BCR) is an integral membrane protein complex that is composed of two immunoglobulin (Ig) heavy chains, two Ig light chains and two heterodimers of Ig-alpha and Ig-beta. After BCR ligation by antigen, three main protein tyrosine kinases (PTKs) -the SRC-family kinase LYN, SYK and the TEC-family kinase BTK- are activated. Phosphatidylinositol 3-kinase (PI3K) and phospholipase C-gamma 2 (PLC-gamma 2) are important downstream effectors of BCR signalling. This signalling ultimately results in the expression of immediate early genes that further activate the expression of other genes involved in B cell proliferation, differentiation and Ig production as well as other processes.
hsa04668	TNF signaling pathway	Tumor necrosis factor (TNF), as a critical cytokine, can induce a wide range of intracellular signal pathways including apoptosis and cell survival as well as inflammation and immunity. Activated TNF is assembled to a homotrimer and binds to its receptors (TNFR1, TNFR2) resulting in the trimerization of TNFR1 or TNFR2. TNFR1 is expressed by nearly all cells and is the major receptor for TNF (also called TNF-alpha). In contrast, TNFR2 is expressed in limited cells such as CD4 and CD8 T lymphocytes, endothelial cells, microglia, oligodendrocytes, neuron subtypes, cardiac myocytes, thymocytes and human mesenchymal stem cells. It is the receptor for both TNF and LTA (also called TNF-beta). Upon binding of the ligand, TNFR mediates the association of some adaptor proteins such as TRADD or TRAF2, which in turn initiate recruitment of signal transducers. TNFR1 signaling induces activation of many genes, primarily controlled by two distinct pathways, NF-kappa B pathway and the MAPK cascade, or apoptosis and necroptosis. TNFR2 signaling activates NF-kappa B pathway including PI3K-dependent NF-kappa B pathway and JNK pathway leading to survival.
hsa04722	Neurotrophin signaling pathway	Neurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Neurotrophins exert their functions through engagement of Trk tyrosine kinase receptors or p75 neurotrophin receptor (p75NTR). Neurotrophin/Trk signaling is regulated by connecting a variety of intracellular signaling cascades, which include MAPK pathway, PI-3 kinase pathway, and PLC pathway, transmitting positive signals like enhanced survival and growth. On the other hand, p75NTR transmits both positive and nagative signals. These signals play an important role for neural development and additional higher-order activities such as learning and memory.
hsa04917	Prolactin signaling pathway	Prolactin (PRL) is a polypeptide hormone known to be involved in a wide range of biological functions including osmoregulation, lactation, reproduction, growth and development, endocrinology and metabolism, brain and behavior, and immunomodulation. PRL mediates its action through PRLR, a transmembrane protein of the hematopoietin cytokine receptor superfamily. At the protein level, the long PRLR isoform (long-R) and several short PRLR isoforms (short-R) have been detected. Acting through the long-R, PRL activates many signaling cascades including Jak2/Stat, the major cascade, Src kinase, phosphatidylinositol-3-kinase (PI3K)/AKT, and mitogen-activated protein kinase (MAPK) pathways. PRL cannot activate Jak2/Stat5 through the short-R, but can activate pathways including MAPK and PI3K pathways.
hsa04920	Adipocytokine signaling pathway	Increased adipocyte volume and number are positively correlated with leptin production, and negatively correlated with production of adiponectin.Leptin is an important regulator of energy intake and metabolic rate primarily by acting at hypothalamic nuclei. Leptin exerts its anorectic effects by modulating the levels of neuropeptides such as NPY, AGRP, and alpha-MSH. This leptin action is through the JAK kinase, STAT3 phosphorylation, and nuclear transcriptional effect.Adiponectin lowers plasma glucose and FFAs. These effects are partly accounted for by adiponectin-induced AMPK activation, which in turn stimulates skeletal muscle fatty acid oxidation and glucose uptake. Furthermore, activation of AMPK by adiponectin suppresses endogenous glucose production, concomitantly with inhibition of PEPCK and G6Pase expression.The proinflammatory cytokine TNFalpha has been implicated as a link between obesity and insulin resistance. TNFalpha interferes with early steps of insulin signaling. Several data have shown that TNFalpha inhibits IRS1 tyrosine phosphorylation by promoting its serine phosphorylation. Among the serine/threonine kinases activated by TNFalpha, JNK, mTOR and IKK have been shown to be involved in this phosphorylation.
hsa04926	Relaxin signaling pathway	Human relaxin-2 (relaxin), originally identified as a peptidic hormone of pregnancy, is now known to exert a range of pleiotropic effects including vasodilatory, anti-fibrotic and angiogenic effects in both males and females. It belongs to the so-called relaxin peptide family which includes the insulin-like peptides INSL3 and INSL5, and relaxin-3 (H3) as well as relaxin. INSL3 has clearly defined specialist roles in male and female reproduction, relaxin-3 is primarily a neuropeptide involved in stress and metabolic control, and INSL5 is widely distributed particularly in the gastrointestinal tract. These members of relaxin peptide family exert such effects binding to different kinds of receptors, classified as relaxin family peptide (RXFP) receptors: RXFP1, RXFP2, RXFP3, and RXFP4. These G protein-coupled receptors predominantly bind relaxin, INSL3, relaxin-3, and INSL-5, respectively. RXFP1 activates a wide spectrum of signaling pathways to generate second messengers that include cAMP and nitric oxide, whereas RXFP2 activates a subset of these pathways. Both RXFP3 and RXFP4 inhibit cAMP production, and RXFP3 activate MAP kinases.
hsa04931	Insulin resistance	Insulin resistance is a condition where cells become resistant to the effects of insulin. It is often found in people with health disorders, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, and cardiovascular diseases. In this diagram multiple mechanisms underlying insulin resistance are shown: (a) increased phosphorylation of IRS (insulin receptor substrate) protein through serine/threonine kinases, such as JNK1 and IKKB, and protein kinase C, (b) increased IRS-1 proteasome degradation via mTOR signaling pathway, (c) decreased activation of signaling molecules including PI3K and AKT, (d) increase in activity of phosphatases including PTPs, PTEN, and PP2A. Regulatory actions such as oxidative stress, mitochondrial dysfunction, accumulation of intracellular lipid derivatives (diacylglycrol and ceramides), and inflammation (via IL-6 and TNFA) contribute to these mechanisms. Consequently, insulin resistance causes reduced GLUT4 translocation, resulting in glucose takeup and glycogen synthesis in skeletal muscle as well as increased hepatic gluconeogenesis and decreased glycogen synthesis in liver. At the bottom of the diagram, interplay between O-GlcNAcylation and serine/threonine phosphorylation is shown. Studies suggested that elevated O-GlcNAc level was correlated to high glucose-induced insulin resistance. Donor UDP-GlcNAc is induced through hexosamine biosynthesis pathway and added to proteins by O-GlcNAc transferase. Elevation of O-GlcNAc modification alters phosphorylation and function of key insulin signaling proteins including IRS-1, PI3K, PDK1, Akt and other transcription factor and cofactors, resulting in the attenuation of insulin signaling cascade.
hsa04932	Non-alcoholic fatty liver disease (NAFLD)	Non-alcoholic fatty liver disease (NAFLD) represents a spectrum ranging from simple steatosis to more severe steatohepatitis with hepatic inflammation and fibrosis, known as nonalcoholic steatohepatitis (NASH). NASH may further lead to cirrhosis and hepatocellular carcinoma (HCC). This map shows a stage-dependent progression of NAFLD. In the first stage of NAFLD, excess lipid accumulation has been demonstrated. The main cause is the induction of insulin resistance, which leads to a defect in insulin suppression of free fatty acids (FAAs) disposal. In addition, two transcription factors, SREBP-1c and PPAR-alpha, activate key enzymes of lipogenesis and increase the synthesis of FAAs in liver. In the second stage, as a consequence of the progression to NASH, the production of reactive oxygen species (ROS) is enhanced due to oxidation stress through mitochondrial beta-oxidation of fatty acids and endoplamic reticulum (ER) stress, leading to lipid peroxidation. The lipid peroxidation can further cause the production of cytokines (Fas ligand, TNF-alpha, IL-8 and TGF), promoting cell death, inflammation and fibrosis. The activation of JNK, which is induced by ER stress, TNF-alpha and FAAs, is also associated with NAFLD progression. Increased JNK promotes cytokine production and initiation of HCC.
hsa04933	AGE-RAGE signaling pathway in diabetic complications	Advanced glycation end products (AGEs) are a complex group of compounds produced through the non-enzymatic glycation and oxidation of proteins, lipids and nucleic acids, primarily due to aging and under certain pathologic condition such as huperglycemia. Some of the best chemically characterized AGEs include N-epsilon-carboxy-methyl-lysine (CML), N-epsilon-carboxy-ethyl-lysine (CEL), and Imidazolone. The major receptor for AGEs, known as receptor for advanced glycation end products (RAGE or AGER), belongs to the immunoglobulin superfamily and has been described as a pattern recognition receptor. AGE/RAGE signaling elicits activation of multiple intracellular signal pathways involving NADPH oxidase, protein kinase C, and MAPKs, then resulting in NF-kappaB activity. NF-kappa B promotes the expression of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha and a variety of atherosclerosis-related genes, including VCAM-1, tissue factor, VEGF, and RAGE. In addition, JAK-STAT-mediated and PI3K-Akt-dependent pathways are induced via RAGE, which in turn participate in cell proliferation and apoptosis respectively. Hypoxia-mediated induction of Egr-1 was also shown to require the AGE-RAGE interaction. The results of these signal transductions have been reported to be the possible mechanism that initates diabetic complications.
hsa05030	Cocaine addiction	Drug addiction is a chronic, relapsing disorder in which compulsive drug-seeking and drug-taking behavior persists despite serious negative consequences.There is strong evidence that the dopaminergic system that projects from the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens (NAc), and to other forebrain sites, is the major substrate of reward and reinforcement for both natural rewards and addictive drugs. Cocaine binds strongly to the dopamine-reuptake transporter, preventing the reuptake of dopamine into the nerve terminal. Because of this blocking effect, dopamine remains at high concentrations in the synapse and continues to affect adjacent neurons, producing the characteristic cocaine high.Activated D1 receptor activates the PKA signaling pathway, and this pathway plays a critical role in mediating the behavioral responses to cocaine administration. Cocaine-induced neuroadaptations, including dopamine depletion, may underlie craving and hedonic dysregulation.
hsa05120	Epithelial cell signaling in Helicobacter pylori infection	Two major virulence factors of H. pylori are the vacuolating cytotoxin (VacA) and the cag type-IV secretion system (T4SS) and its translocated effector protein, cytotoxin-associated antigen A (CagA).VacA binds to lipid rafts and glycosylphosphatidylinositol-anchored proteins (GPI-APs) of the target cell membrane. After insertion into the plasma membrane, VacA channels are endocytosed and eventually reach late endosomal compartments, increasing their permeability to anions with enhancement of the electrogenic vacuolar ATPase (v-ATPase) proton pump. In the presence of weak bases, osmotically active acidotropic ions will accumulate in the endosomes. This leads to water influx and vesicle swelling, an essential step in vacuole formation. In addition, it is reported that the VacA cleavage product binds to the tyrosine phosphatase receptor zeta (Ptprz) on epithelial cells and the induced signaling leads to the phosphorylation of the G protein-coupled receptor kinase-interactor 1 (Git1) and induces ulcerogenesis in mice.The other virulence factor cag T4SS mediates the translocation of the effector protein CagA, which is subsequently phosphorylated by a Src kinase. Phosphorylated CagA interacts with the protein tyrosine phosphatase SHP-2, thus stimulating its phosphatase activity. Activated SHP-2 is able to induce MAPK signalling through Ras/Raf-dependent and -independent mechanisms. Deregulation of this pathway by CagA may lead to abnormal proliferation and movement of gastric epithelial cells.
hsa05131	Shigellosis	Shigellosis, or bacillary dysentery, is an intestinal infection caused by Shigella, a genus of enterobacteria. Shigella are potential food-borne pathogens that are capable of colonizing the intestinal epithelium by exploiting epithelial-cell functions and circumventing the host innate immune response. During basolateral entry into the host-cell cytoplasm, Shigella deliver a subset of effectors into the host cells through the type III secretion system. The effectors induce membrane ruffling through the stimulation of the Rac1-WAVE-Arp2/3 pathway, enabling bacterial entry into the epithelial cells. During multiplication within the cells, Shigella secrete another subset of effectors. VirG induces actin polymerization at one pole of the bacteria, allowing the bacteria to spread intracellularly and to infect adjacent cells. OspF, OspG and IpaH(9.8) downregulate the production of proinflammatory cytokines such as IL-8, helping bacteria circumvent the innate immune response.
hsa05132	Salmonella infection	Salmonella infection usually presents as a self-limiting gastroenteritis or the more severe typhoid fever and bacteremia. The common disease-causing Salmonella species in human is a single species, Salmonella enterica, which has numerous serovars.Following intestinal colonization Salmonella inject effector proteins into the host cells using a type III secretion system (T3SS), T3SS1. Then a small group of effector proteins induce rearrangement of the actin cytoskeleton resulting in membrane ruffles and rapid internalization of the bacteria.The T3SS2 is responsible for translocating effector proteins that direct Salmonella-containing vacuole (SCV) maturation. The majority of the bacteria are known to survive and replicate in SCV.
hsa05133	Pertussis	Pertussis, also known as whooping cough, is an acute respiratory infectious disease caused by a bacteria called Bordetella Pertussis. The characteristic symptoms are paroxysmal cough, inspiratory wheezing and post-tussive vomiting.Following the inhalation of respiratory secretions from an infected individual, bacteria enter the upper respiratory tract and adhere to epithelial cells. Several adhesion factors have been implicated: the filamentous hemagglutinin (FHA), fimbriae, and pertactin (Prn).Pertussis toxin (Ptx) and adenylate cyclase toxin (ACT) have been identified so far as major protein toxins of B. pertussis. PTX is a hexameric AB5-type exotoxin. Catalytic A subunit catalyzes the ADP-ribosylation of the Gi subunits of the heterotrimeric G protein, then inhibits multiple downstream pathways. ACT is able to penetrate the cytoplasmic membrane of host cells and becomes activated through the cleavage and the binding of calmodulin (CaM). Activated ACT converts ATP to cyclic AMP and subverts cellular signaling pathways.
