DEPOD - human DEPhOsphorylation Database

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	CREB1 (QuickGO)	Interactive visualization of CREB1 structures (A quick tutorial to explore the interctive visulaization) Representative structure: 5ZK1
Synonyms	CREB1
Protein Name	CREB1
Alternative Name(s)	Cyclic AMP-responsive element-binding protein 1;CREB-1;cAMP-responsive element-binding protein 1;
Protein Family	Belongs to the bZIP family
EntrezGene ID	1385 (Comparitive Toxicogenomics)
UniProt AC (Human)	P16220 (protein sequence)
Enzyme Class	N/A
Molecular Weight	36688 Dalton
Protein Length	341 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000118260 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree \| eggNOG - KOG3584 \| eggNOG - ENOG410ZZJZ
Phosphorylation Network	Visualize

Domain organization, Expression, Diseases

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Localization, Function, Catalytic activity and Sequence

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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: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:0001077	sequence-specific DNA binding
GO:0001102	F:transcriptional activator activity
GO:0001190	RNA polymerase II proximal promoter sequence-specific DNA binding
GO:0001225	F:RNA polymerase II activating transcription factor binding
GO:0001228	F:transcriptional activator activity
GO:0001666	RNA polymerase II transcription factor binding
GO:0003700	F:RNA polymerase II transcription coactivator binding
GO:0003705	F:transcriptional activator activity
GO:0003712	RNA polymerase II transcription regulatory region sequence-specific DNA binding
GO:0005634	P:response to hypoxia
GO:0005654	F:DNA-binding transcription factor activity
GO:0005719	F:transcription factor activity
GO:0005759	RNA polymerase II distal enhancer sequence-specific binding
GO:0006468	F:transcription coregulator activity
GO:0007165	C:nucleus
GO:0007179	C:nucleoplasm
GO:0007409	C:nuclear euchromatin
GO:0007568	C:mitochondrial matrix
GO:0007595	P:protein phosphorylation
GO:0007613	P:signal transduction
GO:0007623	P:transforming growth factor beta receptor signaling pathway
GO:0008361	P:axonogenesis
GO:0008542	P:aging
GO:0010033	P:lactation
GO:0010944	P:memory
GO:0014823	P:circadian rhythm
GO:0016032	P:regulation of cell size
GO:0019899	P:visual learning
GO:0021983	P:response to organic substance
GO:0030424	P:negative regulation of transcription by competitive promoter binding
GO:0030544	P:response to activity
GO:0032916	P:viral process
GO:0033363	F:enzyme binding
GO:0033762	P:pituitary gland development
GO:0034670	C:axon
GO:0035035	F:Hsp70 protein binding
GO:0035094	P:positive regulation of transforming growth factor beta3 production
GO:0035497	P:secretory granule organization
GO:0035729	P:response to glucagon
GO:0036120	P:chemotaxis to arachidonic acid
GO:0040018	F:histone acetyltransferase binding
GO:0042752	P:response to nicotine
GO:0042802	F:cAMP response element binding
GO:0043065	P:cellular response to hepatocyte growth factor stimulus
GO:0045600	P:cellular response to platelet-derived growth factor stimulus
GO:0045672	P:positive regulation of multicellular organism growth
GO:0045893	P:regulation of circadian rhythm
GO:0045899	F:identical protein binding
GO:0045944	P:positive regulation of apoptotic process
GO:0046887	P:positive regulation of fat cell differentiation
GO:0046889	P:positive regulation of osteoclast differentiation
GO:0048145	P:positive regulation of transcription
GO:0050821	DNA-templated
GO:0055025	P:positive regulation of RNA polymerase II transcriptional preinitiation complex assembly
GO:0060251	P:positive regulation of transcription by RNA polymerase II
GO:0060430	P:positive regulation of hormone secretion
GO:0060509	P:positive regulation of lipid biosynthetic process
GO:0071294	P:regulation of fibroblast proliferation
GO:0071300	P:protein stabilization
GO:0071398	P:positive regulation of cardiac muscle tissue development
GO:1900273	P:regulation of glial cell proliferation
GO:1901215	P:lung saccule development
GO:1902065	P:type I pneumocyte differentiation
GO:1990090	P:cellular response to zinc ion
GO:1990314	P:cellular response to retinoic acid
GO:1990589	P:cellular response to fatty acid
GO:1990763	P:positive regulation of long-term synaptic potentiation
GO:1990830	P:negative regulation of neuron death

KEGG Pathway
Reactome Pathway

Pathway ID	Pathway Name	Pathway Description (KEGG)
hsa04022	cGMP-PKG signaling pathway	Cyclic GMP (cGMP) is the intracellular second messenger that mediates the action of nitric oxide (NO) and natriuretic peptides (NPs), regulating a broad array of physiologic processes. The elevated intracellular cGMP level exerts its physiological action through two forms of cGMP-dependent protein kinase (PKG), cGMP-regulated phosphodiesterases (PDE2, PDE3) and cGMP-gated cation channels, among which PKGs might be the primary mediator. PKG1 isoform-specific activation of established substrates leads to reduction of cytosolic calcium concentration and/or decrease in the sensitivity of myofilaments to Ca2+ (Ca2+-desensitization), resulting in smooth muscle relaxation. In cardiac myocyte, PKG directly phosphorylates a member of the transient potential receptor canonical channel family, TRPC6, suppressing this nonselective ion channel's Ca2+ conductance, G-alpha-q agonist-induced NFAT activation, and myocyte hypertrophic responses. PKG also opens mitochondrial ATP-sensitive K+ (mitoKATP) channels and subsequent release of ROS triggers cardioprotection.
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.
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.
hsa04152	AMPK signaling pathway	AMP-activated protein kinase (AMPK) is a serine threonine kinase that is highly conserved through evolution. AMPK system acts as a sensor of cellular energy status. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Several upstream kinases, including liver kinase B1 (LKB1), calcium/calmodulin kinase kinase-beta (CaMKK beta), and TGF-beta-activated kinase-1 (TAK-1), can activate AMPK by phosphorylating a threonine residue on its catalytic alpha-subunit. Once activated, AMPK leads to a concomitant inhibition of energy-consuming biosynthetic pathways, such as protein, fatty acid and glycogen synthesis, and activation of ATP-producing catabolic pathways, such as fatty acid oxidation and glycolysis.
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.
hsa04261	Adrenergic signaling in cardiomyocytes	Cardiac myocytes express at least six subtypes of adrenergic receptor (AR) which include three subtypes of beta-AR (beta-1, beta-2, beta-3) and three subtypes of the alpha-1-AR (alpha-1A, alpha-1B, and alpha-1C). In the human heart the beta-1-AR is the pre- dominate receptor. Acute sympathetic stimulation of cardiac beta-1-ARs induces positive inotropic and chronotropic effects, the most effective mechanism to acutely increase output of the heart, by coupling to Gs, formation of cAMP by adenylyl cyclase (AC), and PKA- dependent phosphorylation of various target proteins (e.g., ryanodine receptor [RyR]; phospholamban [PLB], troponin I [TnI], and the L-type Ca2+ channel [LTCC]). Chronic beta-1-AR stimulation is detrimental and induces cardiomyocyte hypertrophy and apoptosis. beta-2-AR coupled to Gs exerts a proapoptotic action as well as beta-1-AR, while beta-2-AR coupled to Gi exerts an antiapoptotic action.
