DEPOD - human DEPhOsphorylation Database

Basic Information
Phosphatases
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	IRS1 (QuickGO)	Interactive visualization of IRS1 structures (A quick tutorial to explore the interctive visulaization) Representative structure: 2Z8C
Synonyms	IRS1
Protein Name	IRS1
Alternative Name(s)	Insulin receptor substrate 1;IRS-1;
Protein Family	noSimilarity_annotations
EntrezGene ID	3667 (Comparitive Toxicogenomics)
UniProt AC (Human)	P35568 (protein sequence)
Enzyme Class	N/A
Molecular Weight	131591 Dalton
Protein Length	1242 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000169047 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree \| eggNOG - ENOG410IXEK \| eggNOG - ENOG410Z9EP
Phosphorylation Network	Visualize

Domain organization, Expression, Diseases

(show / hide)

Localization, Function, Catalytic activity and Sequence

(show / hide)

Motif information from Eukaryotic Linear Motif atlas (ELM)

(show / hide)

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

(show / hide)

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.
hsa04068	FoxO signaling pathway	The forkhead box O (FOXO) family of transcription factors regulates the expression of genes in cellular physiological events including apoptosis, cell-cycle control, glucose metabolism, oxidative stress resistance, and longevity. A central regulatory mechanism of FOXO proteins is phosphorylation by the serine-threonine kinase Akt/protein kinase B (Akt/PKB), downstream of phosphatidylinositol 3-kinase (PI3K), in response to insulin or several growth factors. Phosphorylation at three conserved residues results in the export of FOXO proteins from the nucleus to the cytoplasm, thereby decreasing expression of FOXO target genes. In contrast, the stress-activated c-Jun N-terminal kinase (JNK) and the energy sensing AMP-activated protein kinase (AMPK), upon oxidative and nutrient stress stimuli phosphorylate and activate FoxOs. Aside from PKB, JNK and AMPK, FOXOs are regulated by multiple players through several post-translational modifications, including phosphorylation, but also acetylation, methylation and ubiquitylation.
hsa04140	Autophagy - animal	Autophagy (or macroautophagy) is a cellular catabolic pathway involving in protein degradation, organelle turnover, and non-selective breakdown of cytoplasmic components, which is evolutionarily conserved among eukaryotes and exquisitely regulated. This progress initiates with production of the autophagosome, a double-membrane intracellular structure of reticular origin that engulfs cytoplasmic contents and ultimately fuses with lysosomes for cargo degradation. Autophagy is regulated in response to extra- or intracellular stress and signals such as starvation, growth factor deprivation and ER stress. Constitutive level of autophagy plays an important role in cellular homeostasis and maintains quality control of essential cellular components.
hsa04150	mTOR signaling pathway	The mammalian (mechanistic) target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase, which exists in two complexes termed mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 contains mTOR, Raptor, PRAS40, Deptor, mLST8, Tel2 and Tti1. mTORC1 is activated by the presence of growth factors, amino acids, energy status, stress and oxygen levels to regulate several biological processes, including lipid metabolism, autophagy, protein synthesis and ribosome biogenesis. On the other hand, mTORC2, which consists of mTOR, mSin1, Rictor, Protor, Deptor, mLST8, Tel2 and Tti1, responds to growth factors and controls cytoskeletal organization, metabolism and survival.
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.
hsa04213	Longevity regulating pathway - multiple species	Aging is a complex process of accumulation of molecular, cellular, and organ damage, leading to loss of function and increased vulnerability to disease and death. Despite the complexity of aging, recent work has shown that dietary restriction (DR) and genetic down-regulation of nutrient-sensing pathways, namely IIS (insulin/insulin-like growth factor signalling) and TOR (target-of- rapamycin) can substantially increase healthy life span of laboratory model organisms. These nutrient signaling pathways are conserved in various organisms. In worms, flies, and mammals, DR reduces signalling through IIS/TOR pathways, deactivating the PI3K/Akt/TOR intracellular signalling cascade and consequently activating the antiaging FOXO family transcription factor(s). In yeast, the effects of DR on life- span extension are associated with reduced activities of the TOR/Sch9 and Ras/PKA pathways and require the serine-threonine kinase Rim15 and transcription factors Gis1 and Msn2/4. These transcription factors (FOXO, DAF-16, Gis1, and Msn2/4) transactivate genes involved in resistance to oxidative stress, energy metabolism, DNA damage repair, glucose metabolism, autophagy and protection of proteins by chaperones.