hsa05134	Legionellosis	Legionellosis is a potentially fatal infectious disease caused by the bacterium Legionella pneumophila and other legionella species. Two distinct clinical and epidemiological syndromes are associated with Legionella species: Legionnaires' disease is the more severe form of the infection, which may involve pneumonia, and Pontiac fever is a milder respiratory illness.The pathogenesis of L. pneumophila is derived from its growth within lung macrophages. One of the L. pneumophila's type IV secretion systems, the Dot/Icm secretion system, is of critical importance for its ability to replicate and to cause disease. The Dot/Icm substrates modulate multiple host cell processes and in particular, redirect trafficking of the L. pneumophila phagosome and mediate its conversion into an ER-derived organelle competent for intracellular bacterial replication. L. pneumophila also manipulates host cell death and survival pathways in a way that allows continued intracellular replication.
hsa05140	Leishmaniasis	Leishmania is an intracellular protozoan parasite of macrophages that causes visceral, mucosal, and cutaneous diseases. The parasite is transmitted to humans by sandflies, where they survive and proliferate intracellularly by deactivating the macrophage. Successful infection of Leishmania is achieved by alteration of signaling events in the host cell, leading to enhanced production of the autoinhibitory molecules like TGF-beta and decreased induction of cytokines such as IL12 for protective immunity. Nitric oxide production is also inhibited. In addition, defective expression of major histocompatibility complex (MHC) genes silences subsequent T cell activation mediated by macrophages, resulting in abnormal immune responses.
hsa05142	Chagas disease (American trypanosomiasis)	Trypanosoma cruzi is an intracellular protozoan parasite that causes Chagas disease. The parasite life cycle involves hematophagous reduviid bugs as vectors. Once parasites enter the host body, they invade diverse host cells including cardiomyocytes. Establishment of infection depends on various parasite molecules such as cruzipain, oligopeptidase B, and trans-sialidase that activate Ca2+ signaling. Internalized parasites escape from the parasitophorous vacuole using secreted pore-forming TcTOX molecule and replicate in the cytosol. Multiplied parasites eventually lyse infected host cells and are released in the circulation. During these events, the parasites manipulate host innate immunity and elicit cardiomyocyte hypertrophy. T lymphocyte responses are also disturbed.
hsa05145	Toxoplasmosis	Toxoplasma gondii is an obligate intracellular parasite that is prevalent worldwide. The tachyzoite form acquired by oral ingestion downmodulates proinflammatory signaling pathways via various mechanisms. During early infection, nuclear translocation of NFkB is temporally blocked and p38 MAPK phosphorylation is prevented, suppressing IL-12 production. Another pathway for IL-12 induction occurs through CCR5 dependent pathway, but parasitic induction of an eicosanoid LXA4 contributes to the downregulation of IL-12. Direct activation of STAT3 by the parasite enhance anti-inflammatory function of IL-10 and TGF beta. T. gondii can cause lifelong chronic infection by establishing an anti-apoptotic environment through induction of bcl-2 or IAPs and by redirecting LDL-mediated cholesterol transport to scavenge nutrients from the host.
hsa05146	Amoebiasis	Entamoeba histolytica, an extracellular protozoan parasite is a human pathogen that invades the intestinal epithelium. Infection occurs on ingestion of contaminated water and food. The pathogenesis of amoebiasis begins with parasite attachment and disruption of the intestinal mucus layer, followed by apoptosis of host epithelial cells. Intestinal tissue destruction causes severe dysentery and ulcerations in amoebic colitis. Several amoebic proteins such as lectins, cysteine proteineases, and amoebapores are associated with the invasion process. The parasite can cause extraintestinal infection like amoebic liver abscess by evading immune response.
hsa05152	Tuberculosis	Tuberculosis, or TB, is an infectious disease caused by Mycobacterium tuberculosis. One third of the world's population is thought to be infected with TB. About 90% of those infected result in latent infections, and about 10% of latent infections develop active diseases when their immune system is impaired due to the age, other diseases such as AIDS or exposure to immunosuppressive drugs. TB is transmitted through the air and primarily attacks the lungs, then it can spread by the circulatory system to other parts of body. Once TB bacilli have entered the host by the respiratory route and infected macrophages in the lungs, they interfere with phagosomal maturation, antigen presentation, apoptosis and host immune system to establish persistent or latent infection.
hsa05160	Hepatitis C	Hepatitis C virus (HCV) is a major cause of chronic liver disease. The HCV employ several strategies to perturb host cell immunity. After invasion, HCV RNA genome functions directly as an mRNA in the cytoplasm of the host cell and forms membrane-associated replication complexes along with non-structural proteins. Viral RNA can trigger the RIG-I pathway and interferon production during this process. Translated HCV protein products regulate immune response to inhibit the action of interferon. HCV core and NS5A proteins appear to be the most important molecules with regulatory functions that modulate transcription, cellular proliferation, and apoptosis.
hsa05161	Hepatitis B	Hepatitis B virus (HBV) is an enveloped virus and contains a partially double-stranded relaxed circular DNA (RC-DNA) genome. After entry into hepatocytes, HBV RC-DNA is transported to the nucleus and converted into a covalently closed circular molecule cccDNA. The cccDNA is the template for transcription of all viral RNAs including the pregenomic RNA (pgRNA), encoding for 7 viral proteins: large, middle, and small envelope proteins (LHBs, MHBs, and SHBs) that form the surface antigen (HBsAg), the core antigen (HBcAg), the e antigen (HBeAg), the HBV polymerase, and the regulatory protein X (HBx). The pgRNA interacts with the viral polymerase protein to initiate the encapsidation into the core particles. Through endoplasmic reticulum, the core particles finish assembling with the envelope proteins and are released. HBV infection leads to a wide spectrum of liver diseases raging from chronic hepatitis, cirrhosis to hepatocellular carcinoma. The mechanism of liver injury is still not clear. However, HBV proteins target host proteins, involved in a variety of functions, thus regulating transcription, cellular signaling cascades, proliferation, differentiation, and apoptosis.
hsa05162	Measles	Measles virus (MV) is highly contagious virus that leads infant death worldwide. Humans are the unique natural reservoir for this virus. It causes severe immunosuppression favouring secondary bacterial infections. Several MV proteins have been suggested to disturb host immunity. After infection of host lymphoid cells via SLAM, MV inhibits cytokine response by direct interference with host signaling systems. Three proteins (P, V, and C) associate with Jak/STAT proteins in interferon-triggered pathway and other important proteins related to apoptosis. Interaction between MV and host brings about the shift towards a Th2 response by decreasing IL-12 production and induces lymphopenia by suppressing cell proliferation.
hsa05163	Human cytomegalovirus infection	Human cytomegalovirus (HCMV) is an enveloped, double-stranded DNA virus that is a member of beta-herpesvirus family. HCMV is best known for causing significant morbidity and mortality in immunocompromised populations. As with other herpesviruses, HCMV gB and gH/gL envelope glycoproteins are essential for virus entry. HCMV gB could activate the PDGFRA, and induce activation of the oncogenic PI3-K/AKT pathway. Though it is unlikely that HCMV by itself can act as an oncogenic factor, HCMV may have an oncomodulatory role, to catalyze an oncogenic process that has already been initiated. US28, one of the four HCMV-encoded vGPCRs (US27, US28, UL33 and UL78), also has a specific role in the oncomodulatory properties. In addition, HCMV has developed numerous mechanisms for manipulating the host immune system. The virally encoded US2, US3, US6 and US11 gene products all interfere with major histocompatibility complex (MHC) class I antigen presentation. HCMV encodes several immediate early (IE) antiapoptotic proteins (IE1, IE2, vMIA and vICA). These proteins might avoid immune clearance of infected tumor cells by cytotoxic lymphocytes and NK cells.
hsa05164	Influenza A	Influenza is a contagious respiratory disease caused by influenza virus infection. Influenza A virus is responsible for both annual seasonal epidemics and periodic worldwide pandemics. Novel strains that cause pandemics arise from avian influenza virus by genetic reassortment among influenza viruses and two surface glycoproteins HA and NA form the basis of serologically distinct virus types. The innate immune system recognizes invaded virus through multiple mechanisms. Viral non-structural NS1 protein is a multifunctional virulence factor that interfere IFN-mediated antiviral response. It inhibits IFN production by blocking activation of transcription factors such as NF-kappa B, IRF3 and AP1. NS1 further inhibits the activation of IFN-induced antiviral genes. PB1-F2 protein is another virulence factor that induce apoptosis of infected cells, which results in life-threatening bronchiolitis.
hsa05165	Human papillomavirus infection	Human papillomavirus (HPV) is a non-enveloped, double-stranded DNA virus. HPV infect mucoal and cutaneous epithelium resulting in several types of pathologies, most notably, cervical cancer. All types of HPV share a common genomic structure and encode eight proteins: E1, E2, E4, E5, E6, and E7 (early) and L1 and L2 (late). It has been demonstrated that E1 and E2 are involved in viral transcription and replication. The functions of the E4 protein is not yet fully understood. E5, E6, and E7 act as oncoproteins. E5 inhibits the V-ATPase, prolonging EGFR signaling and thereby promoting cell proliferation. The expression of E6 and E7 not only inhibits the tumor suppressors p53 and Rb, but also alters additional signalling pathways. Among these pathways, PI3K/Akt signalling cascade plays a very important role in HPV-induced carcinogenesis. The L1 and L2 proteins form icosahedral capsids for progeny virion generation.
hsa05166	Human T-cell leukemia virus 1 infection	Human T-cell leukemia virus type 1 (HTLV-1) is a pathogenic retrovirus that is associated with adult T-cell leukemia/lymphoma (ATL). It is also strongly implicated in non-neoplastic chronic inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Expression of Tax, a viral regulatory protein is critical to the pathogenesis. Tax is a transcriptional co-factor that interfere several signaling pathways related to anti-apoptosis or cell proliferation. The modulation of the signaling by Tax involve its binding to transcription factors like CREB/ATF, NF-kappa B, SRF, and NFAT.
hsa05167	Kaposi sarcoma-associated herpesvirus infection	Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is the most recently identified human tumor virus, and is associated with the pathogenesis of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and Multicentric Castleman's disease (MCD). Like all other herpesviruses, KSHV displays two modes of life cycle, latency and lytic replication, which are characterized by the patterns of viral gene expression. Genes expressed in latency (LANA, v-cyclin, v-FLIP, Kaposins A, B and C and viral miRNAs) are mainly thought to facilitate the establishment of life long latency in its host and survival against the host innate, and adaptive immune surveillance mechanisms. Among the viral proteins shown to be expressed during lytic replication are potent signaling molecules such as vGPCR, vIL6, vIRFs, vCCLs, K1 and K15, which have been implicated experimentally in the angiogenic and inflammatory phenotype observed in KS lesions. Several of these latent viral and lytic proteins are known to transform host cells, linking KSHV with the development of severe human malignancies.
hsa05168	Herpes simplex infection	Herpes simplex virus (HSV) infections are very common worldwide, with the prevalence of HSV-1 reaching up to 80%-90%. Primary infection with HSV takes place in the mucosa, followed by the establishment of latent infection in neuronal ganglia. HSV is the main cause of herpes infections that lead to the formation of characteristic blistering lesion. HSV express multiple viral accessory proteins that interfere with host immune responses and are indispensable for viral replication. Among these proteins, the immediate early (IE) gene ICP0, ICP4, and ICP27 are essential for regulation of HSV gene expression in productive infection. On the other hand, ORF P and ORF O gene are transcribed during latency and blocks the expression of the IE genes, thus maintaining latent infection.
hsa05169	Epstein-Barr virus infection	Epstein-Barr virus (EBV) is a gamma-herpes virus that widely infects human populations predominantly at an early age but remains mostly asymptomatic. EBV has been linked to a wide spectrum of human malignancies, including nasopharyngeal carcinoma and other hematologic cancers, like Hodgkin's lymphoma, Burkitt's lymphoma (BL), B-cell immunoblastic lymphoma in HIV patients, and posttransplant-associated lymphoproliferative diseases. EBV has the unique ability to establish life-long latent infection in primary human B lymphocytes. During latent infection, EBV expresses a small subset of genes, including 6 nuclear antigens (EBNA-1, -2, -3A, -3B, -3C, and -LP), 3 latent membrane proteins (LMP-1, -2A, and -2B), 2 small noncoding RNAs (EBER-1 and 2). On the basis of these latent gene expression, three different latency patterns associated with the types of cancers are recognized.
hsa05170	Human immunodeficiency virus 1 infection	Human immunodeficiency virus type 1 (HIV-1) , the causative agent of AIDS (acquired immunodeficiency syndrome), is a lentivirus belonging to the Retroviridae family. The primary cell surface receptor for HIV-1, the CD4 protein, and the co-receptor for HIV-1, either CCR5 or CXCR4, are found on macrophages and T lymphocytes. At the earliest step, sequential binding of virus envelope (Env) glycoprotein gp120 to CD4 and the co-receptor CCR5 or CXCR4 facilitates HIV-1 entry and has the potential to trigger critical signaling that may favor viral replication. At advanced stages of the disease, HIV-1 infection results in dramatic induction of T-cell (CD4+ T and CD8+ T cell) apoptosis both in infected and uninfected bystander T cells, a hallmark of HIV-1 pathogenesis. On the contrary, macrophages are resistant to the cytopathic effect of HIV-1 and produce virus for longer periods of time.
hsa05200	Pathways in cancer
hsa05202	Transcriptional misregulation in cancer	In tumor cells, genes encoding transcription factors (TFs) are often amplified, deleted, rearranged via chromosomal translocation and inversion, or subjected to point mutations that result in a gain- or loss-of- function. In hematopoietic cancers and solid tumors, the translocations and inversions increase or deregulate transcription of the oncogene. Recurrent chromosome translocations generate novel fusion oncoproteins, which are common in myeloid cancers and soft-tissue sarcomas. The fusion proteins have aberrant transcriptional function compared to their wild-type counterparts. These fusion transcription factors alter expression of target genes, and thereby result in a variety of altered cellular properties that contribute to the tumourigenic process.