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.
hsa04612	Antigen processing and presentation
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.
hsa04710	Circadian rhythm	Circadian rhythm is an internal biological clock, which enables to sustain an approximately 24-hour rhythm in the absence of environmental cues. In mammals, the circadian clock mechanism consists of cell-autonomous transcription-translation feedback loops that drive rhythmic, 24-hour expression patterns of core clock components. The first negative feedback loop is a rhythmic transcription of period genes (PER1, PER2, and PER3) and chryptochrome genes (CRY1 and CRY2). PER and CRY proteins form a heterodimer, which acts on the CLOCK/BMAL1 heterodimer to repress its own transcription. PER and CRY proteins are phosphorylated by casein kinase epsilon (CKIepsilon), which leads to degradation and restarting of the cycle. The second loop is a positive feedback loop driven by the CLOCK/BMAL1 heterodimer, which initiates transcription of target genes containing E-box cis-regulatory enhancer sequences.
hsa04713	Circadian entrainment	Circadian entrainment is a fundamental property by which the period of the internal biological clock is entrained by recurring exogenous signals, such that the organism's endocrine and behavioral rhythms are synchronized to environmental cues. In mammals, a master clock is located in the suprachiasmatic nuclei (SCN) of the hypothalamus and may synchronize circadian oscillators in peripheral tissues. Light signal is the dominant synchronizer for master SCN clock. Downstream from the retina, glutamate and PACAP are released and trigger the activation of signal transduction cascades, including CamKII and nNOS activity, cAMP- and cGMP-dependent protein kinases, and mitogen-activated protein kinase (MAPK). Of non-photic entrainment, important phase shifting capabilities have been found for melatonin, which inhibits light-induced phase shifts through inhibition of adenylate cyclase (AC). Multiple entrainment pathways converge into CREB regulation. In turn, phosphorylated CREB activates clock gene expression.
hsa04714	Thermogenesis	Thermogenesis is essential for warm-blooded animals, ensuring normal cellular and physiological function under conditions of environmental challenge. Thermogenesis in brown and beige adipose tissue is mainly controlled by norepinephrine, which is released from sympathetic nervous system in response to cold or dietary stimuli. The mitochondrial uncoupling protein 1 (UCP1) is responsible for the process whereby chemical energy is converted into heat in these adipocytes. Activation of these adipocytes leads to an increase in calorie consumption and is expected to improve overweight conditions, providing a potential strategy for treating obesity and its related metabolic disorders.
hsa04725	Cholinergic synapse	Acetylcholine (ACh) is a neurotransmitter widely distributed in the central (and also peripheral, autonomic and enteric) nervous system (CNS). In the CNS, ACh facilitates many functions, such as learning, memory, attention and motor control. When released in the synaptic cleft, ACh binds to two distinct types of receptors: Ionotropic nicotinic acetylcholine receptors (nAChR) and metabotropic muscarinic acetylcholine receptors (mAChRs). The activation of nAChR by ACh leads to the rapid influx of Na+ and Ca2+ and subsequent cellular depolarization. Activation of mAChRs is relatively slow (milliseconds to seconds) and, depending on the subtypes present (M1-M5), they directly alter cellular homeostasis of phospholipase C, inositol trisphosphate, cAMP, and free calcium. In the cleft, ACh may also be hydrolyzed by acetylcholinesterase (AChE) into choline and acetate. The choline derived from ACh hydrolysis is recovered by a presynaptic high-affinity choline transporter (CHT).
hsa04728	Dopaminergic synapse	Dopamine (DA) is an important and prototypical slow neurotransmitter in the mammalian brain, where it controls a variety of functions including locomotor activity, motivation and reward, learning and memory, and endocrine regulation. Once released from presynaptic axonal terminals, DA interacts with at least five receptor subtypes in the central nervous system (CNS), which have been divided into two groups: the D1-like receptors (D1Rs), comprising D1 and D5 receptors, both positively coupled to adenylyl cyclase and cAMP production, and the D2-like receptors (D2Rs), comprising D2, D3, and D4 receptors, whose activation results in inhibition of adenylyl cyclase and suppression of cAMP production. In addition, D1Rs and D2Rs modulate intracellular Ca2+ levels and a number of Ca2+ -dependent intracellular signaling processes. Through diverse cAMP- and Ca2+-dependent and - independent mechanisms, DA influences neuronal activity, synaptic plasticity, and behavior. Presynaptically localized D2Rs regulate synthesis and release of DA as the main autoreceptor of the dopaminergic system.
hsa04911	Insulin secretion	Pancreatic beta cells are specialised endocrine cells that continuously sense the levels of blood sugar and other fuels and, in response, secrete insulin to maintain normal fuel homeostasis. Glucose-induced insulin secretion and its potentiation constitute the principal mechanism of insulin release. Glucose is transported by the glucose transporter (GLUT) into the pancreatic beta-cell. Metabolism of glucose generates ATP, which inhibits ATP-sensitive K+ channels and causes voltage-dependent Ca2+ influx. Elevation of [Ca2+]i triggers exocytotic release of insulin granules. Insulin secretion is further regulated by several hormones and neurotransmitters. Peptide hormones, such as glucagon-like peptide 1 (GLP-1), increase cAMP levels and thereby potentiate insulin secretion via the combined action of PKA and Epac2. Achetylcholine (ACh), a major parasympathetic neurotransmitter, binds to Gq-coupled receptors and activates phospholipase C- (PLC-), and the stimulatory effects involve activation of protein kinase C (PKC), which stimulates exocytosis. In addition, ACh mobilizes intracellular Ca2+ by activation of IP3 receptors.
hsa04915	Estrogen signaling pathway	Estrogens are steroid hormones that regulate a plethora of physiological processes in mammals, including reproduction, cardiovascular protection, bone integrity, cellular homeostasis, and behavior. Estrogen mediates its cellular actions through two signaling pathways classified as nuclear-initiated steroid signalingand membrane-initiated steroid signaling. In the nuclearpathway, estrogen binds either ERalpha or ERbeta, which in turn translocates to the nucleus, binds DNA at ERE elements and activates the expression of ERE-dependent genes. In membranepathway, Estrogen can exert its actions through a subpopulation of ER at the plasma membrane (mER) or novel G-protein coupled E2 receptors (GPER). Upon activation of these receptors various signaling pathways (i.e. Ca2+, cAMP, protein kinase cascades) are rapidly activated and ultimately influence downstream transcription factors.
hsa04916	Melanogenesis	Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents. The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortic peptides. MC1R activates the cyclic AMP (cAMP) response-element binding protein (CREB). Increased expression of MITF and its activation by phosphorylation (P) stimulate the transcription of tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerase (DCT), which produce melanin. Melanin synthesis takes place within specialized intracellular organelles named melanosomes. Melanin-containing melanosomes then move from the perinuclear region to the dendrite tips and are transferred to keratinocytes by a still not well-characterized mechanism.