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.
hsa04910	Insulin signaling pathway	Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR.Other signal transduction proteins interact with IRS including GRB2. GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. SHC is another substrate of INSR. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1.
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.
hsa04923	Regulation of lipolysis in adipocytes	Lipolysis in adipocytes, the hydrolysis of triacylglycerol (TAG) to release fatty acids (FAs) and glycerol for use by other organs as energy substrates, is a unique function of white adipose tissue. Lipolysis is under tight hormonal control. During fasting, catecholamines, by binding to Gs-coupled-adrenergic receptors (-AR), activate adenylate cyclase (AC) to increase cAMP and activate protein kinase A (PKA). PKA phosphorylates target protein such as hormone-sensitive lipase (HSL) and perilipin 1 (PLIN). PLIN phosphorylation is a key event in the sequential activation of TAG hydrolysis involving adipose triglyceride lipase (ATGL), HSL, and monoglyceride lipase (MGL). During the fed state, insulin, through activation of phosphodiesterase-3B (PDE-3B), inhibits catecholamine-induced lipolysis via the degradation of cAMP.
hsa04930	Type II diabetes mellitus	Insulin resistance is strongly associated with type II diabetes. Diabetogenicfactors including FFA, TNFalpha and cellular stress induce insulin resistance through inhibition of IRS1 functions. Serine/threonine phosphorylation, interaction with SOCS, regulation of the expression, modification of the cellular localization, and degradation represent the molecular mechanisms stimulated by them. Various kinases (ERK, JNK, IKKbeta, PKCzeta, PKCtheta and mTOR) are involved in this process.The development of type II diabetes requires impaired beta-cell function. Chronic hyperglycemia has been shown to induce multiple defects in beta-cells. Hyperglycemia has been proposed to lead to large amounts of reactive oxygen species (ROS) in beta-cells, with subsequent damage to cellular components including PDX-1. Loss of PDX-1, a critical regulator of insulin promoter activity, has also been proposed as an important mechanism leading to beta-cell dysfunction.Although there is little doubt as to the importance of genetic factors in type II diabetes, genetic analysis is difficult due to complex interaction among multiple susceptibility genes and between genetic and environmental factors. Genetic studies have therefore given very diverse results. Kir6.2 and IRS are two of the candidate genes. It is known that Kir6.2 and IRS play central roles in insulin secretion and insulin signal transmission, 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.
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.
hsa04960	Aldosterone-regulated sodium reabsorption	Sodium transport across the tight epithelia of Na+ reabsorbing tissues such as the distal part of the kidney nephron and colon is the major factor determining total-body Na+ levels, and thus, long-term blood pressure. Aldosterone plays a major role in sodium and potassium metabolism by binding to epithelial mineralocorticoid receptors (MR) in the renal collecting duct cells localized in the distal nephron, promoting sodium resorption and potassium excretion. Aldosterone enters a target cell and binds MR, which translocates into the nucleus and regulates gene transcription. Activation of MR leads to increased expression of Sgk-1, which phosphorylates Nedd4-2, an ubiquitin-ligase which targets ENAC to proteosomal degradation. Phosphorylated Nedd4-2 dissociates from ENAC, increasing its apical membrane abundance. Activation of MR also leads to increased expression of Na+/K+-ATPase, thus causing a net increase in sodium uptake from the renal filtrate. The specificity of MR for aldosterone is provided by 11beta-HSD2 by the rapid conversion of cortisol to cortisone in renal cortical collecting duct cells. Recently, besides genomic effects mediated by activated MR, rapid aldosterone actions that are independent of translation and transcription have been documented.