hsa05203	Viral carcinogenesis	There is a strong association between viruses and the development of human malignancies. We now know that at least six human viruses, Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV), human T-cell lymphotropic virus (HTLV-1) and Kaposi's associated sarcoma virus (KSHV) contribute to 10-15% of the cancers worldwide. Via expression of many potent oncoproteins, these tumor viruses promote an aberrant cell-proliferation via modulating cellular cell-signaling pathways and escape from cellular defense system such as blocking apoptosis. Human tumor virus oncoproteins can also disrupt pathways that are necessary for the maintenance of the integrity of host cellular genome. Viruses that encode such activities can contribute to initiation as well as progression of human cancers.
hsa05212	Pancreatic cancer	Infiltrating ductal adenocarcinoma is the most common malignancy of the pancreas. When most investigators use the term 'pancreatic cancer' they are referring to pancreatic ductal adenocarcinoma (PDA). Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors (PanINs). The overexpression of HER-2/neu and activating point mutations in the K-ras gene occur early, inactivation of the p16 gene at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Activated K-ras engages multiple effector pathways. Although EGF receptors are conventionally regarded as upstream activators of RAS proteins, they can also act as RAS signal transducers via RAS-induced autocrine activation of the EGFR family ligands. Moreover, PDA shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in p53 and BRCA2 are likely to contribute to these phenotypes. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor-beta signalling pathway.
hsa05215	Prostate cancer	Prostate cancer constitutes a major health problem in Western countries. It is the most frequently diagnosed cancer among men and the second leading cause of male cancer deaths. The identification of key molecular alterations in prostate-cancer cells implicates carcinogen defenses (GSTP1), growth-factor-signaling pathways (NKX3.1, PTEN, and p27), and androgens (AR) as critical determinants of the phenotype of prostate-cancer cells. Glutathione S-transferases (GSTP1) are detoxifying enzymes. Cells of prostatic intraepithelial neoplasia, devoid of GSTP1, undergo genomic damage mediated by carcinogens. NKX3.1, PTEN, and p27 regulate the growth and survival of prostate cells in the normal prostate. Inadequate levels of PTEN and NKX3.1 lead to a reduction in p27 levels and to increased proliferation and decreased apoptosis. Androgen receptor (AR) is a transcription factor that is normally activated by its androgen ligand. During androgen withdrawal therapy, the AR signal transduction pathway also could be activated by amplification of the AR gene, by AR gene mutations, or by altered activity of AR coactivators. Through these mechanisms, tumor cells lead to the emergence of androgen-independent prostate cancer.
hsa05220	Chronic myeloid leukemia	Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of a pluripotent stem cell. The natural history of CML has a triphasic clinical course comprising of an initial chronic phase (CP), which is characterized by expansion of functionally normal myeloid cells, followed by an accelerated phase (AP) and finally a more aggressive blast phase (BP), with loss of terminal differentiation capacity. On the cellular level, CML is associated with a specific chromosome abnormality, the t(9; 22) reciprocal translocation that forms the Philadelphia (Ph) chromosome. The Ph chromosome is the result of a molecular rearrangement between the c-ABL proto-oncogene on chromosome 9 and the BCR (breakpoint cluster region) gene on chromosome 22. The BCR/ABL fusion gene encodes p210 BCR/ABL, an oncoprotein, which, unlike the normal p145 c-Abl, has constitutive tyrosine kinase activity and is predominantly localized in the cytoplasm. While fusion of c-ABL and BCR is believed to be the primary cause of the chronic phase of CML, progression to blast crisis requires other molecular changes. Common secondary abnormalities include mutations in TP53, RB, and p16/INK4A, or overexpression of genes such as EVI1. Additional chromosome translocations are also observed,such as t(3;21)(q26;q22), which generates AML1-EVI1.
hsa05221	Acute myeloid leukemia	Acute myeloid leukemia (AML) is a disease that is characterized by uncontrolled proliferation of clonal neoplastic cells and accumulation in the bone marrow of blasts with an impaired differentiation program. AML accounts for approximately 80% of all adult leukemias and remains the most common cause of leukemia death. Two major types of genetic events have been described that are crucial for leukemic transformation. A proposed necessary first event is disordered cell growth and upregulation of cell survival genes. The most common of these activating events were observed in the RTK Flt3, in N-Ras and K-Ras, in Kit, and sporadically in other RTKs. Alterations in myeloid transcription factors governing hematopoietic differentiation provide second necessary event for leukemogenesis. Transcription factor fusion proteins such as AML-ETO, PML-RARalpha or PLZF-RARalpha block myeloid cell differentiation by repressing target genes. In other cases, the transcription factors themselves are mutated.
hsa05222	Small cell lung cancer	Lung cancer is a leading cause of cancer death among men and women in industrialized countries. Small cell lung carcinoma (SCLC) is a highly aggressive neoplasm, which accounts for approximately 25% of all lung cancer cases. Molecular mechanisms altered in SCLC include induced expression of oncogene, MYC, and loss of tumorsuppressor genes, such as p53, PTEN, RB, and FHIT. The overexpression of MYC proteins in SCLC is largely a result of gene amplification. Such overexpression leads to more rapid proliferation and loss of terminal differentiation. Mutation or deletion of p53 or PTEN can lead to more rapid proliferation and reduced apoptosis. The retinoblastoma gene RB1 encodes a nuclear phosphoprotein that helps to regulate cell-cycle progression. The fragile histidine triad gene FHIT encodes the enzyme diadenosine triphosphate hydrolase, which is thought to have an indirect role in proapoptosis and cell-cycle control.
hsa05321	Inflammatory bowel disease (IBD)	Inflammatory bowel disease (IBD), which includes Crohn disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract due to environmental and genetic factors, infectious microbes, and the dysregulated immune system. Although many environmental factors (for example, geographic locations, smoking, etc.) affect the development of IBD, the most crucial might be the luminal (external) environment of the epithelial cells. There are pathogens that are found in increasing frequency in IBD. The microbial components such as flagellin, peptidoglycan, and lipopolysaccharide are recognized by receptors such as toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD) proteins, and also by antigen-presenting cells (APCs) in genetically susceptible host. The TLR recognition triggers the activation of NF-kappaB, leading to an inflammatory response. APC-expressed gene NOD2 has been associated with Crohn disease. In case of mutations of NOD2, negative regulation of IL-12 production is reduced with the stimulation of muramyl dipeptide (MDP), leading to CD. In addition, the APC mediates the differentiation of naive T cells into effector T cells (Th1, Th17, Th2) and natural killer T (NKT) cells. Th1 and Th17 cells produce high levels of IFN-gamma and IL-17, -22, respectively, both of which promote CD. In contrast, Th2 cells produce IL-4, -5, -10, which together with IL-13 from NKT induce UC.
hsa05418	Fluid shear stress and atherosclerosis	Shear stress represents the frictional force that the flow of blood exerts at the endothelial surface of the vessel wall and plays a central role in vascular biology and contributes to the progress of atherosclerosis. Sustained laminar flow with high shear stress upregulates expressions of endothelial cell (EC) genes and proteins that are protective against atherosclerosis. The key shear stress-induced transcription factors that govern the expression of these genes are Kruppel-like factor 2 (KLF2) and nuclear factor erythroid 2-like 2 (Nrf2). On the other hand, disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote oxidative and inflammatory states in the artery wall, resulting in atherogenesis. Important transcriptional events that reflect this condition of ECs in disturbed flow include the activation of activator protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB).

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-1169091	Activation of NF-kappaB in B cells.	DAG and calcium activate protein kinase C beta (PKC-beta, Kochs et al. 1991) which phosphorylates CARMA1 and other proteins (Sommer et al. 2005). Phosphorylated CARMA1 recruits BCL10 and MALT1 to form the CBM complex (Sommer et al. 2005, Tanner et al. 2007) which, in turn, recruits the kinase TAK1 and the IKK complex (Sommer et al. 2005, Shinohara et al. 2005 using chicken cells). TAK1 phosphorylates the IKK-beta subunit, activating it (Wang et al. 2001). The IKK complex then phosphorylates IkB complexed with NF-kappaB dimers in the cytosol (Zandi et al. 1998, Burke et al. 1999, Heilker et al. 1999), resulting in the degradation of IkB (Miyamoto et al. 1994, Traenckner et al. 1994, Alkalay et al. 1995, DiDonato et al. 1995, Li et al. 1995, Lin et al. 1995, Scherer et al. 1995, Chen et al. 1995). NF-kappaB dimers are thereby released and are translocated to the nucleus where they activate transcription (Baeuerle and Baltimore 1988, Blank et al. 1991, Ghosh et al. 2008, Fagerlund et al. 2008)
R-HSA-1810476	RIP-mediated NFkB activation via ZBP1.	Overexpression of human or murine ZBP1 (DAI) in human embryonic kidney 293T cells (HEK293T) activated NF-kB-dependent promoter in a dose-dependent manner. Two RHIM-contaning kinases RIP1 and RIP3 are implicated in ZBP1-induced NFkB activation (Rebsamen M et al 2009; Kaiser WJ et al 2008)
R-HSA-193692	Regulated proteolysis of p75NTR.	p75NTR undergoes a process of regulated intramembrane proteolysis (RIP) similar to other transmembrane proteins such as NOTCH, beta-amyloid precursor protein (APP), and ERBB4. Each of these proteins is subjected to two sequential cleavages. The first one occurs in the extracellular part of the protein and is mediated by the metalloproteinase alpha-secretase which causes shedding of the extracellular domain. The second cleavage occurs in the intramembrane region and is mediated by gamma-secretase and causes release of the intracellular domain, ICD, and of a small peptide. The ICD often traffics to the nucleus and, in some instances (e.g. NOTCH), was found to act as transcriptional regulator. Whether the p75NTR ICD does translocate to the nucleus to regulate gene expression in a way similar to the NOTCH receptor remains to be seen. The alpha- and gamma-secretase mediated cleavage of p75 appears to be regulated by neurotrophin (NGF, BDNF) binding to TRKA or TRKB. p75NTR processing also occurs in response to MAG in cerebellar granule neurons
R-HSA-202424	Downstream TCR signaling.	Changes in gene expression are required for the T cell to gain full proliferative competence and to produce effector cytokines. Three transcription factors in particular have been found to play a key role in TCR-stimulated changes in gene expression, namely NF-kB, NFAT and AP-1. A key step in NF-kB activation is the stimulation and translocation of PKC theta. The critical element that effects PKC theta activation is PI3K. This enzyme complex translocates to the plasma membrane by interacting with phospho-tyrosines on CD28 via its two SH2 domains located in p85 subunit. The p110 subunit of PI3K phosphorylates the inositol ring of PIP2 to generate PIP3 (steps 17-18). PIP3 may also be dephosphorylated by the phosphatase SHIP to generate PI-3,4-P2. PIP3 and PI-3,4-P2 acts as binding sites to the PH domain of PKB/Akt and PDK1 (steps 19, 21 and 22). PKB is activated in response to PI3K stimulation by PDK1 (step 23). PDK1 has an essential role in regulating the activation of PKC theta and recruitment of CBM complex to the immune synapse. PKC theta is a member of novel class (DAG dependent, Ca++ independent) of PKC and the only member known to translocate to this synapse. Prior to TCR stimulation PKC theta exists in an inactive closed conformation. Upon release of DAG, it binds to PKC theta via the C1 domain and undergoes phosphorylation on tyrosine 90 by Lck to attain an open conformation. PKC theta is further phosphorylated by PDK1 on threonine 538. This step is critical for PKC activity (steps 24-26). CARMA1 translocates to the plasma membrane following the interaction of its SH3 domain with the 'PxxP' motif on PDK1. CARMA1 is phosphorylated by PKC-theta on residue S552, leading to the oligomerization of CARMA1. This complex acts as a scaffold, recruiting Bcl10 to the synapse by interacting with their CARD domains. Bcl10 undergoes phosphorylation mediated by the enzyme RIP2. Activated Bcl10 then mediates the ubiquitination of NEMO by recruiting MALT1 and TRAF6. MALT1 binds to Bcl10 with its Ig-like domains and undergoes oligomerization. TRAF6 binds to the oligomerized MALT1 and also undergoes oligomerization. Oligomerized TRAF6 acts as a ubiquitin-protein ligase, catalyzing auto-K63-linked polyubiquitination (steps 27-33). This K-63 ubiquitinated TRAF6 activates TAK1 kinase bound to TAB2 and also ubiquitinates NEMO/IKK-gamma in the IKK complex. TAK1 undergoes autophosphorylation on residues T184 and T187 and gets activated. Activated TAK1 kinase phosphorylates IKK-beta on residues S177 and S181 in the activation loop and activates the IKK kinase activity. IKK-beta phosphorylates the IkB-alpha bound to the NF-kB heterodimer, on residues S19 and S23 and directs IkB-beta to 26S proteasome degradation (step 34-38 & 40). The NF-kB heterodimer with a free NTS sequence finally migrates to the nucleus to regulate gene transcription (step 39)