hsa04918	Thyroid hormone synthesis	Thyroid hormones triiodothyronine (T3) and thyroxine (T4) are essential for normal development, growth and metabolic homeostasis in all vertebrates, and synthesized in the thyroid gland. The functional unit of the thyroid gland is the follicle, delimited by a monolayer of thyrocytes. Polarized thyrocytes surround the follicular lumen; with their basal and apical surfaces facing the bloodstream and the lumen, respectively. To synthesize thyroid hormones, thyrocytes take up iodide at their basal side and concentrate it into the lumen. They also secrete in this lumen the specialized protein thyroglobulin (TG) which serves as a store for the hormones. In the follicular lumen oxidation of iodine, iodination of tyrosines (MIT, 3-monoiodotyrosine; DIT, 3,5-diiodotyrosine) and coupling of iodotyrosines takes place on tyrosine residues in TG, resulting in T3 and T4 synthesis. Iodinated TG is resorbed through the apical membrane and degraded to form T3/T4 in lysosomes; the T3/T4 is then secreted through the basal membrane.
hsa04922	Glucagon signaling pathway	Glucagon is conventionally regarded as a counterregulatory hormone for insulin and plays a critical anti-hypoglycemic role by maintaining glucose homeostasis in both animals and humans. To increase blood glucose, glucagon promotes hepatic glucose output by increasing glycogenolysis and gluconeogenesis and by decreasing glycogenesis and glycolysis in a concerted fashion via multiple mechanisms. Glucagon also stimulates hepatic mitochondrial beta-oxidation to supply energy for glucose production. Glucagon performs its main effect via activation of adenylate cyclase. The adenylate-cyclase-derived cAMP activates protein kinase A (PKA), which then phosphorylates downstream targets, such as cAMP response element binding protein (CREB) and the bifunctional enzyme 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase (one of the isoforms being PFK/FBPase 1, encoded by PFKFB1).
hsa04924	Renin secretion	The aspartyl-protease renin is the key regulator of the renin-angiotensin-aldosterone system, which is critically involved in extracellular fluid volume and blood pressure homeostasis of the body. Renin is synthesized, stored in, and released into circulation by the juxtaglomerular (JG) cells of the kidney. Secretion of renin from JG cells at the organ level is controlled by the four main mechanisms: the sympathetic nervous system, the local JG apparatus baroreflex, the macula densa mechanism, and several hormones acting locally within the JG apparatus. Renin secretion at the level of renal JG cells appears to be controlled mainly by classic second messengers, namely cAMP, cGMP, and free cytosolic calcium concentration. While cAMP generally stimulates renin release and the intracellular calcium concentration suppresses the exocytosis of renin, the effects of cGMP in the regulation of the renin system are more complex as it both may stimulate or inhibit renin release.
hsa04925	Aldosterone synthesis and secretion	Aldosterone is a steroid hormone synthesized in and secreted from the outer layer of the adrenal cortex, the zona glomerulosa. Aldosterone plays an important role in the regulation of systemic blood pressure through the absorption of sodium and water. Angiotensin II (Ang II), potassium (K+) and adrenocorticotropin (ACTH) are the main extracellular stimuli which regulate aldosterone secretion. These physiological agonists all converge on two major intracellular signaling pathways: calcium (Ca2+) mobilization and an increase in cAMP production. The increase in cytosolic calcium levels activates calcium/calmodulin- dependent protein kinases (CaMK), and the increased cAMP levels stimulate the activity of cAMP-dependent protein kinase, or protein kinase A (PKA). The activated CaMK, and possibly PKA, activates transcription factors (NURR1 and NGF1B, CREB) to induce StAR and CYP11B2 expression, the early and late rate- limiting steps in aldosterone biosynthesis, respectively, thereby stimulating aldosterone secretion.
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.
hsa04927	Cortisol synthesis and secretion	Cortisol is the main endogenous glucocorticoid, which affects a plethora of physiological functions, e.g., lipid and glucose metabolism, metabolic homeostasis and adaptation to stress. Cortisol production is primarily regulated by corticotropin (ACTH) in zona fasciculata. The stimulatory effect of ACTH on cortisol synthesis depends on cAMP dependent signaling, but also involves membrane depolarization and increased cytosolic Ca2+. Each of cAMP and Ca2+ induces the expression of StAR, stimulating intramitochondrial cholesterol transfer, as well as the steroidogenic enzymes in the pathway from cholesterol to cortisol (e.g., CHE, CYP17A1, CYP11B1).
hsa04928	Parathyroid hormone synthesis, secretion and action	Parathyroid hormone (PTH) is a key regulator of calcium and phosphorus homeostasis. The principal regulators of PTH secretion are extracellular ionized calcium (Ca2+) and 1,25-dihydroxyvitamin D (1,25(OH)2D3). Under conditions of dietary Ca restriction, a decrement in serum Ca concentration induces release of PTH from the parathyroid gland. PTH acts on bone and kidney to stimulate bone turnover, increase the circulating levels of 1,25(OH)2D3 and calcium and inhibit the reabsorption of phosphate from the glomerular filtrate. This hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R). PTH1R primarily activates two sub-types of heterotrimeric Gproteins: Gs and Gq , which in turn regulate the activity of adenylyl cyclases and phospholipase C (PLC) that control the flow of cAMP/PKA and IP/PKC signaling cascades, respectively.
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.
hsa04934	Cushing syndrome	Cushing syndrome (CS) is a rare disorder resulting from prolonged exposure to excess glucocorticoids via exogenous and endogenous sources. The typical clinical features of CS are related to hypercortisolism and include accumulation of central fat, moon facies, neuromuscular weakness, osteoporosis or bone fractures, metabolic complications, and mood changes. Traditionally, endogenous CS is classified as adrenocorticotropic hormone (ACTH)-dependent (about 80%) or ACTH- independent (about 20%). Among ACTH-dependent forms, pituitary corticotroph adenoma (Cushing's disease) is most common. Most pituitary tumors are sporadic, resulting from monoclonal expansion of a single mutated cell. Recently recurrent activating somatic driver mutations in the ubiquitin-specific protease 8 gene (USP8) were identified in almost half of corticotroph adenoma. Germline mutations in MEN1 (encoding menin), AIP (encoding aryl-hydrocarbon receptor-interacting protein), PRKAR1A (encoding cAMP-dependent protein kinase type I alpha regulatory subunit) and CDKN1B (encoding cyclin-dependent kinase inhibitor 1B; also known as p27 Kip1) have been identified in familial forms of pituitary adenomas. However, the frequency of familial pituitary adenomas is less than 5% in patients with pituitary adenomas. Among ACTH-independent CS, adrenal adenoma is most common. Rare adrenal causes of CS include primary bilateral macronodular adrenal hyperplasia (BMAH) or primary pigmented nodular adrenocortical disease (PPNAD).
hsa04962	Vasopressin-regulated water reabsorption	In the kidney, the antidiuretic hormone vasopressin (AVP) is a critical regulator of water homeostasis by controlling the water movement from lumen to the interstitium for water reabsorption and adjusting the urinary water excretion. In normal physiology, AVP is secreted into the circulation by the posterior pituitary gland, in response to an increase in serum osmolality or a decrease in effective circulating volume. When reaching the kidney, AVP binds to V2 receptors on the basolateral surface of the collecting duct epithelium, triggering a G-protein-linked signaling cascade, which leads to water channel aquaporin-2 (AQP2) vesicle insertion into the apical plasma membrane. This results in higher water permeability in the collecting duct and, driven by an osmotic gradient, pro-urinary water then passes the membrane through AQP2 and leaves the cell on the basolateral side via AQP3 and AQP4 water channels, which are constitutively expressed on the basolateral side of these cells. When isotonicity is restored, reduced blood AVP levels results in AQP2 internalization, leaving the apical membrane watertight again.