hsa05206	MicroRNAs in cancer	MicroRNA (miRNA) is a cluster of small non-encoding RNA molecules of 21 - 23 nucleotides in length, which controls gene expression post-transcriptionally either via the degradation of target mRNAs or the inhibition of protein translation. Using high-throughput profiling, dysregulation of miRNAs has been widely observed in different stages of cancer. The upregulation (overexpression) of specific miRNAs could lead to the repression of tumor suppressor gene expression, and conversely the downregulation of specific miRNAs could result in an increase of oncogene expression; both these situations induce subsequent malignant effects on cell proliferation, differentiation, and apoptosis that lead to tumor growth and progress. The miRNA signatures of cancer observed in various studies differ significantly. These inconsistencies occur due to the differences in the study populations and methodologies used. This pathway map shows the summarized results from various studies in 9 cancers, each of which is presented in a review article.

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-109704	PI3K Cascade.	The PI3K (Phosphatidlyinositol-3-kinase) - AKT signaling pathway stimulates cell growth and survival
R-HSA-112399	IRS-mediated signalling.	Release of phospho-IRS from the insulin receptor triggers a cascade of signalling events via PI3K, SOS, RAF and the MAP kinases
R-HSA-112412	SOS-mediated signalling.	SOS is recruited to the plasma membrane and mediates activation of Ras
R-HSA-1257604	PIP3 activates AKT signaling.	Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007
R-HSA-1266695	Interleukin-7 signaling.	Interleukin-7 (IL7) is produced primarily by T zone fibroblastic reticular cells found in lymphoid organs, and also expressed by non-hematopoietic stromal cells present in other tissues including the skin, intestine and liver. It is an essential survival factor for lymphocytes, playing a key anti-apoptotic role in T-cell development, as well as mediating peripheral T-cell maintenance and proliferation. This dual function is reflected in a dose-response relationship that distinguishes the survival function from the proliferative activity; low doses of IL7 (<1 ng/ml) sustain only survival, higher doses (>1 ng/ml) promote survival and cell cycling (Kittipatarin et al. 2006, Swainson et al. 2007).The IL7 receptor is a heterodimeric complex of the the common cytokine-receptor gamma chain (IL2RG, CD132, or Gc) and the IL7-receptor alpha chain (IL7R, IL7RA, CD127). Both chains are members of the type 1 cytokine family. Neither chain is unique to the IL7 receptor as IL7R is utilized by the receptor for thymic stromal lymphopoietin (TSLP) while IL2RG is shared with the receptors for IL2, IL4, IL9, IL15 and IL21. IL2RG consists of a single transmembrane region and a 240aa extracellular region that includes a fibronectin type III (FNIII) domain thought to be involved in receptor complex formation. It is expressed on most lymphocyte populations. Null mutations of IL2RG in humans cause X-linked severe combined immunodeficiency (X-SCID), which has a phenotype of severely reduced T-cell and natural killer (NK) cell populations, but normal numbers of B cells. In addition to reduced T- and NK-cell numbers, Il2rg knockout mice also have dramatically reduced B-cell populations suggesting that Il2rg is more critical for B-cell development in mice than in humans. Patients with severe combined immunodeficiency (SCID) phenotype due to IL7R mutations (see Puel & Leonard 2000), or a partial deficiency of IL7R (Roifman et al. 2000) have markedly reduced circulating T cells, but normal levels of peripheral blood B cells and NK cells, similar to the phenotype of IL2RG mutations, highlighting a requirement for IL7 in T cell lymphopoiesis. It has been suggested that IL7 is essential for murine, but not