R-HSA-209560	NF-kB is activated and signals survival.	Upon activation in response to NGF, NF-kB moves to the nucleus, where it turns on genes that promote survival, and triggers the expression of HES1/5 to modulate dendritic growth
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP).	The culture medium of senescent cells in enriched in secreted proteins when compared with the culture medium of quiescent i.e. presenescent cells and these secreted proteins constitute the so-called senescence-associated secretory phenotype (SASP), also known as the senescence messaging secretome (SMS). SASP components include inflammatory and immune-modulatory cytokines (e.g. IL6 and IL8), growth factors (e.g. IGFBPs), shed cell surface molecules (e.g. TNF receptors) and survival factors. While the SASP exhibits a wide ranging profile, it is not significantly affected by the type of senescence trigger (oncogenic signalling, oxidative stress or DNA damage) or the cell type (epithelial vs. mesenchymal) (Coppe et al. 2008). However, as both oxidative stress and oncogenic signaling induce DNA damage, the persistent DNA damage may be a deciding SASP initiator (Rodier et al. 2009). SASP components function in an autocrine manner, reinforcing the senescent phenotype (Kuilman et al. 2008, Acosta et al. 2008), and in the paracrine manner, where they may promote epithelial-to-mesenchymal transition (EMT) and malignancy in the nearby premalignant or malignant cells (Coppe et al. 2008). Interleukin-1-alpha (IL1A), a minor SASP component whose transcription is stimulated by the AP-1 (FOS:JUN) complex (Bailly et al. 1996), can cause paracrine senescence through IL1 and inflammasome signaling (Acosta et al. 2013). Here, transcriptional regulatory processes that mediate the SASP are annotated. DNA damage triggers ATM-mediated activation of TP53, resulting in the increased level of CDKN1A (p21). CDKN1A-mediated inhibition of CDK2 prevents phosphorylation and inactivation of the Cdh1:APC/C complex, allowing it to ubiquitinate and target for degradation EHMT1 and EHMT2 histone methyltransferases. As EHMT1 and EHMT2 methylate and silence the promoters of IL6 and IL8 genes, degradation of these methyltransferases relieves the inhibition of IL6 and IL8 transcription (Takahashi et al. 2012). In addition, oncogenic RAS signaling activates the CEBPB (C/EBP-beta) transcription factor (Nakajima et al. 1993, Lee et al. 2010), which binds promoters of IL6 and IL8 genes and stimulates their transcription (Kuilman et al. 2008, Lee et al. 2010). CEBPB also stimulates the transcription of CDKN2B (p15-INK4B), reinforcing the cell cycle arrest (Kuilman et al. 2008). CEBPB transcription factor has three isoforms, due to three alternative translation start sites. The CEBPB-1 isoform (C/EBP-beta-1) seems to be exclusively involved in growth arrest and senescence, while the CEBPB-2 (C/EBP-beta-2) isoform may promote cellular proliferation (Atwood and Sealy 2010 and 2011). IL6 signaling stimulates the transcription of CEBPB (Niehof et al. 2001), creating a positive feedback loop (Kuilman et al. 2009, Lee et al. 2010). NF-kappa-B transcription factor is also activated in senescence (Chien et al. 2011) through IL1 signaling (Jimi et al. 1996, Hartupee et al. 2008, Orjalo et al. 2009). NF-kappa-B binds IL6 and IL8 promoters and cooperates with CEBPB transcription factor in the induction of IL6 and IL8 transcription (Matsusaka et al. 1993, Acosta et al. 2008). Besides IL6 and IL8, their receptors are also upregulated in senescence (Kuilman et al. 2008, Acosta et al. 2008) and IL6 and IL8 may be master regulators of the SASP. IGFBP7 is also an SASP component that is upregulated in response to oncogenic RAS-RAF-MAPK signaling and oxidative stress, as its transcription is directly stimulated by the AP-1 (JUN:FOS) transcription factor. IGFBP7 negatively regulates RAS-RAF (BRAF)-MAPK signaling and is important for the establishment of senescence in melanocytes (Wajapeyee et al. 2008). Please refer to Young and Narita 2009 for a recent review
R-HSA-2871837	FCERI mediated NF-kB activation.	The increase in intracellular Ca+2 in conjunction with DAG also activates PKC and RasGRP, which inturn contributes to cytokine production by mast cells (Kambayashi et al. 2007). Activation of the FCERI engages CARMA1, BCL10 and MALT1 complex to activate NF-kB through PKC-theta (Klemm et al. 2006, Chen et al. 2007). FCERI stimulation leads to phosphorylation, and degradation of IkB which allows the release and nuclear translocation of the NF-kB proteins. Activation of the NF-kB transcription factors then results in the synthesis of several cytokines. NF-kB activation by FCERI is critical for proinflammatory cytokine production during mast cell activation and is crucial for allergic inflammatory diseases (Klemm et al. 2006)
R-HSA-3134963	DEx/H-box helicases activate type I IFN and inflammatory cytokines production.	DHX36 and DHX9 are aspartate-glutamate-any amino acid aspartate/histidine (DExD/H) box helicase (DHX) proteins that localize in the cytosol. The DHX RNA helicases family includes a large number of proteins that are implicated in RNA metabolism. Members of this family, RIG-1 and MDA5, have been shown to sense a non-self RNA leading to type I IFN production. RNA helicases DHX36 and DHX9 were found to trigger host responses to non-self DNA in MyD88-dependent manner. DHX36 sensed CpG class A, while DHX9 sensed CpG class B. Both DHX36 and DHX9 were critical for antiviral immune responses in viral DNA-stimulated human plasmacytoid dendritic cells (pDC) (Kim T et al. 2010)
R-HSA-3214841	PKMTs methylate histone lysines.	Lysine methyltransferases (KMTs) and arginine methyltransferases (RMTs) have a common mechanism of catalysis. Both families transfer a methyl group from a common donor, S-adenosyl-L-methionine (SAM), to the nitrogen atom on the epsilon-amino group of lysine or arginine (Smith & Denu 2009) using a bimolecular nucleophillic substitution (SN2) methyl transfer mechanism (Smith & Denu 2009, Zhang & Bruice 2008). All human KMTs except DOT1L (KMT4) (Feng et al. 2002, van Leeuwen et al. 2002, Lacoste et al. 2002) have a ~130 amino acid catalytic domain referred to as the SET domain (Del Rizzo & Trievel 2011, Dillon et al. 2005, Herz et al. 2013). Some KMTs selectively methylate a particular lysine residue on a specific histone type. The extent of this methylation (mono-, di- or tri-methylation) also can be stringent (Herz et al. 2013, Copeland et al. 2009). Many KMTs also have non-histone substrates (Herz et al 2013), which are not discussed in this module.The coordinates of post-translational modifications represented and described here follow UniProt standard practice whereby coordinates refer to the translated protein before any processing. Histone literature typically refers to specific residues by numbers which are determined after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared to the histone literature.SET domain-containing proteins are classified in one of 7 families (Dillon et al. 2005). First to be discovered were the SUV39 family named after founding member SUV39H1 (KMT1A), which selectively methylates lysine-10 of histone H3 (H3K9) (Rea et al. 2000). Family member EHMT2 (KMT1C, G9A) is the predominant H3K9 methyltransferase in mammals (Tachibana et al. 2002). SETDB1 (KMT1E, ESET) also predominantly methylates H3K9, most effectively when complexed with ATF7IP (MCAF, hAM) (Wang et al. 2003). SETD2 (KMT3A, HYPB), a member of the SET2 family, specifically methylates histone H3 lysine-37 (H3K36) (Sun et al. 2005). WHSC1 (KMT3G, NSD2, MMSET) a member of the same family, targets H3K36 when provided with nucleosome substrates but also can methylate histone H4 lysine-45 when octameric native or recombinant nucleosome substrates are provided (Li et al. 2009); dimethylation of histone H3 at lysine-37 (H3K36me2) is thought to be the principal chromatin-regulatory activity of WHSC1 (Kuo et al. 2011). Relatives NSD1 (KMT3B) and WHSC1L1 (KMT3F, NSD3) also methylate nucleosomal H3K36. NSD1 is active on unmethylated or a mimetic monomethylated H3K36, but not di- or trimethylated H3K36 mimetics (Li et al. 2009). Human SETD7 (KMT7, SET7/9), not classified within the 7 SET-domain containing families, mono-methylates lysine-5 of histone H3 (H3K4) (Xiao et al. 2003)
R-HSA-381340	Transcriptional regulation of white adipocyte differentiation.	Adipogenesis is the process of cell differentiation by which preadipocytes become adipocytes. During this process the preadipocytes cease to proliferate, begin to accumulate lipid droplets and develop morphologic and biochemical characteristics of mature adipocytes such as hormone responsive lipogenenic and lipolytic programs. The most intensively studied model system for adipogenesis is differentiation of the mouse 3T3-L1 preadipocyte cell line by an induction cocktail of containing mitogens (insulin/IGF1), glucocorticoid (dexamethasone), an inducer of cAMP (IBMX), and fetal serum (Cao et al. 1991, reviewed in Farmer 2006). More recently additional cellular models have become available to study adipogenesis that involve almost all stages of development (reviewed in Rosen and MacDougald 2006). In vivo knockout mice lacking putative adipogenic factors have also been extensively studied. Human pathways are traditionally inferred from those discovered in mouse but are now beginning to be validated in cellular models derived from human adipose progenitors (Fischer-Posovszky et al. 2008, Wdziekonski et al. 2011).Adipogenesis is controlled by a cascade of transcription factors (Yeh et al. 1995, reviewed in Farmer 2006, Gesta et al. 2007). One of the first observable events during adipocyte differentiation is a transient increase in expression of the CEBPB (CCAAT/Enhancer Binding Protein Beta, C/EBPB) and CEBPD (C/EBPD) transcription factors (Cao et al. 1991, reviewed in Lane et al. 1999). This occurs prior to the accumulation of lipid droplets. However, it is the subsequent inductions of CEBPA and PPARG that are critical for morphological, biochemical and functional adipocytes.Ectopic expression of CEBPB alone is capable of inducing substantial adipocyte differentiation in fibroblasts while CEBPD has a minimal effect. CEBPB is upregulated in response to intracellular cAMP (possibly via pCREB) and serum mitogens (possibly via Krox20). CEBPD is upregulated in response to glucocorticoids. The exact mechanisms that upregulate the CEBPs are not fully known.CEBPB and CEBPD act directly on the Peroxisome Proliferator-activated Receptor Gamma (PPARG) gene by binding its promoter and activating transcription. CEBPB and CEBPD also directly activate the EBF1 gene (and possibly other EBFs) and KLF5 (Jimenez et al. 2007, Oishi 2005). The EBF1 and KLF5 proteins, in turn bind, and activate the PPARG promoter. Other hormones, such as insulin, affect PPARG expression and other transcription factors, such as ADD1/SREBP1c, bind the PPARG promoter. This is an area of ongoing research.During adipogenesis the PPARG gene is transcribed to yield 2 variants. The adipogenic variant 2 mRNA encodes 30 additional amino acids at the N-terminus compared to the widely expressed variant 1 mRNA.PPARG encodes a type II nuclear hormone receptor (remains in the nucleus in the absence of ligand) that forms a heterodimer with the Retinoid X Receptor Alpha (RXRA). The heterodimer was initially identified as a complex regulating the aP2/FABP4 gene and named ARF6 (Tontonoz et al. 1994).The PPARG:RXRA heterodimer binds a recognition sequence that consists of two hexanucleotide motifs (DR1 motifs) separated by 1 nucleotide. Binding occurs even in the absence of ligands, such as fatty acids, that activate PPARG. In the absence of activating ligands, the PPARG:RXRA complex recruits repressors of transcription such as SMRT/NCoR2, NCoR1, and HDAC3 (Tontonoz and Spiegelman 2008).Each molecule of PPARG can bind 2 molecules of activating ligands. Although, the identity of the endogenous ligands of PPARG is unknown, exogenous activators include fatty acids and the thiazolidinedione class of antidiabetic drugs (reviewed in Berger et al. 2005, Heikkinen et al. 2007, Lemberger et al. 1996). The most potent activators of PPARG in vitro are oxidized derivatives of unsaturated fatty acids.. Upon binding activating ligands PPARG causes a rearrangement of adjacent factors: Corepressors such as SMRT/NCoR2 are lost and coactivators such as TIF2, PRIP, CBP, and p300 are recruited (Tontonoz and Spiegelman). PPARG also binds directly to the TRAP220 subunit of the TRAP/Mediator complex that recruits RNA polymerase II. Thus binding of activating ligand by PPARG causes transcription of PPARG target genes.Targets of PPARG include genes involved in differentiation (PGAR/HFARP, Perilipin, aP2/FABP4, CEBPA), fatty acid transport (LPL, FAT/CD36), carbohydrate metabolism (PEPCK-C, AQP7, GK, GLUT4 (SLC2A4)), and energy homeostasis (LEPTIN and ADIPONECTIN) (Perera et al. 2006).Within 10 days of differentiation CEBPB and CEBPD are no longer located at the PPARG promoter. Instead CEBPA is present. EBF1 and PPARG bind the CEBPA promoter and activate transcription of CEBPA, one of the key transcription factors in adipogenesis. A current hypothesis posits a self-reinforcing loop that maintains PPARG expression and the differentiated state: PPARG activates CEBPA and CEBPA activates PPARG. Additionally EBF1 (and possibly other EBFs) activates CEBPA, CEBPA activates EBF1, and EBF1 activates PPARG