hsa05016	Huntington disease	Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). The symptoms are choreiform, involuntary movements, personality changes and dementia. HD is caused by a CAG repeat expansion in the IT15gene, which results in a long stretch of polyglutamine close to the amino-terminus of the HD protein huntingtin (Htt). Mutant Htt (mHtt) has effects both in the cytoplasm and in the nucleus. In the cytoplasm, full-length mHtt can interfere with BDNF vesicular transport on microtubules. This mutant protein also may lead to abnormal endocytosis and secretion in neurons, because normal Htt form a complex with the proteins Hip1, clathrin and AP2 that are involved in endocytosis. In addition, mHtt affects Ca2+ signaling by sensitizing InsP3R1 to activation by InsP3, stimulating NMDAR activity, and destabilizing mitochondrial Ca2+ handling. The mHtt translocates to the nucleus, where it forms intranuclear inclusions. Nuclear toxicity is believed to be caused by interference with gene transcription, leading to loss of transcription of neuroprotective molecules such as BDNF. While mHtt binds to p53 and upregulates levels of nuclear p53 as well as p53 transcriptional activity. Augmented p53 mediates mitochondrial dysfunction.
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.
hsa05031	Amphetamine addiction	Amphetamine is a psychostimulant drug that exerts persistent addictive effects. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the brain reward circuit. Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. Acute administration of amphetamine induces phosphorylation of cAMP response element-binding protein (CREB) and expression of a number of immediate early genes (IEGs), such as c-fos. The IEGs is likely to initiate downstream molecular events, which may have important roles in the induction and maintenance of addictive states. Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
hsa05034	Alcoholism	Alcoholism, also called dependence on alcohol (ethanol), is a chronic relapsing disorder that is progressive and has serious detrimental health outcomes. As one of the primary mediators of the rewarding effects of alcohol, dopaminergic ventral tegmental area (VTA) projections to the nucleus accumbens (NAc) have been identified. Acute exposure to alcohol stimulates dopamine release into the NAc, which activates D1 receptors, stimulating PKA signaling and subsequent CREB-mediated gene expression, whereas chronic alcohol exposure leads to an adaptive downregulation of this pathway, in particular of CREB function. The decreased CREB function in the NAc may promote the intake of drugs of abuse to achieve an increase in reward and thus may be involved in the regulation of positive affective states of addiction. PKA signaling also affects NMDA receptor activity and may play an important role in neuroadaptation in response to chronic alcohol exposure.
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.
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.
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.
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.
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.
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.

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-111931	PKA-mediated phosphorylation of CREB.	Cyclic adenosine 3',5'-monophosphate (cAMP) induces gene transcription through activation of cAMP-dependent protein kinase (PKA), and subsequent phosphorylation of the transcription factor cAMP response element-binding protein, CREB, at serine-133
R-HSA-111932	CaMK IV-mediated phosphorylation of CREB.	The Ca2+-calmodulin-dependent protein kinase (CaM kinase) cascade includes three kinases: CaM-kinase kinase (CaMKK); and the CaM kinases CaMKI and CaMKIV, which are phosphorylated and activated by CaMKK. Members of this cascade respond to elevation of intracellular Ca2+ levels. CaMKK and CaMKIV localize both to the nucleus and to the cytoplasm, whereas CaMKI is only cytosolic. Nuclear CaMKIV regulates transcription through phosphorylation of several transcription factors, including CREB. In the cytoplasm, there is extensive cross-talk between CaMKK, CaMKIV and other signaling cascades, including those that involve the cAMP-dependent kinase (PKA), MAP kinases and protein kinase B (PKB/Akt)
R-HSA-198693	AKT phosphorylates targets in the nucleus.	After translocation into the nucleus, AKT can phosphorylate a number of targets there such as CREB, forkhead transcription factors, SRK and NUR77
R-HSA-199920	CREB phosphorylation.	Nerve growth factor (NGF) activates multiple signalling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133. CREB phosphorylation at serine 133 is a crucial event in neurotrophin signalling, being mediated by ERK/RSK, ERK/MSK1 and p38/MAPKAPK2 pathways. Several kinases, such as MSK1, RSK1/2/3 (MAPKAPK1A/B/C), and MAPKAPK2, are able to directly phosphorylate CREB at S133. MSK1 is also able to activate ATF (Cyclic-AMP-dependent transcription factor). However, the NGF-induced CREB phosphorylation appears to correlate better with activation of MSK1 rather than RSK1/2/3, or MAPKAPK2. In retrograde signalling, activation of CREB occurs within 20 minutes after neurotrophin stimulation of distal axons
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis.	Phosphorylated PPARGC1A (PGC-1alpha) does not bind DNA directly but instead interacts with other transcription factors, notably NRF1 and NRF2 (via HCF1). NRF1 and NRF2 together with PPARGC1A activate the transcription of nuclear-encoded, mitochondrially targeted proteins such as TFB2M, TFB1M, and TFAM. PGC-1beta and PPRC appear to act similarly to PGC-1alpha but have not been as well studied. Transcription of PPARGC1A itself is upregulated by CREB1 (in response to calcium), MEF2C/D, ATF2, and PPARGC1A. Transcription of PPARGC1A is repressed by NR1D1 (REV-ERBA)
R-HSA-2197563	NOTCH2 intracellular domain regulates transcription.	In the nucleus, NICD2 forms a complex with RBPJ (CBF1, CSL) and MAML (mastermind). NICD2:RBPJ:MAML complex activates transcription from RBPJ-binding promoter elements (RBEs) (Wu et al. 2000). Besides NICD2, RBPJ and MAML, NOTCH2 coactivator complex likely includes other proteins, shown as components of the NOTCH1 coactivator complex. NOTCH2 coactivator complex directly stimulates transcription of HES1 and HES5 genes (Shimizu et al. 2002), both of which are known NOTCH1 targets.The promoter of FCER2 (CD23A) contains several RBEs that are occupied by NOTCH2 but not NOTCH1 coactivator complexes, and NOTCH2 activation stimulates FCER2 transcription. Overexpression of FCER2 (CD23A) is a hallmark of B-cell chronic lymphocytic leukemia (B-CLL) and correlates with the malfunction of apoptosis, which is thought be an underlying mechanism of B-CLL development. The Epstein-Barr virus protein EBNA2 can also activate FCER2 transcription through RBEs, possibly by mimicking NOTCH2 signaling (Hubmann et al. 2002).NOTCH2 coactivator complex occupies the proximal RBE of the GZMB (granzyme B) promoter and at the same time interacts with phosphorylated CREB1, bound to an adjacent CRE site. EP300 transcriptional coactivator is also recruited to this complex through association with CREB1 (Maekawa et al. 2008). NOTCH2 coactivator complex together with CREBP1 and EP300 stimulates transcription of GZMB (granzyme B), which is important for the cytotoxic function of CD8+ T-cells (Maekawa et al. 2008).There are indications that NOTCH2 genetically interacts with hepatocyte nuclear factor 1-beta (HNF1B) in kidney development (Massa et al. 2013, Heliot et al. 2013) and with hepatocyte nuclear factor 6 (HNF6) in bile duct formation (Vanderpool et al. 2012), but the exact nature of these genetic interactions has not been defined