human B cell development, but recent studies indicate that IL7 is essential for human B cell production from adult bone marrow and that IL7-induced expansion of the progenitor B cell compartment is increasingly critical for human B cell production during later stages of development (Parrish et al. 2009).IL7 has been shown to induce rapid and dose-dependent tyrosine phosphorylation of JAKs 1 and 3, and concomitantly tyrosine phosphorylation and DNA-binding activity of STAT5a/b (Foxwell et al. 1995). IL7R was shown to directly induce the activation of JAKs and STATs by van der Plas et al. (1996). Jak1 and Jak3 knockout mice displayed severely impaired thymic development, further supporting their importance in IL7 signaling (Rodig et al. 1998, Nosaka et al. 1995).The role of STAT5 in IL7 signaling has been studied largely in mouse models. Tyr449 in the cytoplasmic domain of IL7RA is required for T-cell development in vivo and activation of JAK/STAT5 and PI3k/Akt pathways (Jiang et al. 2004, Pallard et al. 1999). T-cells from an IL7R Y449F knock-in mouse did not activate STAT5 (Osbourne et al. 2007), indicating that IL7 regulates STAT5 activity via this key tyrosine residue. STAT5 seems to enhance proliferation of multiple cell lineages in mouse models but it remains unclear whether STAT5 is required solely for survival signaling or also for the induction of proliferative activity (Kittipatarin & Khaled, 2007).The model for IL7 receptor signaling is believed to resemble that of other Gc family cytokines, based on detailed studies of the IL2 receptor, where IL2RB binds constitutively to JAK1 while JAK3 is pre-associated uniquely with the IL2RG chain. Extending this model to IL7 suggests a similar series of events: IL7R constitutively associated with JAK1 binds IL7, the resulting trimer recruits IL2RG:JAK3, bringing JAK1 and JAK3 into proximity. The association of both chains of the IL7 receptor orients the cytoplasmic domains of the receptor chains so that their associated kinases (Janus and phosphatidylinositol 3-kinases) can phosphorylate sequence elements on the cytoplasmic domains (Jiang et al. 2005). JAKs have low intrinsic enzymatic activity, but after mutual phosphorylation acquire much higher activity, leading to phosphorylation of the critical Y449 site on IL7R. This site binds STAT5 and possibly other signaling adapters, they in turn become phosphorylated by JAK1 and/or JAK3. Phosphorylated STATs translocate to the nucleus and trigger the transcriptional events of their target genes.The role of the PI3K/AKT pathway in IL7 signaling is controversial. It is a potential T-cell survival pathway because in many cell types PI3K signaling regulates diverse cellular functions such as cell cycle progression, transcription, and metabolism. The ERK/MAPK pathway does not appear to be involved in IL7 signaling (Crawley et al. 1996).It is not clear how IL7 influences cell proliferation. In the absence of a proliferative signal such as IL7 or IL3, dependent lymphocytes arrest in the G0/G1 phase of the cell cycle. To exit this phase, cells typically activate specific G1 Cyclin-dependent kinases/cyclins and down regulate cell cycle inhibitors such as Cyclin-dependent kinase inhibitor 1B (Cdkn1b or p27kip1). There is indirect evidence suggesting a possible role for IL7 stimulated activation of PI3K/AKT signaling, obtained from transformed cell lines and thymocytes, but not confirmed by observations using primary T-cells (Kittipatarin & Khaled, 2007). IL7 withdrawal results in G1/S cell cycle arrest and is correlated with loss of cdk2 activity (Geiselhart et al. 2001), both events which are known to be regulated by the dephosphorylating activity of Cdc25A. Expression of a p38 MAPK-resistant Cdc25A mutant in an IL-7-dependent T-cell line as well as in peripheral, primary T-cells was sufficient to sustain cell survival