R-HSA-445989	TAK1 activates NFkB by phosphorylation and activation of IKKs complex.	NF-kappaB is sequestered in the cytoplasm in a complex with inhibitor of NF-kappaB (IkB). Almost all NF-kappaB activation pathways are mediated by IkB kinase (IKK), which phosphorylates IkB resulting in dissociation of NF-kappaB from the complex. This allows translocation of NF-kappaB to the nucleus where it regulates gene expression
R-HSA-448706	Interleukin-1 processing.	The IL-1 family of cytokines that interact with the Type 1 IL-1R include IL-1α (IL1A), IL-1β (IL1B) and the IL-1 receptor antagonist protein (IL1RAP). IL1RAP is synthesized with a signal peptide and secreted as a mature protein via the classical secretory pathway. IL1A and IL1B are synthesised as cytoplasmic precursors (pro-IL1A and pro-IL1B) in activated cells. They have no signal sequence, precluding secretion via the classical ER-Golgi route (Rubartelli et al. 1990). Processing of pro-IL1B to the active form requires caspase-1 (Thornberry et al. 1992), which is itself activated by a molecular scaffold termed the inflammasome (Martinon et al. 2002). Processing and release of IL1B are thought to be closely linked, because mature IL1B is only seen inside inflammatory cells just prior to release (Brough et al. 2003). It has been reported that in monocytes a fraction of cellular IL1B is released by the regulated secretion of late endosomes and early lysosomes, and that this may represent a cellular compartment where caspase-1 processing of pro-IL1B takes place (Andrei et al. 1999). Shedding of microvesicles from the plasma membrane has also been proposed as a mechanism of secretion (MacKenzie et al. 2001). These proposals superceded previous models in which non-specific release due to cell lysis and passage through a plasma membrane pore were considered. However, there is evidence in the literature that supports all of these mechanisms and there is still controversy over how IL1B exits from cells (Brough & Rothwell 2007). A calpain-like potease has been reported to be important for the processing of pro-IL1A, but much less is known about how IL1A is released from cells and what specific roles it plays in biology
R-HSA-4755510	SUMOylation of immune response proteins.	NF-kappaB transcription factors are sequestered in the cytosol due to their association with IkappaB. During activation of NF-kappaB, IKK phosphorylates IkappaB, releasing NF-kappaB for importation into the nucleus. NF-kappaB transcription factors, the NFKBIA component of IkappaB, and subunits of the IKK complex can be SUMOylated (reviewed in Kracklauer and Schmidt 2003, Liu et al. 2013). SUMOylations of IkappaB, NFKBIA, and RELA inhibit NF-kappaB signaling; SUMOylation of NFKB2 is required for proteolytic processing
R-HSA-5603029	IkBA variant leads to EDA-ID.	The nuclear factor kappa B (NFkB) family of transcription factors is kept inactive in the cytoplasm by the inhibitor of kappa B (IkB) family members IKBA (IkB alpha), IKBB (IkB beta) and IKBE (IkB epsilon) (Oeckinghaus A and Ghosh S 2009). Multiple stimuli such as inflammatory cytokines, microbial products or various types of stress activate NFkB signaling leading to stimuli-induced phosphorylation of IkB molecule (Scherer DC et al. 1995; Alkalay I et al. 1995; Lawrence T 2009; Hoesel B and Schmid JA 2013). The phosphorylation of IkB proteins triggers their polyubiquitination and subsequent degradation by 26S proteasome, allowing free NFkB dimer to translocate to the nucleus where it directs the expression of target genes. Studies have identified an autosomal dominant form of ectodermal dysplasia with immunodeficiency (AD-EDA-ID) caused by a hypermorphic heterozygous mutation of NFKBIA/IKBA gene. The IKBA defects prevent the phosphorylation and degradation of IKBA protein resulting in gain-of-function condition with the enhanced inhibitory capacity of IKBA in sequestering NF?B dimers in the cytoplasm (Courtois G et al. 2003; Lopes-Granados E et al. 2008; Schimke LF et al. 2013)
R-HSA-5607761	Dectin-1 mediated noncanonical NF-kB signaling.	In addition to the activation of canonical NF-kB subunits, activation of SYK pathway by Dectin-1 leads to the induction of the non-canonical NF-kB pathway, which mediates the nuclear translocation of RELB-p52 dimers through the successive activation of NF-kB-inducing kinase (NIK) and IkB kinase-alpha (IKKa) (Geijtenbeek & Gringhuis 2009, Gringhuis et al. 2009). Noncanonical activity tends to build more slowly and remain sustained several hours longer than does the activation of canonical NF-kB. The noncanonical NF-kB pathway is characterized by the post-translational processing of NFKB2 (Nuclear factor NF-kappa-B) p100 subunit to the mature p52 subunit. This subsequently leads to nuclear translocation of p52:RELB (Transcription factor RelB) complexes to induce cytokine expression of some genes (C-C motif chemokine 17 (CCL17) and CCL22) and transcriptional repression of others (IL12B) (Gringhuis et al. 2009, Geijtenbeek & Gringhuis 2009, Plato et al. 2013)
R-HSA-5607764	CLEC7A (Dectin-1) signaling.	CLEC7A (also known as Dectin-1) is a pattern-recognition receptor (PRR) expressed by myeloid cells (macrophages, dendritic cells and neutrophils) that detects pathogens by binding to beta-1,3-glucans in fungal cell walls and triggers direct innate immune responses to fungal and bacterial infections. CLEC7A belongs to thetype-II C-type lectin receptor (CLR) family that can mediate its own intracellular signaling. Upon binding particulate beta-1,3-glucans, CLEC7A mediates intracellular signalling through its cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM)-like motif (Brown 2006). CLEC7A signaling can induce the production of various cytokines and chemokines, including tumour-necrosis factor (TNF), CXC-chemokine ligand 2 (CXCL2, also known as MIP2), interleukin-1beta (IL-1b), IL-2, IL-10 and IL-12 (Brown et al. 2003), it also triggers phagocytosis and stimulates the production of reactive oxygen species (ROS), thus contributing to microbial killing (Gantner et al. 2003, Herre et al. 2004, Underhill et al. 2005, Goodridge at al. 2011, Reid et al. 2009). These cellular responses mediated by CLEC7A rely on both Syk-dependent and Syk-independent signaling cascades. The pathways leading to the Syk-dependent activation of NF-kB can be categorised into both canonical and non-canonical routes (Gringhuis et al. 2009). Activation of the canonical NF-kB pathway is essential for innate immunity, whereas activation of the non-canonical pathway is involved in lymphoid organ development and adaptive immunity (Plato et al. 2013)
R-HSA-5621575	CD209 (DC-SIGN) signaling.	CD209 (also called as DC-SIGN (DC-specific intracellular adhesion molecule-3-grabbing non-integrin)) is a type II transmembrane C-type lectin receptor preferentially expressed on dendritic cells (DCs). CD209 functions as a pattern recognition receptor (PRR) that recognises several microorganisms and pathogens, contributing to generation of pathogen-tailored immune responses (Gringhuis & Geijtenbeek 2010, den Dunnen et al. 2009, Svajger et al. 2010). CD209 interacts with different mannose-expressing pathogens such as Mycobacterium tuberculosis and HIV-1 (Gringhuis et al. 2007, Geijtenbeek et al. 2000a). It also acts as an adhesion receptor that interacts with ICAM2 (intracellular adhesion molecule-2) on endothelial cells and ICAM3 on T cells (Geijtenbeek et al. 2000b,c). \nCD209 functions not only as an independent PRR, but is also implicated in the modulation of Toll-like receptor (TLR) signaling at the level of the transcription factor NF-kB (Gringhuis et al. 2009). CLEC7A (Dectin-1) and CD209 (DC-SIGN) signalling modulates Toll-like receptor (TLR) signalling through the kinase RAF1 that is independent of the SYK pathway but integrated with it at the level of NF-kB activation. The activation of RAF1 by CLEC7A or CD209 does not lead to activation of extracellular signal-regulated kinase 1 (ERK1)/2 or Mitogen-activated protein kinase kinase 1 (MEK1)/2 but leads to the phosphorylation and subsequent acetylation of RELA (p65). RELA phosphorylated on S276 not only positively regulates the activity of p65 through acetylation of p65, but also represses RELB activity by sequestering active RELB into inactive p65-RELB dimers that do not bind DNA (Gringhuis et al. 2007, Svajger et al. 2010, Jacque et al. 2005). RAF1-dependent signaling pathway is crucial in dectin-1 mediated immunity as it modulates both the canonical (promoting p65 phosphorylation and acetylation) and non-canonical (forming inactive p65-RELB dimers) NK-kB activation
R-HSA-5660668	CLEC7A/inflammasome pathway.	Antifungal immunity through the induction of T-helper 17 cells (TH17) responses requires the production of mature, active interleukin-1beta (IL1B). CLEC7A (dectin-1) through the SYK route induces activation of NF-kB and transcription of the gene encoding pro-IL1B via the CARD9-BCL10-MALT1 complex as well as the formation and activation of a MALT1-caspase-8-ASC complex that mediated the processing of pro-IL1B. The inactive precursor pro-IL1B has to be processed into mature bioactive form of IL1B and is usually mediated by inflammatory cysteine protease caspase-1. Gringhuis et al. showed that CLEC7A mediated processing of IL1B occurs through two distinct mechanisms: CLEC7A triggering induced a primary noncanonical caspase-8 inflammasome for pro-IL1B processing that was independent of caspase-1 activity, whereas some fungi triggered a second additional mechanism that required activation of the NLRP3/caspase 1 inflammasome. Unlike the canonical caspase-1 inflammasome, CLEC7A mediated noncanonical caspase-8-dependent inflammasome is independent of pathogen internalization. CLEC7A/inflammasome pathway enables the host immune system to mount a protective TH17 response against fungi and bacterial infection (Gringhuis et al. 2012, Cheng et al. 2011)
R-HSA-844456	The NLRP3 inflammasome.	The NLRP3 (Cryopyrin) inflammasome is currently the best characterized. It consists of NLRP3, ASC (PYCARD) and procaspase-1; CARD8 (Cardinal) is also suggested to be a component. It is activated by a number of pathogens and bacterial toxins as well as diverse PAMPs, danger-associated molecular patterns (DAMPS) such as hyaluronan and uric acid, and exogenous irritants such as silica and asbestos (see Table S1 Schroder & Tschopp, 2010). Mutations in NLRP3 which lead to constitutive activation are linked to the human diseases Muckle-Wells syndrome, familial cold autoinflammatory syndrome and NOMID (Ting et al. 2006), characterized by skin rashes and other symptoms associated with generalized inflammation. The cause of these symptoms is uncontrolled IL-1 beta production.\nMultiple studies have shown that activation of the NLRP3 inflammasome by particulate activators (e.g. Hornung et al. 2008) requires phagocytosis, but this is not required for the response to ATP, which is mediated by the P2X7 receptor (Kahlenberg & Dubyak, 2004) and appears to involve the pannexin membrane channel (Pellegrin & Suprenenant 2006). Direct binding of activators to NLRP3 has not been demonstrated and the exact process of activation is unclear, though it is speculated to involve changes in conformation that free the NACHT domain for oligomerization (Inohara & Nunez 2001, 2003)
R-HSA-9020702	Interleukin-1 signaling.	Interleukin 1 (IL1) signals via Interleukin 1 receptor 1 (IL1R1), the only signaling-capable IL1 receptor. This is a single chain type 1 transmembrane protein comprising an extracellular ligand binding domain and an intracellular region called the Toll/Interleukin-1 receptor (TIR) domain that is structurally conserved and shared by other members of the two families of receptors (Xu et al. 2000). This domain is also shared by the downstream adapter molecule MyD88. IL1 binding to IL1R1 leads to the recruitment of a second receptor chain termed the IL1 receptor accessory protein (IL1RAP or IL1RAcP) enabling the formation of a high-affinity ligand-receptor complex that is capable of signal transduction. Intracellular signaling is initiated by the recruitment of MyD88 to the IL-1R1/IL1RAP complex. IL1RAP is only recruited to IL1R1 when IL1 is present; it is believed that a TIR domain signaling complex is formed between the receptor and the adapter TIR domains. The recruitment of MyD88 leads to the recruitment of Interleukin-1 receptor-associated kinase (IRAK)-1 and -4, probably via their death domains. IRAK4 then activates IRAK1, allowing IRAK1 to autophosphorylate. Both IRAK1 and IRAK4 then dissociate from MyD88 (Brikos et al. 2007) which remains stably complexed with IL-1R1 and IL1RAP. They in turn interact with Tumor Necrosis Factor Receptor (TNFR)-Associated Factor 6 (TRAF6), which is an E3 ubiquitin ligase (Deng et al. 2000). TRAF6 is then thought to auto-ubiquinate, attaching K63-polyubiquitin to itself with the assistance of the E2 conjugating complex Ubc13/Uev1a. K63-pUb-TRAF6 recruits Transforming Growth Factor (TGF) beta-activated protein kinase 1 (TAK1) in a complex with TAK1-binding protein 2 (TAB2) and TAB3, which both contain nuclear zinc finger motifs that interact with K63-polyubiquitin chains (Ninomiya-Tsuji et al. 1999). This activates TAK1, which then activates inhibitor of NF-kappaB (IkappaB) kinase 2 (IKK2 or IKKB) within the IKK complex, the kinase responsible for phosphorylation of IkappaB. The IKK complex also contains the scaffold protein NF-kappa B essential modulator (NEMO). TAK1 also couples to the upstream kinases for p38 and c-jun N-terminal kinase (JNK). IRAK1 undergoes K63-linked polyubiquination; Pellino E3 ligases are important in this process. (Butler et al. 2007; Ordureau et al. 2008). The activity of these proteins is greatly enhanced by IRAK phosphorylation (Schauvliege et al. 2006), leading to K63-linked polyubiquitination of IRAK1. This recruits NEMO to IRAK1, with NEMO binding to polyubiquitin (Conze et al. 2008).TAK1 activates IKKB (and IKK), resulting in phosphorylation of the inhibitory IkB proteins and enabling translocation of NFkB to the nucleus; IKKB also phosphorylates NFkB p105, leading to its degradation and the subsequent release of active TPL2 that triggers the extracellular-signal regulated kinase (ERK)1/2 MAPK cascade. TAK1 can also trigger the p38 and JNK MAPK pathways via activating the upstream MKKs3, 4 and 6. The MAPK pathways activate a number of downstream kinases and transcription factors that co-operate with NFkB to induce the expression of a range of TLR/IL-1R-responsive genes. There are reports suggesting that IL1 stimulation increases nuclear localization of IRAK1 (Bol et al. 2000) and that nuclear IRAK1 binds to the promoter of NFkB-regulated gene and IkBa, enhancing binding of the NFkB p65 subunit to NFkB responsive elements within the IkBa promoter. IRAK1 is required for IL1-induced Ser-10 phosphorylation of histone H3 in vivo (Liu et al. 2008). However, details of this aspect of IRAK1 signaling mechanisms remain unclear.\nInterleukin-18 is another Interleukin-1 related cytokine which signals through IL18R and IL18RAP subunit receptors (which share homology with IL1R and IL1RAP in the cytokine signaling cascade). Later it follows a MYD88/IRAK1/TRAF6 cascade signaling until reach the NFKB activation (Moller et al. 2002). Interleukin 33, 36, 37 and 38 are relatively recently discovered Interleukin-1 related citokines which are also able to signal through IL1 receptor subunits or other as IL18R, IL37R (Schmitz et al. 2005, Yi et al. 2016, Lunding et al. 2015, van de Veendorck et al. 2012, Lin et al. 2001)