R-HSA-375165	NCAM signaling for neurite out-growth.	The neural cell adhesion molecule, NCAM, is a member of the immunoglobulin (Ig) superfamily and is involved in a variety of cellular processes of importance for the formation and maintenance of the nervous system. The role of NCAM in neural differentiation and synaptic plasticity is presumed to depend on the modulation of intracellular signal transduction cascades. NCAM based signaling complexes can initiate downstream intracellular signals by at least two mechanisms: (1) activation of FGFR and (2) formation of intracellular signaling complexes by direct interaction with cytoplasmic interaction partners such as Fyn and FAK. Tyrosine kinases Fyn and FAK interact with NCAM and undergo phosphorylation and this transiently activates the MAPK, ERK 1 and 2, cAMP response element binding protein (CREB) and transcription factors ELK and NFkB. CREB activates transcription of genes which are important for axonal growth, survival, and synaptic plasticity in neurons.NCAM1 mediated intracellular signal transduction is represented in the figure below. The Ig domains in NCAM1 are represented in orange ovals and Fn domains in green squares. The tyrosine residues susceptible to phosphorylation are represented in red circles and their positions are numbered. Phosphorylation is represented by red arrows and dephosphorylation by yellow. Ig, Immunoglobulin domain; Fn, Fibronectin domain; Fyn, Proto-oncogene tyrosine-protein kinase Fyn; FAK, focal adhesion kinase; RPTPalpha, Receptor-type tyrosine-protein phosphatase; Grb2, Growth factor receptor-bound protein 2; SOS, Son of sevenless homolog; Raf, RAF proto-oncogene serine/threonine-protein kinase; MEK, MAPK and ERK kinase; ERK, Extracellular signal-regulated kinase; MSK1, Mitogen and stress activated protein kinase 1; CREB, Cyclic AMP-responsive element-binding protein; CRE, cAMP response elements
R-HSA-400253	Circadian Clock.	At the center of the mammalian circadian clock is a negative transcription/translation-based feedback loop: The BMAL1:CLOCK/NPAS2 (ARNTL:CLOCK/NPAS2) heterodimer transactivates CRY and PER genes by binding E-box elements in their promoters; the CRY and PER proteins then inhibit transactivation by BMAL1:CLOCK/NPAS2. BMAL1:CLOCK/NPAS2 activates transcription of CRY, PER, and several other genes in the morning. Levels of PER and CRY proteins rise during the day and inhibit expression of CRY, PER, and other BMAL1:CLOCK/NPAS2-activated genes in the afternoon and evening. During the night CRY and PER proteins are targeted for degradation by phosphorylation and polyubiquitination, allowing the cycle to commence again in the morning. Transcription of the BMAL1 (ARNTL) gene is controlled by ROR-alpha and REV-ERBA (NR1D1), both of which are targets of BMAL1:CLOCK/NPAS2 in mice and both of which compete for the same element (RORE) in the BMAL1 promoter. ROR-alpha (RORA) activates transcription of BMAL1; REV-ERBA represses transcription of BMAL1. This mutual control forms a secondary, reinforcing loop of the circadian clock. REV-ERBA shows strong circadian rhythmicity and confers circadian expression on BMAL1. BMAL1 can form heterodimers with either CLOCK or NPAS2, which act redundantly but show different tissue specificity. The BMAL1:CLOCK and BMAL1:NPAS2 heterodimers activate a set of genes that possess E-box elements (consensus CACGTG) in their promoters. This confers circadian expression on the genes. The PER genes (PER1, PER2, PER3) and CRY genes (CRY1, CRY2) are among those activated by BMAL1:CLOCK and BMAL1:NPAS2. PER and CRY mRNA accumulates during the morning and the proteins accumulate during the afternoon. PER and CRY proteins form complexes in the cytosol and these are bound by either CSNK1D or CSNK1E kinases which phosphorylate PER and CRY. The phosphorylated PER:CRY:kinase complex is translocated into the nucleus due to the nuclear localization signal of PER and CRY. Within the nucleus the PER:CRY complexes bind BMAL1:CLOCK and BMAL1:NPAS2, inhibiting their transactivation activity and their phosphorylation. This reduces expression of the target genes of BMAL1:CLOCK and BMAL1:NPAS2 during the afternoon and evening. PER:CRY complexes also traffic out of the nucleus into the cytosol due to the nuclear export signal of PER. During the night PER:CRY complexes are polyubiquitinated and degraded, allowing the cycle to begin again. Phosphorylated PER is bound by Beta-TrCP1, a cytosolic F-box type component of some SCF E3 ubiquitin ligases. CRY is bound by FBXL3, a nucleoplasmic F-box type component of some SCF E3 ubiquitin ligases. Phosphorylation of CRY1 by Adenosine monophosphate-activated kinase (AMPK) enhances degradation of CRY1. PER and CRY are subsequently polyubiquitinated and proteolyzed by the 26S proteasome.The circadian clock is cell-autonomous and some, but not all cells of the body exhibit circadian rhythms in metabolism, cell division, and gene transcription. The suprachiasmatic nucleus (SCN) in the hypothalamus is the major clock in the body and receives its major input from light (via retinal neurons) and a minor input from nutrient intake. The SCN and other brain tissues determine waking and feeding cycles and influence the clocks in other tissues by hormone secretion and nervous stimulation. Independently of the SCN, other tissues such as liver receive inputs from signals from the brain and from nutrients
R-HSA-442717	CREB phosphorylation through the activation of CaMKK.	Transient increase in intracellular Ca2+ concentration after NMDA receptor activation leads to the activation of the CaMKIV via the activation of CaM-kinase kinase. CaM-kinase kinase and CaMKIV are both activated upon binding Ca2+/Calmodulin after Ca2+ influx through activated NMDA receptor
R-HSA-442720	CREB phosphorylation through the activation of Adenylate Cyclase.	Ca2+ signal generated through NMDA receptor in the post-synaptic neuron activates adenylate cyclase signal transduction, leading to the activation of PKA and phosphorylation and activation of CREB-induced transcription.\nThe isoforms of adenylate cyclase that are activated by Ca2+ in the brain are I, III and IX
R-HSA-442729	CREB phosphorylation through the activation of CaMKII.	Ca2+ signal generated through NMDA receptor in the post-synaptic neuron activates adenylate cyclase signal transduction, leading to the activation of PKA and phosphorylation and activation of CREB-induced transcription.\nThe isoforms of adenylate cyclase that are activated by Ca2+ in the brain are I, III and IX
R-HSA-442742	CREB phosphorylation through the activation of Ras.	Ca2+ influx through the NMDA receptor initiates subsequent molecular pathways that have a defined role in establishing long-lasting synaptic changes. The molecular signaling initiated by a rise in Ca2+ within the spine leads to phosphorylation of Cyclic AMP Response Element binding protein (CREB) at serine 133 which is involved in the transcription of genes that results in long lasting changes in the synapse. The phosphorylation of CREB by increased Ca2+ can be brought about by distinct molecular pathways that may involve MAP kinase, activation of adenylate cyclase, activation of CaMKII and/or the activation of CaMKIV
R-HSA-5674400	Constitutive Signaling by AKT1 E17K in Cancer.	While AKT1 gene copy number, expression level and phosphorylation are often increased in cancer, only one low frequency point mutation has been repeatedly reported in cancer and functionally studied. This mutation represents a substitution of a glutamic acid residue with lysine at position 17 of AKT1, and acts by enabling AKT1 to bind PIP2. PIP2-bound AKT1 is phosphorylated by TORC2 complex and by PDPK1 that is always present at the plasma membrane, due to low affinity for PIP2. Therefore, E17K substitution abrogates the need for PI3K in AKT1 activation (Carpten et al. 2007, Landgraf et al. 2008)