and promote cell cycling for several days in the absence of IL7 (Khaled et al. 2005). Cdkn1b is a member of the CIP/KIP family of cyclin-dependent cell cycle inhibitors (CKIs) that negatively regulates the G1/S transition. In IL7 dependent T-cells, the expression of Cdkn1b was sufficient to cause G1 arrest in the presence of IL7. Withdrawal of IL7 induced the upregulation of Cdkn1b and arrested cells in G1 while siRNA knockout of Cdkn1b enhanced cell cycle progression. However, adoptive transfer of Cdkn1b-deficient lymphocytes into IL7 deficient mice indicated that loss of Cdkn1b could only partially compensate for the IL7 signal needed by T-cells to expand in a lymphopenic environment (Li et al. 2006), so though Cdkn1b may be involved in negative regulation of the cell cycle through an effect on cdk2 activity, its absence is not sufficient to fully induce cell cycling under lymphopenic conditions
R-HSA-198203	PI3K/AKT activation.	PI3K/AKT signalling is a major regulator of neuron survival. It blocks cell death by both impinging on the cytoplasmic cell death machinery and by regulating the expression of genes involved in cell death and survival. In addition, it may also use metabolic pathways to regulate cell survival.The PI3K/AKT pathway also affects axon diameter and branching (Marcus et al, 2002) and regulates small G proteins like RhoA (Vanhaesebroeck, B and Waterman, MD, 1999), which control the behaviour of the F-actin cytoskeleton. Moreover, through its connection with the TOR pathway, it promotes translation of a subset of mRNAs
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer.	Signaling by PI3K/AKT is frequently constitutively activated in cancer via gain-of-function mutations in one of the two PI3K subunits - PI3KCA (encoding the catalytic subunit p110alpha) or PIK3R1 (encoding the regulatory subunit p85alpha). Gain-of-function mutations activate PI3K signaling by diverse mechanisms. Mutations affecting the helical domain of PIK3CA and mutations affecting nSH2 and iSH2 domains of PIK3R1 impair inhibitory interactions between these two subunits while preserving their association. Mutations in the catalytic domain of PIK3CA enable the kinase to achieve an active conformation. PI3K complexes with gain-of-function mutations therefore produce PIP3 and activate downstream AKT in the absence of growth factors (Huang et al. 2007, Zhao et al. 2005, Miled et al. 2007, Horn et al. 2008, Sun et al. 2010, Jaiswal et al. 2009, Zhao and Vogt 2010, Urick et al. 2011)
R-HSA-2428928	IRS-related events triggered by IGF1R.	The phosphorylated type 1 insulin-like growth factor receptor phosphorylates IR1, IRS2, IRS4 and possibly other IRS/DOK family members (reviewed in Pavelic et al. 2007, Chitnis et al. 2008, Maki et al. 2010, Parrella et al. 2010, Siddle et al. 2012). The phosphorylated IRS proteins serve as scaffolds that bind the effector molecules PI3K and GRB2:SOS. PI3K then activates PKB (AKT) signaling while GRB2:SOS activates RAS-RAF-MAPK signaling
R-HSA-2586552	Signaling by Leptin.	Leptin (LEP, OB, OBS), a circulating adipokine, and its receptor LEPR (DB, OBR) control food intake and energy balance and are implicated in obesity-related diseases (recently reviewed in Amitani et al. 2013, Dunmore and Brown 2013, Cottrell and Mercer 2012, La Cava 2012, Marroqui et al. 2012, Paz-Filho et al. 2012, Denver et al. 2011, Lee 2011, Marino et al. 2011, Morton and Schwartz 2011, Scherer and Buettner 2011, Shan and Yeo 2011, Wauman and Tavernier 2011, Dardeno et al. 2010, Bjorbaek 2009, Morris and Rui 2009, Myers et al. 2008), including cancer (Guo et al. 2012), inflammation (Newman and Gonzalez-Perez 2013, Iikuni et al. 2008), and angiogenesis (Gonzalez-Perez et al. 2013).The identification of spontaneous mutations in the leptin gene (ob or LEP) and the leptin receptor gene (Ob-R, db or LEPR) genes in