R-HSA-933542	TRAF6 mediated NF-kB activation.	The TRAF6/TAK1 signal activates a canonical IKK complex, resulting in the activation of NF-kB as well as MAPK cascades leading to the activation of AP-1. Although TRAF6/TAK1 has been implicated in Tool like receptor (TLR) mediated cytokine production, the involvement of these molecules in the regulation of type I IFN induction mediated by RIG-I/MDA5 pathway is largely unknown. According to the study done by Yoshida et al RIG-I/IPS-1 pathway requires TRAF6 and MAP3K, MEKK1 to activate NF-kB and MAP Kinases for optimal induction of type I IFNs

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ABCA1	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
ACTA1	Affinity Capture-MS	physical	14690596, (Europe PMC)	NA	BioGRID
AES	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	10660609, 15489227, (Europe PMC)	NA	BioGRID
AFF1	Affinity Capture-MS, Affinity Capture-Western	physical	21030982, (Europe PMC)	NA	BioGRID
AGO1	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
AHR	Affinity Capture-Western	physical	11114727, 12181450, (Europe PMC)	NA	BioGRID
AKAP8L	Affinity Capture-MS, tandem affinity purification	physical, physical association	14743216, (Europe PMC)	0.40	BioGRID, IntAct
AKIP1	Affinity Capture-Western	physical	16998474, (Europe PMC)	NA	BioGRID
ALOX5	Affinity Capture-Western	physical	9681993, (Europe PMC)	NA	BioGRID
ANXA1	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	21383699, (Europe PMC)	0.40	BioGRID, IntAct
APBA2	Affinity Capture-Western, Two-hybrid	physical	10777610, (Europe PMC)	NA	BioGRID
AR	Phenotypic Suppression	genetic	9482849, (Europe PMC)	NA	BioGRID
ATF3	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	association, direct interaction, physical, physical association	16291753, (Europe PMC)	0.62	BioGRID, IntAct
ATM	Co-localization	physical	24957606, (Europe PMC)	NA	BioGRID
BANP	Affinity Capture-Western	physical	18981184, (Europe PMC)	NA	BioGRID
BARD1	Affinity Capture-Western	physical	12700228, (Europe PMC)	NA	BioGRID
BATF2	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
BECN1	Affinity Capture-Western	physical	28128446, (Europe PMC)	NA	BioGRID
BRCA1	Affinity Capture-Western, Reconstituted Complex	physical	12700228, 21908405, (Europe PMC)	NA	BioGRID
BRMS1	Affinity Capture-Western, Reconstituted Complex	physical	17000776, (Europe PMC)	NA	BioGRID
BTRC	Affinity Capture-MS, Affinity Capture-Western, Proximity Label-MS	physical	25900982, 28514442, 9990853, (Europe PMC)	NA	BioGRID
C1QB	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
CARM1	Affinity Capture-Western, Reconstituted Complex	physical	15616592, 16497732, 18280497, (Europe PMC)	NA	BioGRID
CCL5	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
CCNB1	Affinity Capture-Western	physical	9560267, (Europe PMC)	NA	BioGRID
CCND1	Affinity Capture-Western	physical	25331947, (Europe PMC)	NA	BioGRID
CDC34	Biochemical Activity	physical	14690596, (Europe PMC)	NA	BioGRID
CDK4	Affinity Capture-Western	physical	25331947, (Europe PMC)	NA	BioGRID
CDK9	Affinity Capture-Western, Reconstituted Complex	physical	12173051, (Europe PMC)	NA	BioGRID
CDKN2A	Affinity Capture-Western	physical	25331947, (Europe PMC)	NA	BioGRID
CDX2	Affinity Capture-Western	physical	15013430, 17876541, (Europe PMC)	NA	BioGRID
CEBPB	Affinity Capture-Western, Reconstituted Complex	physical	12707271, 16785565, 9570146, (Europe PMC)	NA	BioGRID
CEBPD	Reconstituted Complex	physical	9570146, (Europe PMC)	NA	BioGRID
CEBPZ	Affinity Capture-Western	physical	22139845, (Europe PMC)	NA	BioGRID
CENPJ	Affinity Capture-Western, Proximity Label-MS, Reconstituted Complex, Two-hybrid, proximity-dependent biotin identification	association, physical	15687488, 26638075, (Europe PMC)	0.35	BioGRID, IntAct
CHEK1	Biochemical Activity	physical	15775976, (Europe PMC)	NA	BioGRID
CHFR	Affinity Capture-Western	physical	19448676, (Europe PMC)	NA	BioGRID
CHUK	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, tandem affinity purification	association, physical, physical association	14743216, 15489227, 16382138, 17434128, 18519641, 21903422, 22689577, 8246997, (Europe PMC)	0.40, 0.56	BioGRID, IntAct
CNNM3	Two-hybrid, two hybrid	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
COL2A1	Two-hybrid	physical	21988832, (Europe PMC)	NA	BioGRID
COMMD1	Affinity Capture-Western, Biochemical Activity, anti bait coimmunoprecipitation, confocal microscopy, pull down	association, physical, physical association	14685242, 15799966, 16573520, 17183367, 19270718, 19339690, 20048074, 25074812, (Europe PMC)	0.69	BioGRID, IntAct
COMMD10	Affinity Capture-Western, pull down	association, physical	15799966, (Europe PMC)	0.35	BioGRID, IntAct
COMMD2	Affinity Capture-Western, pull down	association, physical	15799966, (Europe PMC)	0.35	BioGRID, IntAct
COMMD4	Affinity Capture-Western, pull down	association, physical	15799966, (Europe PMC)	0.35	BioGRID, IntAct
COMMD5	Affinity Capture-Western, pull down	association, physical	15799966, (Europe PMC)	0.35	BioGRID, IntAct
COMMD6	Affinity Capture-Western, pull down	association, physical	15799966, 16573520, (Europe PMC)	0.35	BioGRID, IntAct
COMMD7	Affinity Capture-Western, pull down	association, physical	15799966, (Europe PMC)	0.35	BioGRID, IntAct
COMMD8	Affinity Capture-Western, pull down	association, physical	15799966, (Europe PMC)	0.35	BioGRID, IntAct
CREBBP	Affinity Capture-Western, Phenotypic Enhancement, Phenotypic Suppression, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, pull down	association, direct interaction, genetic, physical, physical association	10235267, 10454579, 10542243, 11931769, 12163591, 14597638, 15140884, 15806143, 16291753, 17138826, 17296604, 17362989, 17434128, 18241676, 25314079, 25733689, 9096323, 9482849, 9548485, 9659924, 9806899, (Europe PMC)	0.69	BioGRID, IntAct
CSN3	Affinity Capture-Western	physical	25486460, (Europe PMC)	NA	BioGRID
CSNK1G1	Affinity Capture-Western, Biochemical Activity	physical	24442433, (Europe PMC)	NA	BioGRID
CSNK2A1	Affinity Capture-Western, Biochemical Activity, anti tag coimmunoprecipitation, protein kinase assay	phosphorylation reaction, physical, physical association	10938077, (Europe PMC)	0.54	BioGRID, IntAct, MINT
CSNK2A2	Affinity Capture-Western, Biochemical Activity	physical	10938077, (Europe PMC)	NA	BioGRID
CUL2	Affinity Capture-Western, pull down	association, physical	19270718, 19327355, 24442433, (Europe PMC)	0.35	BioGRID, IntAct, MINT
DCD	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
DDC	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
DHX9	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	15355351, (Europe PMC)	NA	BioGRID
DIS3L2	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
DNAJA3	Affinity Capture-Western, Reconstituted Complex, tandem affinity purification	physical, physical association	14743216, 15601829, (Europe PMC)	0.40	BioGRID, IntAct
DNMT3B	Co-localization	physical	24952347, (Europe PMC)	NA	BioGRID
DNMT3L	Affinity Capture-Western, Co-localization, Reconstituted Complex	physical	24952347, (Europe PMC)	NA	BioGRID
DPF1	Affinity Capture-Western, anti tag coimmunoprecipitation	association, physical	22334708, (Europe PMC)	0.35	BioGRID, IntAct
DPF2	Affinity Capture-Western, Reconstituted Complex, anti tag coimmunoprecipitation	association, physical	20460684, 22334708, (Europe PMC)	0.35	BioGRID, IntAct
DPF3	Affinity Capture-Western, Co-localization, Reconstituted Complex, anti tag coimmunoprecipitation, chromatin immunoprecipitation assay, pull down	association, physical	22334708, (Europe PMC)	0.35, 0.46	BioGRID, IntAct
ECSIT	Affinity Capture-Western, Reconstituted Complex	physical	25355951, (Europe PMC)	NA	BioGRID
EEF1D	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
EGR1	Reconstituted Complex	physical	10671503, (Europe PMC)	NA	BioGRID
EHMT1	Affinity Capture-Western, Protein-peptide, Reconstituted Complex, anti bait coimmunoprecipitation	association, physical, physical association	21131967, (Europe PMC)	0.50	BioGRID, IntAct
ELF3	Affinity Capture-Western	physical	23687337, (Europe PMC)	NA	BioGRID
EP300	Affinity Capture-Western, Biochemical Activity, Phenotypic Enhancement, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, experimental interaction detection	acetylation reaction, association, genetic, physical	10235267, 11533489, 11567019, 11585920, 12403783, 12419806, 12456660, 12471036, 12960163, 15192014, 16135789, 16291753, 17692505, 17982102, 18280497, 18397880, 20154269, 20333651, 21187066, 23999430, 25074812, 25400040, 9096323, (Europe PMC)	0.53	BioGRID, IntAct, MINT
ESR1	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, pull down	direct interaction, physical, physical association	16331275, 16497877, 17932106, 19350539, 7651415, (Europe PMC)	0.78	BioGRID, IntAct
ETHE1	Affinity Capture-Western, Reconstituted Complex	physical	12398897, 17353187, (Europe PMC)	NA	BioGRID
EZH2	Affinity Capture-Western, Reconstituted Complex	physical	21884980, (Europe PMC)	NA	BioGRID
FAF1	Affinity Capture-Western	physical	14600157, 28414080, (Europe PMC)	NA	BioGRID
FBXW11	Affinity Capture-MS	physical	25332235, 25900982, 28514442, (Europe PMC)	NA	BioGRID
FKBP11	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
FOS	Phenotypic Enhancement, Two-hybrid, fluorescent resonance energy transfer	genetic, physical, physical association	10488148, 18172215, (Europe PMC)	0.40	BioGRID, IntAct
FOXP3	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	15790681, 25712342, (Europe PMC)	0.40	BioGRID, IntAct
FUS	Affinity Capture-Western, Reconstituted Complex	physical	11278855, (Europe PMC)	NA	BioGRID
GAN	Affinity Capture-MS, Affinity Capture-Western	physical	25331947, (Europe PMC)	NA	BioGRID
GFI1	Affinity Capture-Western, Co-localization, anti bait coimmunoprecipitation	physical, physical association	20547752, (Europe PMC)	0.40	BioGRID, IntAct
GOPC	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
GPS1	Affinity Capture-Western	physical	25486460, (Europe PMC)	NA	BioGRID
GSK3B	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	21217772, (Europe PMC)	0.40	BioGRID, IntAct
GTF2B	Reconstituted Complex, pull down	direct interaction, physical	15013781, 7706261, (Europe PMC)	0.44	BioGRID, IntAct, MINT
HDAC1	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, pull down	association, direct interaction, physical, physical association	11564889, 11931769, 12419806, 15192014, 16291753, 16483679, 17000776, 17827154, 20001970, 21983014, (Europe PMC)	0.66	BioGRID, IntAct
HDAC2	Affinity Capture-Western, Co-localization, Reconstituted Complex, proximity ligation assay	physical, physical association	10958685, 11395507, 12138131, 12419806, 17827154, 20065107, 20388487, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
HDAC3	Affinity Capture-Western, coimmunoprecipitation	physical, physical association	11533489, 15192014, (Europe PMC)	0.40	BioGRID, IntAct, MINT
HDAC6	Affinity Capture-Western	physical	26388610, (Europe PMC)	NA	BioGRID
HERC3	Affinity Capture-Western	physical	26476452, (Europe PMC)	NA	BioGRID
HEXIM1	Reconstituted Complex	physical	12581153, (Europe PMC)	NA	BioGRID
HIF1A	Affinity Capture-Western	physical	23123196, (Europe PMC)	NA	BioGRID
HMGA2	Reconstituted Complex	physical	12693954, (Europe PMC)	NA	BioGRID
HMGB1	Affinity Capture-Western	physical	12665595, (Europe PMC)	NA	BioGRID
HSPA1A	Affinity Capture-Western	physical	24175631, (Europe PMC)	NA	BioGRID
HSPA1L	Co-localization, proximity ligation assay, tandem affinity purification	physical, physical association	14743216, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
HSPA4	Affinity Capture-Western, Reconstituted Complex	physical	9250404, (Europe PMC)	NA	BioGRID
HSPA5	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
HSPA8	Affinity Capture-Western, tandem affinity purification	physical, physical association	14743216, 24175631, (Europe PMC)	0.40	BioGRID, IntAct
HYPK	Affinity Capture-MS	physical	23272104, (Europe PMC)	NA	BioGRID
IKBKB	Affinity Capture-Western, Biochemical Activity, Co-localization, experimental interaction detection, protein kinase assay, proximity ligation assay	phosphorylation reaction, physical, physical association	10521409, 12842894, 15489227, 16046471, 18519641, 22689577, 25241761, (Europe PMC)	0.69	BioGRID, IntAct, MINT