R-HSA-881907	Gastrin-CREB signalling pathway via PKC and MAPK.	Gastrin is a hormone whose main function is to stimulate secretion of hydrochloric acid by the gastric mucosa, which results in gastrin formation inhibition. This hormone also acts as a mitogenic factor for gastrointestinal epithelial cells. Gastrin has two biologically active peptide forms, G34 and G17.Gastrin gene expression is upregulated in both a number of pre-malignant conditions and in established cancer through a variety of mechanisms. Depending on the tissue where it is expressed and the level of expression, differential processing of the polypeptide product leads to the production of different biologically active peptides. In turn, acting through the classical gastrin cholecystokinin B receptor CCK-BR, its isoforms and alternative receptors, these peptides trigger signalling pathways which influence the expression of downstream genes that affect cell survival, angiogenesis and invasion (Wank 1995, de Weerth et al

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Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
AKT1	Biochemical Activity	physical	9829964, (Europe PMC)	NA	BioGRID
ANKRD17	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
ARHGAP22	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
ARIH1	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
ARNT	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
ARV1	Affinity Capture-MS	physical	26186194, (Europe PMC)	NA	BioGRID
ATF1	Affinity Capture-MS, peptide array, pull down, tandem affinity purification	association, direct interaction, physical, physical association	20102225, 25609649, (Europe PMC)	0.70	BioGRID, IntAct, MINT
ATF2	Co-fractionation	physical	26344197, (Europe PMC)	NA	BioGRID
ATF6	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
ATF7	Co-fractionation	physical	22939629, (Europe PMC)	NA	BioGRID
ATF7IP	Two-hybrid	physical	20936779, (Europe PMC)	NA	BioGRID
ATM	Biochemical Activity	physical	15073328, (Europe PMC)	NA	BioGRID
ATR	Biochemical Activity, protein kinase assay	phosphorylation reaction, physical	16293623, (Europe PMC)	0.44	BioGRID, IntAct
ATXN3	Affinity Capture-Western	physical	11572863, (Europe PMC)	NA	BioGRID
BRCA1	Phenotypic Enhancement, pull down	direct interaction, genetic	10945975, 9926942, (Europe PMC)	0.44	BioGRID, IntAct, MINT
C16orf71	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
C5orf24	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
CAMK2A	Biochemical Activity	physical	8663317, (Europe PMC)	NA	BioGRID
CARM1	Affinity Capture-Western	physical	16330542, (Europe PMC)	NA	BioGRID
CCDC6	Affinity Capture-Western, Biochemical Activity, Co-localization, Reconstituted Complex	physical	20498639, (Europe PMC)	NA	BioGRID
CEBPB	Affinity Capture-Western, Reconstituted Complex	physical	12773552, (Europe PMC)	NA	BioGRID
CHD3	Two-hybrid, two hybrid pooling approach	physical, physical association	16169070, (Europe PMC)	0.37	BioGRID, IntAct
CHD8	Two-hybrid	physical	20936779, (Europe PMC)	NA	BioGRID
CREB1	FRET, peptide array, tandem affinity purification	association, direct interaction, physical	20102225, 23661758, 25609649, (Europe PMC)	0.59	BioGRID, IntAct, MINT
CREBBP	Affinity Capture-Western, Co-crystal Structure, FRET, Far Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, pull down	physical, physical association	10848610, 10866654, 11259575, 11313407, 11564156, 12196545, 12198160, 12933667, 15073328, 15585582, 15691881, 16799563, 17476304, 17707401, 18599546, 20403362, 20541704, 27789289, 7870179, 8028671, 8413673, 8663317, 9413984, 9786917, 9829964, (Europe PMC)	0.70	BioGRID, IntAct, MINT
CREM	Affinity Capture-MS, Affinity Capture-Western, tandem affinity purification	association, physical	22531917, 25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
CRTC1	Two-hybrid	physical	20936779, (Europe PMC)	NA	BioGRID
CSGALNACT2	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
CTNNB1	Affinity Capture-Western	physical	17962194, (Europe PMC)	NA	BioGRID
DACH1	Affinity Capture-Western	physical	16980615, (Europe PMC)	NA	BioGRID
DAXX	Affinity Capture-Western, Two-hybrid	physical	22185778, (Europe PMC)	NA	BioGRID
DEAF1	Affinity Capture-Western	physical	23846693, (Europe PMC)	NA	BioGRID
DNMT3B	Affinity Capture-Western	physical	19786833, (Europe PMC)	NA	BioGRID
DNMT3L	Reconstituted Complex	physical	24952347, (Europe PMC)	NA	BioGRID
DR1	Co-fractionation	physical	22939629, (Europe PMC)	NA	BioGRID
EP300	Affinity Capture-Western, Co-localization, Far Western, Reconstituted Complex, anti bait coimmunoprecipitation	physical, physical association	10506141, 11313407, 12665587, 17476304, 21212407, 21268077, 22787115, 7870179, (Europe PMC)	0.40	BioGRID, IntAct, MINT
ERG28	Two-hybrid	physical	16169070, (Europe PMC)	NA	BioGRID
FAM192A	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FEZ1	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
FHL2	Affinity Capture-Western, Two-hybrid	physical	11046156, (Europe PMC)	NA	BioGRID
FHL3	Affinity Capture-Western, Two-hybrid	physical	11046156, (Europe PMC)	NA	BioGRID
FHL5	Affinity Capture-Western, Two-hybrid	physical	11046156, (Europe PMC)	NA	BioGRID
FOXA1	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FOXC1	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FOXC2	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FOXE1	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
GLI2	Reconstituted Complex	physical	10074179, (Europe PMC)	NA	BioGRID
GPS2	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
GSK3A	Biochemical Activity	physical	14635195, (Europe PMC)	NA	BioGRID
GSK3B	Biochemical Activity	physical	14635195, (Europe PMC)	NA	BioGRID
GTF2A1	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
HDAC1	Affinity Capture-Western, Reconstituted Complex	physical	12567184, 20473547, (Europe PMC)	NA	BioGRID
HDAC2	Affinity Capture-Western	physical	12567184, 20473547, (Europe PMC)	NA	BioGRID
HDAC8	Affinity Capture-Western	physical	19070599, (Europe PMC)	NA	BioGRID
HIPK3	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
HIST1H2BA	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HIST1H2BJ	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HIST1H3A	Affinity Capture-Western	physical	12933667, (Europe PMC)	NA	BioGRID
HIST1H3B	Affinity Capture-Western	physical	19279000, (Europe PMC)	NA	BioGRID
HIST3H3	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HMGA1	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HMGA2	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HNF1B	Two-hybrid	physical	9671480, (Europe PMC)	NA	BioGRID
HOXD13	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HTT	Affinity Capture-Western	physical	16207717, (Europe PMC)	NA	BioGRID
IFT74	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
JUN	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, tandem affinity purification	association, physical	2138276, 25609649, (Europe PMC)	0.46	BioGRID, IntAct, MINT
JUND	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
KAT5	Affinity Capture-Western, Reconstituted Complex	physical	10720489, (Europe PMC)	NA	BioGRID
KCNIP3	Affinity Capture-Western	physical	12198160, (Europe PMC)	NA	BioGRID
KIAA2026	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
LAX1	Affinity Capture-MS	physical	26186194, (Europe PMC)	NA	BioGRID
MAPK14	Affinity Capture-Western	physical	23532963, (Europe PMC)	NA	BioGRID
MECP2	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
MEIS1	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, chromatin immunoprecipitation assay	association, physical, physical association	20159610, 20541704, (Europe PMC)	0.68	BioGRID, IntAct