mice opened up a new field in obesity research. Leptin was discovered as the product of the gene affected by the ob (obesity) mutation, which causes obesity in mice. Likewise LEPR is the product of the gene affected by the db (diabetic) mutation. Leptin binding to LEPR induces canonical (JAK2/STATs; MAPK/ERK 1/2, PI-3K/AKT) and non-canonical signaling pathways (PKC, JNK, p38 MAPK and AMPK) in diverse cell types. The binding of leptin to the long isoform of LEPR (OB-Rl) initiates a phosphorylation cascade that results in transcriptional activation of target genes by STAT5 and STAT3 and activation of the PI3K pathway(not shown here), the MAPK/ERK pathway, and the mTOR/S6K pathway. Shorter LEPR isoforms with truncated intracellular domains are unable to activate the STAT pathway, but can transduce signals by way of activation of JAK2, IRS-1 or ERKs, including MAPKs.LEPR is constitutively bound to the JAK2 kinase. Binding of LEP to LEPR causes a conformational change in LEPR that activates JAK2 autophosphorylation followed by phosphorylation of LEPR by JAK2. Phosphorylated LEPR binds STAT3, STAT5, and SHP2 which are then phosphorylated by JAK2. Phosphorylated JAK2 binds SH2B1 which then binds IRS1/2, resulting in phosphorylation of IRS1/2 by JAK2. Phosphorylated STAT3 and STAT5 dimerize and translocate to the nucleus where they activate transcription of target genes (Jovanovic et al. 2010). SHP2 activates the MAPK pathway. IRS1/2 activate the PI3K/AKT pathway which may be the activator of mTOR/S6K.Several isoforms of LEPR have been identified (reviewed in Gorska et al. 2010). The long isoform (LEPRb, OBRb) is expressed in the hypothalamus and all types of immune cells. It is the only isoform known to fully activate signaling pathways in response to leptin. Shorter isoforms (LEPRa, LEPRc, LEPRd, and a soluble isoform LEPRe) are able to interact with JAK kinases and activate other pathways, however their roles in energy homeostasis are not fully characterized
R-HSA-5673001	RAF/MAP kinase cascade.	The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009). The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011)
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.	Phosphatidylinositol-5-phosphate (PI5P) may modulate PI3K/AKT signaling in several ways. PI5P is used as a substrate for production of phosphatidylinositol-4,5-bisphosphate, PI(4,5)P2 (Rameh et al. 1997, Clarke et al. 2008, Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015), which serves as a substrate for activated PI3K, resulting in the production of PIP3 (Mandelker et al. 2009, Burke et al. 2011). The majority of PI(4,5)P2 in the cell, however, is produced from the phosphatidylinositol-4-phosphate (PI4P) substrate (Zhang et al. 1997, Di Paolo et al. 2002, Oude Weernink et al. 2004, Halstead et al. 2006, Oude Weernink et al. 2007). PIP3 is necessary for the activating phosphorylation of AKT. AKT1 can be deactivated by the protein phosphatase 2A (PP2A) complex that contains a regulatory subunit B56-beta (PPP2R5B) or B56-gamma (PPP2R5C). PI5P inhibits AKT1 dephosphorylation by PP2A through an unknown mechanism (Ramel et al. 2009). Increased PI5P levels correlate with inhibitory phosphorylation(s) of the PP2A complex. MAPK1 (ERK2) and MAPK3 (ERK1) are involved in inhibitory phosphorylation of PP2A, in a process that involves IER3 (IEX-1) (Letourneux et al. 2006, Rocher et al. 2007). It is uncertain, however, whether PI5P is in any way involved in ERK-mediated phosphorylation of PP2A or if it regulates another PP2A kinase