IKBKE	Biochemical Activity	physical	15489227, (Europe PMC)	NA	BioGRID
IKBKG	Biochemical Activity	physical	18519641, (Europe PMC)	NA	BioGRID
IL1RN	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
ING4	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, Two-hybrid	physical	15029197, 18779315, 23624912, (Europe PMC)	NA	BioGRID
IQGAP2	Affinity Capture-MS, tandem affinity purification	physical, physical association	14743216, (Europe PMC)	0.40	BioGRID, IntAct
IRF2	Reconstituted Complex	physical	8550813, (Europe PMC)	NA	BioGRID
IRF8	Reconstituted Complex	physical	8550813, (Europe PMC)	NA	BioGRID
IRF9	Reconstituted Complex	physical	8550813, (Europe PMC)	NA	BioGRID
ISL1	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
ITGB3BP	Affinity Capture-Western	physical	12244126, (Europe PMC)	NA	BioGRID
JUN	Phenotypic Enhancement, Two-hybrid	genetic, physical	10488148, (Europe PMC)	NA	BioGRID
KAT2A	Affinity Capture-Western, Reconstituted Complex	physical	19339690, (Europe PMC)	NA	BioGRID
KAT5	Affinity Capture-Western, Two-hybrid	physical	22249179, (Europe PMC)	NA	BioGRID
KDM2A	Affinity Capture-Western, Biochemical Activity, anti bait coimmunoprecipitation	physical, physical association	20080798, (Europe PMC)	0.40	BioGRID, IntAct
KEAP1	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, confocal microscopy, two hybrid, two hybrid array	colocalization, physical, physical association	21262351, 21988832, (Europe PMC)	0.59	BioGRID, IntAct
KLF4	Affinity Capture-Western	physical	22282354, (Europe PMC)	NA	BioGRID
KPNA2	Reconstituted Complex, Two-hybrid, two hybrid array	physical, physical association	12504098, 21988832, (Europe PMC)	0.37	BioGRID, IntAct
KRT5	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
LINC01587	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
LMO2	Affinity Capture-Western, Two-hybrid, confocal microscopy, pull down, two hybrid	colocalization, physical, physical association	21988832, (Europe PMC)	0.54	BioGRID, IntAct
MAFK	Affinity Capture-Western	physical	18241676, (Europe PMC)	NA	BioGRID
MAP2K6	Co-localization, proximity ligation assay	physical, physical association	25241761, (Europe PMC)	0.40	BioGRID, IntAct
MAP3K7	Co-localization, proximity ligation assay	physical, physical association	25241761, (Europe PMC)	0.40	BioGRID, IntAct
MAP3K8	Affinity Capture-MS, anti tag coimmunoprecipitation, tandem affinity purification	association, physical, physical association	14743216, 25331947, 25852190, (Europe PMC)	0.35, 0.40	BioGRID, IntAct
MAPK10	Affinity Capture-Western, Two-hybrid, anti tag coimmunoprecipitation, two hybrid	physical, physical association	21988832, (Europe PMC)	0.51	BioGRID, IntAct
MAPK14	Two-hybrid, two hybrid	physical, physical association	21900206, (Europe PMC)	0.37	BioGRID, IntAct, MINT
MDM2	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, two hybrid array	physical, physical association	21988832, 23839035, (Europe PMC)	0.37	BioGRID, IntAct
MED15	Reconstituted Complex	physical	10235267, (Europe PMC)	NA	BioGRID
MED23	Reconstituted Complex	physical	10235267, (Europe PMC)	NA	BioGRID
MED7	Reconstituted Complex	physical	10235267, (Europe PMC)	NA	BioGRID
MEN1	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, pull down	direct interaction, physical, physical association	11526476, (Europe PMC)	0.40, 0.60	BioGRID, IntAct
MEOX2	Affinity Capture-Western	physical	20421348, (Europe PMC)	NA	BioGRID
MKRN2	Affinity Capture-Western, Biochemical Activity	physical	28378844, (Europe PMC)	NA	BioGRID
MKS1	Proximity Label-MS, proximity-dependent biotin identification	association, physical	26638075, (Europe PMC)	0.35	BioGRID, IntAct
MTDH	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	18316612, (Europe PMC)	0.40	BioGRID, IntAct
MTPN	Affinity Capture-Western, Reconstituted Complex	physical	11971907, (Europe PMC)	NA	BioGRID
MUC3A	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
MX1	Two-hybrid	physical	25447205, (Europe PMC)	NA	BioGRID
MYBBP1A	Affinity Capture-Western	physical	24175631, (Europe PMC)	NA	BioGRID
MYC	Affinity Capture-Western	physical	12027803, 15616592, (Europe PMC)	NA	BioGRID
NCF1	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, fluorescence microscopy, pull down, two hybrid, two hybrid pooling approach	colocalization, direct interaction, physical, physical association	12618429, (Europe PMC)	0.68	BioGRID, IntAct, MINT
NCOA3	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	16331275, 16456540, (Europe PMC)	0.40	BioGRID, IntAct, MINT
NCOA6	Reconstituted Complex	physical	10847592, (Europe PMC)	NA	BioGRID
NCOR2	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	10777532, 12589049, 16382138, (Europe PMC)	NA	BioGRID
NFKB1	Affinity Capture-MS, Affinity Capture-Western, Co-localization, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down, tandem affinity purification, two hybrid, two hybrid array	association, physical, physical association	10498867, 11880271, 11976329, 12414801, 14645533, 14690596, 14743216, 15799966, 16105840, 16204234, 16319923, 16740634, 17982102, 20154269, 20237821, 2050119, 20547752, 21270162, 21544861, 21988832, 22139845, 22261743, 22808155, 23687337, 24175631, 24634218, 25355951, 25609649, 8246997, 8255759, 8798655, 9722548, (Europe PMC)	0.35, 0.40, 0.79, 0.83	BioGRID, IntAct, MINT
NFKB2	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, tandem affinity purification	physical, physical association	14743216, 16009713, 16940413, 8413211, (Europe PMC)	0.40	BioGRID, IntAct
NFKBIA	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Co-localization, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, enzymatic footprinting, footprinting, protein kinase assay, pull down, rna immunoprecipitation, tandem affinity purification, two hybrid, two hybrid array, ubiquitin reconstruction, x-ray crystallography	association, direct interaction, phosphorylation reaction, physical, physical association	10066434, 10085161, 10498867, 11020244, 11231305, 11287411, 11313474, 11533489, 12419806, 14685242, 14690596, 14743216, 15799966, 16105840, 16683270, 16951195, 17003112, 17301240, 17612295, 19219072, 20065107, 20551178, 20797629, 20980497, 21217772, 21988832, 22022389, 22081069, 23563313, 23850221, 24248593, 24457201, 24634218, 25520503, 25609694, 25759022, 26186194, 26463447, 26476452, 26496610, 27923823, 28514442, 7628694, 7739549, 7878004, 8139561, 8657102, 8887627, 8887633, 8978697, 9057089, 9572494, 9738011, 9751059, 9865693, 9990853, (Europe PMC)	0.40, 0.61, 0.97	BioGRID, IntAct, MINT
NFKBIB	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, tandem affinity purification, two hybrid, two hybrid array	association, physical, physical association	10498867, 12672800, 14685242, 14743216, 21988832, 22081069, 26186194, 28514442, 8816457, 8887627, (Europe PMC)	0.40, 0.75	BioGRID, IntAct
NFKBIE	Affinity Capture-Western, Reconstituted Complex, Two-hybrid, tandem affinity purification, two hybrid, two hybrid array	physical, physical association	14743216, 21988832, 9315679, (Europe PMC)	0.40, 0.49	BioGRID, IntAct
NKRF	Reconstituted Complex	physical	10562553, (Europe PMC)	NA	BioGRID
NKX2-1	Affinity Capture-Western	physical	12040027, (Europe PMC)	NA	BioGRID
NOTCH1	Affinity Capture-Western	physical	8642313, (Europe PMC)	NA	BioGRID
NOV	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
NPM1	Affinity Capture-Western, Two-hybrid, tandem affinity purification, two hybrid	physical, physical association	14743216, 19074833, 21988832, (Europe PMC)	0.37, 0.40	BioGRID, IntAct
NR3C1	Affinity Capture-Western, Reconstituted Complex, chromatin immunoprecipitation assay	association, physical	10995388, 25202013, 7659084, 8290595, (Europe PMC)	0.35	BioGRID, IntAct
NSD1	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	20080798, (Europe PMC)	0.40	BioGRID, IntAct
NTRK1	Affinity Capture-MS	physical	25921289, (Europe PMC)	NA	BioGRID
NUFIP2	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
OGT	Affinity Capture-Western, anti bait coimmunoprecipitation	association, physical, physical association	17882263, (Europe PMC)	0.50	BioGRID, IntAct, MINT
PAK1	Affinity Capture-Western	physical	26036343, (Europe PMC)	NA	BioGRID
PARP1	Affinity Capture-Western, Reconstituted Complex, tandem affinity purification	physical, physical association	11590148, 14743216, 16204234, 18280497, (Europe PMC)	0.40	BioGRID, IntAct
PEX1	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
PGR	Reconstituted Complex	physical	8626413, (Europe PMC)	NA	BioGRID
PHF10	Affinity Capture-Western, anti tag coimmunoprecipitation	association, physical	22334708, (Europe PMC)	0.35	BioGRID, IntAct
PIAS3	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, Two-hybrid	physical	15140884, 22649547, (Europe PMC)	NA	BioGRID
PIN1	Affinity Capture-Western	physical	14690596, (Europe PMC)	NA	BioGRID
PIWIL4	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
PKM	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
PLA2G4A	Two-hybrid, two hybrid	physical, physical association	18330356, (Europe PMC)	0.37	BioGRID, IntAct
PLG	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
PLK1	Reconstituted Complex	physical	21610149, (Europe PMC)	NA	BioGRID
PML	Affinity Capture-Western	physical	12540841, 25733689, (Europe PMC)	NA	BioGRID
POLR2A	Co-localization	physical	23994473, (Europe PMC)	NA	BioGRID
POTEE	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
POTEJ	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
POU2F1	Affinity Capture-Western, Reconstituted Complex	physical	12019209, (Europe PMC)	NA	BioGRID
PPARA	Reconstituted Complex	physical	10542237, (Europe PMC)	NA	BioGRID
PPARD	Affinity Capture-Western	physical	18037904, (Europe PMC)	NA	BioGRID
PPARG	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, Two-hybrid	physical	14587029, 17312272, 18556801, 23250430, 23684777, (Europe PMC)	NA	BioGRID
PPARGC1A	Affinity Capture-Western, proximity ligation assay	physical, physical association	17785586, 23174781, (Europe PMC)	0.40	BioGRID, IntAct
PPP1R13L	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	10336463, 12134007, (Europe PMC)	NA	BioGRID
PPP2CA	Reconstituted Complex, cross-linking study, phosphatase assay, pull down	association, dephosphorylation reaction, physical, physical association	11591705, (Europe PMC)	0.59	BioGRID, IntAct, MINT
PPP2CB	Reconstituted Complex	physical	11591705, (Europe PMC)	NA	BioGRID
PPP4C	Reconstituted Complex	physical	9837938, (Europe PMC)	NA	BioGRID
PRKACA	Biochemical Activity, anti bait coimmunoprecipitation, experimental interaction detection, pull down	direct interaction, phosphorylation reaction, physical, physical association	12628924, 20133937, 9150141, (Europe PMC)	0.58	BioGRID, IntAct, MINT
PRKCZ	Affinity Capture-Western, Biochemical Activity, experimental interaction detection	phosphorylation reaction, physical	11684013, 12881425, 21131967, (Europe PMC)	0.31	BioGRID, IntAct, MINT
PRKDC	Affinity Capture-MS, tandem affinity purification	physical, physical association	14743216, 25331947, (Europe PMC)	0.40	BioGRID, IntAct
PRMT1	Affinity Capture-Western, Reconstituted Complex	physical	18280497, (Europe PMC)	NA	BioGRID
PRMT5	Affinity Capture-Western	physical	23904475, 25704480, (Europe PMC)	NA	BioGRID
PSMC2	Affinity Capture-Western	physical	26476452, (Europe PMC)	NA	BioGRID
PSMD10	Affinity Capture-Western, Reconstituted Complex	physical	17904523, 18040287, (Europe PMC)	NA	BioGRID
PSMD4	Affinity Capture-Western	physical	26476452, (Europe PMC)	NA	BioGRID
REL	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, Two-hybrid, tandem affinity purification, two hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical, physical association	10498867, 11967310, 14743216, 25416956, 26186194, 28514442, 8139561, (Europe PMC)	0.37, 0.40, 0.56	BioGRID, IntAct
RELA	Affinity Capture-MS, Affinity Capture-Western, Two-hybrid, anti bait coimmunoprecipitation, tandem affinity purification, two hybrid	physical, physical association	10336463, 10498867, 12456660, 14743216, 18280497, 25331947, 8246997, (Europe PMC)	0.40, 0.57	BioGRID, IntAct
RELB	Affinity Capture-MS, Affinity Capture-Western, Co-localization, anti bait coimmunoprecipitation, proximity ligation assay, tandem affinity purification	association, physical, physical association	14743216, 21884980, 22808155, 25241761, 28514442, (Europe PMC)	0.40, 0.56	BioGRID, IntAct
REV1	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
RFC1	Affinity Capture-Western, Reconstituted Complex	physical	12509469, (Europe PMC)	NA	BioGRID
RIOK2	Two-hybrid	physical	21988832, (Europe PMC)	NA	BioGRID
RNASE1	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
RNF2	Affinity Capture-MS	physical	24457600, (Europe PMC)	NA	BioGRID
RNF25	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	12748188, (Europe PMC)	NA	BioGRID
RPL13	Two-hybrid, two hybrid	physical, physical association	21900206, (Europe PMC)	0.37	BioGRID, IntAct, MINT
RPL23	Two-hybrid, tandem affinity purification, two hybrid array	physical, physical association	14743216, 21988832, (Europe PMC)	0.37, 0.40	BioGRID, IntAct
RPS3	Affinity Capture-Western, Co-localization, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down, tandem affinity purification	association, physical, physical association	14743216, 18045535, 23188828, 24457201, 26526615, (Europe PMC)	0.40, 0.80	BioGRID, IntAct, MINT
RPS6KA5	Affinity Capture-Western, Biochemical Activity, Co-localization, anti tag coimmunoprecipitation, proximity ligation assay	physical, physical association	12628924, 25241761, (Europe PMC)	0.59	BioGRID, IntAct
RXRA	Co-localization, Reconstituted Complex, proximity ligation assay	physical, physical association	10075655, 16608838, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
SAT1	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