MIA2	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
MTF2	Two-hybrid	physical	20211142, (Europe PMC)	NA	BioGRID
MYOD1	Affinity Capture-Western	physical	12665587, (Europe PMC)	NA	BioGRID
NCOR1	Affinity Capture-Western	physical	24315104, (Europe PMC)	NA	BioGRID
NFATC1	Affinity Capture-MS, Affinity Capture-Western, pull down, tandem affinity purification	association, physical, physical association	25609649, 27637333, (Europe PMC)	0.58	BioGRID, IntAct, MINT
NFATC2	Affinity Capture-MS, Affinity Capture-Western, tandem affinity purification	association, physical, physical association	25609649, 27637333, (Europe PMC)	0.50	BioGRID, IntAct, MINT
NFIA	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
NFIC	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
NFIL3	Affinity Capture-MS, peptide array, tandem affinity purification	association, direct interaction, physical	20102225, 25609649, 28514442, (Europe PMC)	0.59	BioGRID, IntAct, MINT
NFIX	Affinity Capture-MS, tandem affinity purification	physical, physical association	25609649, (Europe PMC)	0.40	BioGRID, IntAct, MINT
NFYA	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
NIT2	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
NR3C1	Affinity Capture-Western, Reconstituted Complex	physical	20203101, 8449898, (Europe PMC)	NA	BioGRID
NR5A2	Affinity Capture-Western, Two-hybrid	physical	18191017, (Europe PMC)	NA	BioGRID
ORC6	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
PBX2	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PFDN4	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
PIAS1	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
POGZ	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
POLR2A	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
POU2F1	Affinity Capture-Western, Reconstituted Complex	physical	12391146, (Europe PMC)	NA	BioGRID
PPP1CA	Biochemical Activity	physical	20498639, (Europe PMC)	NA	BioGRID
PRKACA	Reconstituted Complex	physical	11500364, (Europe PMC)	NA	BioGRID
PRKG1	Biochemical Activity	physical	11175347, (Europe PMC)	NA	BioGRID
PRR20E	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
RAB1A	Two-hybrid, two hybrid pooling approach	physical, physical association	16169070, (Europe PMC)	0.37	BioGRID, IntAct
RBBP4	Two-hybrid	physical	10866654, (Europe PMC)	NA	BioGRID
RECQL	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
RECQL5	Two-hybrid, two hybrid pooling approach	physical, physical association	16169070, (Europe PMC)	0.37	BioGRID, IntAct
RFX3	Two-hybrid	physical	20211142, (Europe PMC)	NA	BioGRID
RGS13	Reconstituted Complex	physical	20974683, (Europe PMC)	NA	BioGRID
RNF111	Two-hybrid	physical	20936779, (Europe PMC)	NA	BioGRID
RPS6KA1	Proximity Label-MS, protein kinase assay	phosphorylation reaction, physical	16282323, 21832046, (Europe PMC)	0.44	BioGRID, IntAct
RPS6KA4	Biochemical Activity	physical	9792677, (Europe PMC)	NA	BioGRID
RPS6KA5	Biochemical Activity, Reconstituted Complex	physical	11500364, 9687510, 9873047, (Europe PMC)	NA	BioGRID
SIRT1	Affinity Capture-MS	physical	23382074, (Europe PMC)	NA	BioGRID
SMARCA4	Affinity Capture-Western	physical	16675956, (Europe PMC)	NA	BioGRID
SMARCA5	Affinity Capture-Western	physical	16675956, (Europe PMC)	NA	BioGRID
SRA1	Far Western	physical	20398657, (Europe PMC)	NA	BioGRID
SREBF2	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
STAT3	Affinity Capture-Western	physical	26508788, (Europe PMC)	NA	BioGRID
SUZ12	Two-hybrid	physical	20211142, (Europe PMC)	NA	BioGRID
SYCP1	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
TAF4	Affinity Capture-Western	physical	15703171, (Europe PMC)	NA	BioGRID
TOX4	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
TP53	Affinity Capture-Western, Co-localization, Reconstituted Complex, proximity ligation assay	physical, physical association	10848610, 16611888, 21295542, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
TRAF3	Affinity Capture-Western	physical	26755589, (Europe PMC)	NA	BioGRID
TRIM11	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
TRIM22	Two-hybrid	physical	20211142, (Europe PMC)	NA	BioGRID
TRIM5	Affinity Capture-MS	physical	28514442, (Europe PMC)	NA	BioGRID
TRPV5	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
TSSK4	Two-hybrid, protein kinase assay, pull down, two hybrid	phosphorylation reaction, physical, physical association	15964553, 21988832, (Europe PMC)	0.69	BioGRID, IntAct
TTF2	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
TUFT1	Affinity Capture-MS	physical	26186194, 28514442, (Europe PMC)	NA	BioGRID
UBE2I	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
VIM	Two-hybrid, two hybrid pooling approach	physical, physical association	16169070, (Europe PMC)	0.37	BioGRID, IntAct
XRCC1	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
YAP1	Affinity Capture-Western	physical	23532963, (Europe PMC)	NA	BioGRID
YY1	Reconstituted Complex, Two-hybrid	physical	7769693, (Europe PMC)	NA	BioGRID
ZBTB21	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
ZHX1	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
ZMYM2	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
ZNF131	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
ZNF35	Two-hybrid	physical	20211142, (Europe PMC)	NA	BioGRID
ZNF436	Two-hybrid	physical	20211142, (Europe PMC)	NA	BioGRID
ZNF451	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
ZNF92	Two-hybrid	physical	20211142, (Europe PMC)	NA	BioGRID

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ARNT	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
ATF1	Affinity Capture-MS, peptide array, pull down, tandem affinity purification	association, direct interaction, physical, physical association	20102225, 25609649, (Europe PMC)	0.70	BioGRID, IntAct, MINT
ATF6	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
ATR	Biochemical Activity, protein kinase assay	phosphorylation reaction, physical	16293623, (Europe PMC)	0.44	BioGRID, IntAct
BACH1	peptide array	direct interaction	20102225, (Europe PMC)	0.44	IntAct
BRCA1	Phenotypic Enhancement, pull down	direct interaction, genetic	10945975, 9926942, (Europe PMC)	0.44	BioGRID, IntAct, MINT
C5orf24	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
CHD3	Two-hybrid, two hybrid pooling approach	physical, physical association	16169070, (Europe PMC)	0.37	BioGRID, IntAct
CHD8	two hybrid pooling approach	physical association	20936779, (Europe PMC)	0.37	IntAct
CREB1	FRET, peptide array, tandem affinity purification	association, direct interaction, physical	20102225, 23661758, 25609649, (Europe PMC)	0.59	BioGRID, IntAct, MINT
CREB3L3	peptide array	direct interaction	20102225, (Europe PMC)	0.44	IntAct
CREBBP	Affinity Capture-Western, Co-crystal Structure, FRET, Far Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, pull down	physical, physical association	10848610, 10866654, 11259575, 11313407, 11564156, 12196545, 12198160, 12933667, 15073328, 15585582, 15691881, 16799563, 17476304, 17707401, 18599546, 20403362, 20541704, 27789289, 7870179, 8028671, 8413673, 8663317, 9413984, 9786917, 9829964, (Europe PMC)	0.70	BioGRID, IntAct, MINT
CREM	Affinity Capture-MS, Affinity Capture-Western, tandem affinity purification	association, physical	22531917, 25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
CRTC1	two hybrid array, two hybrid pooling approach, two hybrid prey pooling approach	physical association	20936779, (Europe PMC)	0.62	IntAct
EBI-10049001	electrophoretic mobility supershift assay	physical association	15841182, (Europe PMC)	0.40	IntAct
EBI-10902648	electrophoretic mobility supershift assay	physical association	24223725, (Europe PMC)	0.40	IntAct
EBI-10902691	electrophoretic mobility supershift assay	physical association	24223725, (Europe PMC)	0.40	IntAct