R-HSA-74713	IRS activation.	IRS is one of the mediators of insulin signalling events. It is activated by phosphorylation and triggers a cascade of events involving PI3K, SOS, RAF and the MAP kinases. The proteins mentioned under IRS are examples of IRS family members acting as indicated. More family members are to be confirmed and added in the future.\r\n\r\nUsing receptor mutagenesis studies it is known that IRS1 via its PTB domain binds to the insulin receptor at the juxtamembrane region at tyrosine 972. The interaction is further stabilized by the PH domain of IRS1 which interacts with the phospholipids of the plasma membrane. This allows the receptor to phosphorylate IRS1 on up to 13 of its tyrosine residues. Once phosphorylated the IRS1 falls away from the receptor. Now in a tyrosine phosphorylated and hence activated state other proteins can interact with the IRS proteins
R-HSA-74749	Signal attenuation.	Now with the complete receptor-ligand dissociation and subsequent degradation of insulin in the endosomal lumen, the endosomally associated protein tyrosine phosphatases (PTPs) complete the receptor dephosphorylation. So too are all the receptor substrates dephosphorylated leading to the collapse of the signalling complexes and signal attenuation
R-HSA-9603381	Activated NTRK3 signals through PI3K.	The PI3K complex, composed of PIK3R1 and PIK3CA, co-immunoprecipitates with NTRK3 (TRKC), activated by NTF3 (NT-3) treatment (Yuen and Mobley 1999). Activation of NTRK3 correlates with activating phosphorylation of AKT, the main mediator of PI3K signaling (Tognon et al. 2001, Jin et al. 2008), and is dependent on PI3K activity (Tognon et al. 2001). NTRK3-mediated activation of PI3K signaling depends on SRC activation and the adaptor protein IRS1, but the exact mechanism is not known (Morrison et al. 2002, Lannon et al. 2004, Jin et al. 2008)
R-HSA-982772	Growth hormone receptor signaling.	Growth hormone (Somatotropin or GH) is a key factor in determining lean body mass, stimulating the growth and metabolism of muscle, bone and cartilage cells, while reducing body fat. It has many other roles; it acts to regulate cell growth, differentiation, apoptosis, and reorganisation of the cytoskeleton, affecting diverse processes such as cardiac function, immune function, brain function, and aging. GH also has insulin-like effects such as stimulating amino acid transport, protein synthesis, glucose transport, and lipogenesis. The growth hormone receptor (GHR) is a a member of the cytokine receptor family. When the dimeric receptor binds GH it undergoes a conformational change which leads to phosphorylation of key tyrosine residues in its cytoplasmic domains and activation of associated tyrosine kinase JAK2. This leads to recruitment of signaling molecules such as STAT5 and Src family kinases such as Lyn leading to ERK activation. The signal is attenuated by association of Suppressor of Cytokine Signaling (SOCS) proteins and SHP phosphatases which bind to or dephosphorylate specific phosphorylated tyrosines on GHR/JAK. The availability of GHR on the cell surface is regulated by at least two processes; internalization and cleavage from the suface by metalloproteases

BioGRID
IntAct
MINT
ALL

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ALK	Affinity Capture-Western	physical	14968112, (Europe PMC)	NA	BioGRID
AP3S1	Reconstituted Complex	physical	9792713, (Europe PMC)	NA	BioGRID
APP	Reconstituted Complex	physical	21832049, (Europe PMC)	NA	BioGRID
BCAR3	Affinity Capture-Luminescence, Two-hybrid, luminescence based mammalian interactome mapping, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.57	BioGRID, IntAct
BCL2	Affinity Capture-Western	physical	10679027, (Europe PMC)	NA	BioGRID
BCL2L1	Affinity Capture-Western	physical	10679027, (Europe PMC)	NA	BioGRID
CBL	Affinity Capture-Western	physical	10854852, (Europe PMC)	NA	BioGRID
CBLB	Affinity Capture-Western	physical	16734387, (Europe PMC)	NA	BioGRID
CHUK	Affinity Capture-Western	physical	12351658, (Europe PMC)	NA	BioGRID
CUL7	Affinity Capture-Western	physical	18498745, (Europe PMC)	NA	BioGRID
DVL2	Affinity Capture-Western	physical	24616100, (Europe PMC)	NA	BioGRID