SETD6	Affinity Capture-Western, Biochemical Activity, Co-crystal Structure, Reconstituted Complex, anti bait coimmunoprecipitation	association, physical	21131967, 21515635, (Europe PMC)	0.35	BioGRID, IntAct
SETD7	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, methyltransferase assay, pull down	direct interaction, methylation reaction, physical, physical association	18650421, 19262565, 19864627, 21131967, (Europe PMC)	0.74	BioGRID, IntAct, MINT
SIRT1	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, deacetylase assay	association, deacetylation reaction, physical, physical association	15152190, 17041012, 21081649, (Europe PMC)	0.73	BioGRID, IntAct
SIRT5	Affinity Capture-Western	physical	19135889, (Europe PMC)	NA	BioGRID
SIRT6	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	direct interaction, physical, physical association	19135889, (Europe PMC)	0.60	BioGRID, IntAct
SMAD3	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
SMAD4	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
SMARCA2	Co-localization	physical	22334708, (Europe PMC)	NA	BioGRID
SNAI1	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, chromatin immunoprecipitation assay, fluorescence microscopy	association, colocalization, physical, physical association	19411070, 25314079, (Europe PMC)	0.69	BioGRID, IntAct
SNIP1	Reconstituted Complex	physical	11567019, (Europe PMC)	NA	BioGRID
SNRNP70	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
SNRPD3	Co-fractionation	physical	22863883, (Europe PMC)	NA	BioGRID
SOCS1	Affinity Capture-MS, Affinity Capture-Western, Reconstituted Complex, pull down	physical, physical association	14690596, 17183367, 21084693, (Europe PMC)	0.40	BioGRID, IntAct, MINT
SOCS3	Affinity Capture-Western	physical	21451109, (Europe PMC)	NA	BioGRID
SOCS6	Two-hybrid, two hybrid	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
SORD	Two-hybrid, two hybrid	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
SP1	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation	physical, physical association	12055073, 18249093, 19074833, 20385359, 20861353, 22139845, 7933095, (Europe PMC)	0.40	BioGRID, IntAct
SP3	Affinity Capture-Western	physical	22139845, (Europe PMC)	NA	BioGRID
SPATA31A3	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
SRF	Reconstituted Complex	physical	8670842, (Europe PMC)	NA	BioGRID
SRSF7	Affinity Capture-MS	physical	25331947, (Europe PMC)	NA	BioGRID
SSH3	Proximity Label-MS	physical	27880917, (Europe PMC)	NA	BioGRID
STAT1	Co-localization, proximity ligation assay	physical, physical association	25241761, (Europe PMC)	0.40	BioGRID, IntAct
STAT3	Affinity Capture-Western, Reconstituted Complex	physical	12057007, 14593105, 23335796, (Europe PMC)	NA	BioGRID
STUB1	Affinity Capture-Western	physical	22535373, (Europe PMC)	NA	BioGRID
SUZ12	Affinity Capture-MS, Affinity Capture-Western	physical	21884980, 24457600, (Europe PMC)	NA	BioGRID
TAF1	Reconstituted Complex	physical	9584164, (Europe PMC)	NA	BioGRID
TAF11	Reconstituted Complex	physical	9584164, (Europe PMC)	NA	BioGRID
TAF4B	Reconstituted Complex	physical	9724652, (Europe PMC)	NA	BioGRID
TAF6	Reconstituted Complex	physical	9584164, (Europe PMC)	NA	BioGRID
TAF9	Reconstituted Complex	physical	15489227, (Europe PMC)	NA	BioGRID
TBK1	Affinity Capture-MS, Biochemical Activity	physical	14560022, 14743216, 15489227, (Europe PMC)	NA	BioGRID
TBL1X	Affinity Capture-Western	physical	21189284, (Europe PMC)	NA	BioGRID
TBP	Affinity Capture-Western, Phenotypic Enhancement, Reconstituted Complex	genetic, physical	10839990, 7706261, 9584164, (Europe PMC)	NA	BioGRID
TCAP	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
TCF4	Two-hybrid, two hybrid array, two hybrid prey pooling approach, validated two hybrid	physical, physical association	25416956, (Europe PMC)	0.56	BioGRID, IntAct
TERT	Affinity Capture-Western	physical	12517770, (Europe PMC)	NA	BioGRID
TFAP2A	Affinity Capture-Western, Two-hybrid	physical	19074833, (Europe PMC)	NA	BioGRID
TLE1	Affinity Capture-Western	physical	10660609, (Europe PMC)	NA	BioGRID
TNIP2	Affinity Capture-MS	physical	14743216, (Europe PMC)	NA	BioGRID
TP53	Affinity Capture-Western	physical	17434128, (Europe PMC)	NA	BioGRID
TP63	Affinity Capture-Western	physical	22020940, (Europe PMC)	NA	BioGRID
TRIB3	Affinity Capture-Western	physical	12736262, (Europe PMC)	NA	BioGRID
TRIP4	Reconstituted Complex, Two-hybrid	physical	12077347, 21988832, (Europe PMC)	NA	BioGRID
TWIST1	Affinity Capture-MS, Affinity Capture-Western, pull down	association, physical	12553906, 21983900, (Europe PMC)	0.35	BioGRID, IntAct, MINT
TXN2	Affinity Capture-Western	physical	19570036, (Europe PMC)	NA	BioGRID
TXNIP	Affinity Capture-Western	physical	20826751, (Europe PMC)	NA	BioGRID
UBC	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	physical, physical association	17183367, 19262565, 19322197, 25486460, (Europe PMC)	0.77	BioGRID, IntAct, MINT
UBE2C	Biochemical Activity	physical	14690596, (Europe PMC)	NA	BioGRID
UBE2D1	Biochemical Activity	physical	14690596, (Europe PMC)	NA	BioGRID
UBE2D2	Biochemical Activity	physical	14690596, (Europe PMC)	NA	BioGRID
UBE2D3	Biochemical Activity	physical	14690596, (Europe PMC)	NA	BioGRID
UBE2E1	Biochemical Activity	physical	14690596, (Europe PMC)	NA	BioGRID
UBE2H	Biochemical Activity	physical	14690596, (Europe PMC)	NA	BioGRID
UBE2L3	Biochemical Activity	physical	14690596, (Europe PMC)	NA	BioGRID
UBQLN1	Affinity Capture-Western	physical	26476452, (Europe PMC)	NA	BioGRID
UNC5CL	Affinity Capture-Western	physical	14769797, (Europe PMC)	NA	BioGRID
USF2	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
USP31	Affinity Capture-Western	physical	16214042, (Europe PMC)	NA	BioGRID
USP7	Affinity Capture-Western, Biochemical Activity	physical	23267096, (Europe PMC)	NA	BioGRID
WAS	Affinity Capture-Western	physical	26261240, (Europe PMC)	NA	BioGRID
XPO1	Affinity Capture-MS	physical	26673895, (Europe PMC)	NA	BioGRID
ZBTB33	Affinity Capture-Western	physical	26183023, (Europe PMC)	NA	BioGRID
ZBTB7A	Affinity Capture-Western, Two-hybrid	physical	15917220, (Europe PMC)	NA	BioGRID
ZBTB7B	Affinity Capture-Western	physical	22139845, (Europe PMC)	NA	BioGRID

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
AATF	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation	physical, physical association	17157788, (Europe PMC)	0.52	BioGRID, IntAct
ACTG1	tandem affinity purification	physical association	14743216, (Europe PMC)	0.40	IntAct
AGO1	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
AIFM1	tandem affinity purification	physical association	14743216, (Europe PMC)	0.40	IntAct
AKAP8L	Affinity Capture-MS, tandem affinity purification	physical, physical association	14743216, (Europe PMC)	0.40	BioGRID, IntAct
ANXA1	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	21383699, (Europe PMC)	0.40	BioGRID, IntAct
ATF3	Affinity Capture-Western, Reconstituted Complex, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	association, direct interaction, physical, physical association	16291753, (Europe PMC)	0.62	BioGRID, IntAct
ATP5F1A	tandem affinity purification	physical association	14743216, (Europe PMC)	0.40	IntAct
BAG2	tandem affinity purification	physical association	14743216, (Europe PMC)	0.40	IntAct
BATF2	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
BRD4	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, nuclear magnetic resonance, pull down, x-ray crystallography	direct interaction, physical association	19103749, 22645123, 23686307, (Europe PMC)	0.81	IntAct
C1QB	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
CAD	tandem affinity purification	physical association	14743216, (Europe PMC)	0.40	IntAct
CAMK2D	anti tag coimmunoprecipitation	association	29426014, (Europe PMC)	0.35	IntAct
CCAR2	tandem affinity purification	physical association	14743216, (Europe PMC)	0.40	IntAct
CCL5	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
CCT4	tandem affinity purification	physical association	14743216, (Europe PMC)	0.40	IntAct
CCT8	tandem affinity purification	physical association	14743216, (Europe PMC)	0.40	IntAct
CDK5RAP3	anti bait coimmunoprecipitation, pull down	physical association	17785205, (Europe PMC)	0.52	IntAct
CEBPB	chromatin immunoprecipitation assay	association	19064995, (Europe PMC)	0.35	IntAct
CENPJ	Affinity Capture-Western, Proximity Label-MS, Reconstituted Complex, Two-hybrid, proximity-dependent biotin identification	association, physical	15687488, 26638075, (Europe PMC)	0.35	BioGRID, IntAct
CHUK	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, tandem affinity purification	association, physical, physical association	14743216, 15489227, 16382138, 17434128, 18519641, 21903422, 22689577, 8246997, (Europe PMC)	0.40, 0.56	BioGRID, IntAct
CLTC	tandem affinity purification	physical association	14743216, (Europe PMC)	0.40	IntAct
CNNM3	Two-hybrid, two hybrid	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
COL2A1	two hybrid array	physical association	21988832, (Europe PMC)	0.37	IntAct
COMMD1	Affinity Capture-Western, Biochemical Activity, anti bait coimmunoprecipitation, confocal microscopy, pull down	association, physical, physical association	14685242, 15799966, 16573520, 17183367, 19270718, 19339690, 20048074, 25074812, (Europe PMC)	0.69	BioGRID, IntAct
COMMD10	Affinity Capture-Western, pull down	association, physical	15799966, (Europe PMC)	0.35	BioGRID, IntAct
COMMD2	Affinity Capture-Western, pull down	association, physical	15799966, (Europe PMC)	0.35	BioGRID, IntAct
COMMD4	Affinity Capture-Western, pull down	association, physical	15799966, (Europe PMC)	0.35	BioGRID, IntAct
COMMD5	Affinity Capture-Western, pull down	association, physical	15799966, (Europe PMC)	0.35	BioGRID, IntAct
COMMD6	Affinity Capture-Western, pull down	association, physical	15799966, 16573520, (Europe PMC)	0.35	BioGRID, IntAct
COMMD7	Affinity Capture-Western, pull down	association, physical	15799966, (Europe PMC)	0.35	BioGRID, IntAct
COMMD8	Affinity Capture-Western, pull down	association, physical	15799966, (Europe PMC)	0.35	BioGRID, IntAct
CREBBP	Affinity Capture-Western, Phenotypic Enhancement, Phenotypic Suppression, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, pull down	association, direct interaction, genetic, physical, physical association	10235267, 10454579, 10542243, 11931769, 12163591, 14597638, 15140884, 15806143, 16291753, 17138826, 17296604, 17362989, 17434128, 18241676, 25314079, 25733689, 9096323, 9482849, 9548485, 9659924, 9806899, (Europe PMC)	0.69	BioGRID, IntAct
CRIP2	anti bait coimmunoprecipitation	physical association	21540330, (Europe PMC)	0.40	IntAct
CSNK2A1	Affinity Capture-Western, Biochemical Activity, anti tag coimmunoprecipitation, protein kinase assay	phosphorylation reaction, physical, physical association	10938077, (Europe PMC)	0.54	BioGRID, IntAct, MINT
CTNNA1	anti bait coimmunoprecipitation	association	24509793, (Europe PMC)	0.35	IntAct
CTNNB1	anti bait coimmunoprecipitation	physical association	23273993, 24072822, (Europe PMC)	0.59	IntAct
CUL2	Affinity Capture-Western, pull down	association, physical	19270718, 19327355, 24442433, (Europe PMC)	0.35	BioGRID, IntAct, MINT
DAXX	anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, confocal microscopy	colocalization, physical association	17362989, (Europe PMC)	0.56	IntAct
DDC	Two-hybrid, two hybrid array	physical, physical association	21988832, (Europe PMC)	0.37	BioGRID, IntAct
DDX21	tandem affinity purification	physical association	14743216, (Europe PMC)	0.40	IntAct
DHX9	anti tag coimmunoprecipitation, coimmunoprecipitation, pull down, tandem affinity purification, two hybrid	physical association	14743216, 15355351, (Europe PMC)	0.40, 0.63	IntAct
DNAJA1	tandem affinity purification	physical association	14743216, (Europe PMC)	0.40	IntAct
DNAJA3	Affinity Capture-Western, Reconstituted Complex, tandem affinity purification	physical, physical association	14743216, 15601829, (Europe PMC)	0.40	BioGRID, IntAct
DPF1	Affinity Capture-Western, anti tag coimmunoprecipitation	association, physical	22334708, (Europe PMC)	0.35	BioGRID, IntAct
DPF2	Affinity Capture-Western, Reconstituted Complex, anti tag coimmunoprecipitation	association, physical	20460684, 22334708, (Europe PMC)	0.35	BioGRID, IntAct
DPF3	Affinity Capture-Western, Co-localization, Reconstituted Complex, anti tag coimmunoprecipitation, chromatin immunoprecipitation assay, pull down	association, physical	22334708, (Europe PMC)	0.35, 0.46	BioGRID, IntAct
EBI-10000824	enzyme linked immunosorbent assay	physical association	18363837, (Europe PMC)	0.40	IntAct
EBI-10021813	electrophoretic mobility supershift assay	association, physical association	9120310, (Europe PMC)	0.50	IntAct
EBI-10042296	electrophoretic mobility supershift assay	physical association	19351910, (Europe PMC)	0.40	IntAct
EBI-10051097	electrophoretic mobility supershift assay	physical association	8021507, (Europe PMC)	0.40	IntAct
EBI-10051784	electrophoretic mobility supershift assay	physical association	17709515, (Europe PMC)	0.40	IntAct
EBI-10051787	electrophoretic mobility supershift assay	physical association	17709515, (Europe PMC)	0.40	IntAct
EBI-10052614	electrophoretic mobility shift assay, electrophoretic mobility supershift assay	physical association	9831247, (Europe PMC)	0.52	IntAct
EBI-10106659	electrophoretic mobility supershift assay	physical association	19064995, (Europe PMC)	0.40	IntAct
EBI-10826665	confocal microscopy, electrophoretic mobility shift assay, electrophoretic mobility supershift assay, enzymatic footprinting, footprinting, pull down, rna immunoprecipitation	association, colocalization, direct interaction, physical association	25759022, (Europe PMC)	0.60, 0.69	IntAct
EBI-10827714	pull down	physical association	25759022, (Europe PMC)	0.40	IntAct
EBI-10828686	electrophoretic mobility shift assay, electrophoretic mobility supershift assay	direct interaction	25759022, (Europe PMC)	0.56	IntAct

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