ENSG00000112715	chromatin immunoprecipitation assay	association	26350463, (Europe PMC)	0.35	IntAct
EP300	Affinity Capture-Western, Co-localization, Far Western, Reconstituted Complex, anti bait coimmunoprecipitation	physical, physical association	10506141, 11313407, 12665587, 17476304, 21212407, 21268077, 22787115, 7870179, (Europe PMC)	0.40	BioGRID, IntAct, MINT
ERG28	two hybrid pooling approach	physical association	16169070, (Europe PMC)	0.37	IntAct
FAM192A	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FOXA1	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FOXC1	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FOXC2	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FOXE1	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
GTF2A1	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
HIPK3	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
HIST1H2BA	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HIST1H2BJ	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HIST3H3	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HMGA1	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HMGA2	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HOXD13	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HPS6	two hybrid pooling approach	physical association	16169070, (Europe PMC)	0.37	IntAct
JUN	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, tandem affinity purification	association, physical	2138276, 25609649, (Europe PMC)	0.46	BioGRID, IntAct, MINT
JUND	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
KIAA2026	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
MECP2	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
MEIS1	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, chromatin immunoprecipitation assay	association, physical, physical association	20159610, 20541704, (Europe PMC)	0.68	BioGRID, IntAct
NFATC1	Affinity Capture-MS, Affinity Capture-Western, pull down, tandem affinity purification	association, physical, physical association	25609649, 27637333, (Europe PMC)	0.58	BioGRID, IntAct, MINT
NFATC2	Affinity Capture-MS, Affinity Capture-Western, tandem affinity purification	association, physical, physical association	25609649, 27637333, (Europe PMC)	0.50	BioGRID, IntAct, MINT
NFIA	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
NFIC	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
NFIL3	Affinity Capture-MS, peptide array, tandem affinity purification	association, direct interaction, physical	20102225, 25609649, 28514442, (Europe PMC)	0.59	BioGRID, IntAct, MINT
NFIX	Affinity Capture-MS, tandem affinity purification	physical, physical association	25609649, (Europe PMC)	0.40	BioGRID, IntAct, MINT
NFYA	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
NIT2	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PASK	peptide array, protein kinase assay	phosphorylation reaction	21418524, (Europe PMC)	0.56	IntAct, MINT
PBX2	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PIAS1	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
POGZ	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
POLR2A	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
RAB1A	Two-hybrid, two hybrid pooling approach	physical, physical association	16169070, (Europe PMC)	0.37	BioGRID, IntAct
RECQL	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
RECQL5	Two-hybrid, two hybrid pooling approach	physical, physical association	16169070, (Europe PMC)	0.37	BioGRID, IntAct
RNF111	two hybrid pooling approach	physical association	20936779, (Europe PMC)	0.37	IntAct
RPS6KA1	Proximity Label-MS, protein kinase assay	phosphorylation reaction, physical	16282323, 21832046, (Europe PMC)	0.44	BioGRID, IntAct
SGK1	experimental interaction detection, pull down	phosphorylation reaction, physical association	15733869, (Europe PMC)	0.49	IntAct, MINT
SMCO1	barcode fusion genetics two hybrid, validated two hybrid	physical association	27107012, (Europe PMC)	0.49	IntAct
SREBF2	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
TOX4	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
TP53	Affinity Capture-Western, Co-localization, Reconstituted Complex, proximity ligation assay	physical, physical association	10848610, 16611888, 21295542, 25241761, (Europe PMC)	0.40	BioGRID, IntAct
TSSK4	Two-hybrid, protein kinase assay, pull down, two hybrid	phosphorylation reaction, physical, physical association	15964553, 21988832, (Europe PMC)	0.69	BioGRID, IntAct
TTF2	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
UBE2I	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
ULK2	anti tag coimmunoprecipitation	association	20562859, (Europe PMC)	0.35	IntAct
VIM	Two-hybrid, two hybrid pooling approach	physical, physical association	16169070, (Europe PMC)	0.37	BioGRID, IntAct
XRCC1	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
ZBTB21	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
ZHX1	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
ZMYM2	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct
ZNF131	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
ZNF451	Two-hybrid, two hybrid pooling approach	physical, physical association	20936779, (Europe PMC)	0.37	BioGRID, IntAct

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ARNT	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
ATF1	Affinity Capture-MS, peptide array, pull down, tandem affinity purification	association, direct interaction, physical, physical association	20102225, 25609649, (Europe PMC)	0.70	BioGRID, IntAct, MINT
BRCA1	Phenotypic Enhancement, pull down	direct interaction, genetic	10945975, 9926942, (Europe PMC)	0.44	BioGRID, IntAct, MINT
C5orf24	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
CREB1	FRET, peptide array, tandem affinity purification	association, direct interaction, physical	20102225, 23661758, 25609649, (Europe PMC)	0.59	BioGRID, IntAct, MINT
CREBBP	Affinity Capture-Western, Co-crystal Structure, FRET, Far Western, Reconstituted Complex, Two-hybrid, anti tag coimmunoprecipitation, pull down	physical, physical association	10848610, 10866654, 11259575, 11313407, 11564156, 12196545, 12198160, 12933667, 15073328, 15585582, 15691881, 16799563, 17476304, 17707401, 18599546, 20403362, 20541704, 27789289, 7870179, 8028671, 8413673, 8663317, 9413984, 9786917, 9829964, (Europe PMC)	0.70	BioGRID, IntAct, MINT
CREM	Affinity Capture-MS, Affinity Capture-Western, tandem affinity purification	association, physical	22531917, 25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
EP300	Affinity Capture-Western, Co-localization, Far Western, Reconstituted Complex, anti bait coimmunoprecipitation	physical, physical association	10506141, 11313407, 12665587, 17476304, 21212407, 21268077, 22787115, 7870179, (Europe PMC)	0.40	BioGRID, IntAct, MINT
FAM192A	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FOXA1	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FOXC1	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FOXC2	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
FOXE1	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HIST1H2BA	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HIST1H2BJ	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HIST3H3	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HMGA1	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HMGA2	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
HOXD13	Affinity Capture-MS, tandem affinity purification	association, physical	25609649, (Europe PMC)	0.35	BioGRID, IntAct, MINT
JUN	Affinity Capture-MS, Affinity Capture-Western, anti bait coimmunoprecipitation, tandem affinity purification	association, physical	2138276,

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CREB1