EGFR	Protein-peptide, protein array	direct interaction, physical	16273093, (Europe PMC)	0.44	BioGRID, IntAct, MINT
ERBB2	Protein-peptide, protein array	direct interaction, physical	16273093, (Europe PMC)	0.44	BioGRID, IntAct, MINT
ESR1	Affinity Capture-Western	physical	12821935, (Europe PMC)	NA	BioGRID
FBXO25	Biochemical Activity	physical	23940030, (Europe PMC)	NA	BioGRID
FBXW8	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Reconstituted Complex	physical	18498745, 23045529, (Europe PMC)	NA	BioGRID
GRB10	Affinity Capture-Western, Reconstituted Complex	physical	12783867, 8621530, (Europe PMC)	NA	BioGRID
GRB2	Affinity Capture-MS, Affinity Capture-Western, Protein-peptide, Reconstituted Complex, anti tag coimmunoprecipitation	association, physical	12173038, 21706016, 22974441, 8491186, 8536716, (Europe PMC)	0.35	BioGRID, IntAct
HDAC2	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	15522123, (Europe PMC)	NA	BioGRID
IGF1R	Affinity Capture-Western, Two-hybrid, two hybrid	physical, physical association	10082579, 7541045, 7559507, 8776723, (Europe PMC)	0.37	BioGRID, IntAct
IKBKB	Affinity Capture-Western	physical	12351658, (Europe PMC)	NA	BioGRID
INSR	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down, two hybrid	association, direct interaction, physical, physical association	11606564, 11781100, 16582879, 17167487, 25667086, 7499194, 7935368, 8626379, 8662806, (Europe PMC)	0.35, 0.70	BioGRID, IntAct, MINT
IRS2	Co-fractionation	physical	12554758, (Europe PMC)	NA	BioGRID
JAK1	Affinity Capture-Western, Biochemical Activity	physical	7499365, 9492017, (Europe PMC)	NA	BioGRID
JAK2	Affinity Capture-Western, Biochemical Activity	physical	11208867, 9492017, (Europe PMC)	NA	BioGRID
JAK3	Affinity Capture-Western	physical	7499365, (Europe PMC)	NA	BioGRID
KHDRBS1	Affinity Capture-Western	physical	11604231, 8175658, (Europe PMC)	NA	BioGRID
MAPK3	Biochemical Activity	physical	17640984, (Europe PMC)	NA	BioGRID
MAPK8	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	10722755, 11606564, (Europe PMC)	NA	BioGRID
MTOR	Affinity Capture-Western, Biochemical Activity	physical	11287630, 16354680, (Europe PMC)	NA	BioGRID
NCK2	Reconstituted Complex	physical	9843575, (Europe PMC)	NA	BioGRID
NEDD4	Reconstituted Complex	physical	19953087, (Europe PMC)	NA	BioGRID
NISCH	Affinity Capture-Western	physical	11912194, (Europe PMC)	NA	BioGRID
NUMB	Two-hybrid	physical	25814554, (Europe PMC)	NA	BioGRID
PELI1	Two-hybrid, two hybrid array	physical, physical association	25814554, (Europe PMC)	0.37	BioGRID, IntAct
PIK3CA	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	association, direct interaction, physical, physical association	12933652, 14511371, 16150444, 16354680, 23604317, 23643389, (Europe PMC)	0.75	BioGRID, IntAct, MINT
PIK3CB	Affinity Capture-Western	physical	23604317, (Europe PMC)	NA	BioGRID
PIK3R1	Affinity Capture-Luminescence, Affinity Capture-Western, Far Western, Protein-peptide, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, cross-linking study, enzymatic study, luminescence based mammalian interactome mapping, nuclear magnetic resonance, pull down, surface plasmon resonance, two hybrid, two hybrid array, validated two hybrid	association, physical, physical association	11403293, 11416002, 12107746, 12173038, 12730242, 1381348, 14511371, 14632132, 15514089, 16150444, 16230374, 16354680, 17640984, 19561084, 22974441, 23439647, 23643389, 25814554, 7680095, 7680644, 8175658, 8382612, 8628286, 9564850, (Europe PMC)	0.57, 0.92	BioGRID, IntAct, MINT
PIK3R2	Affinity Capture-Western	physical	23604317, (Europe PMC)	NA	BioGRID
PIK3R3	Affinity Capture-Luminescence, Affinity Capture-Western, Two-hybrid, luminescence based mammalian interactome mapping, two hybrid array, validated two hybrid	physical, physical association	10417350, 25814554, 9415396, (Europe PMC)	0.57	BioGRID, IntAct
PLCG2	Protein-peptide	physical	22974441, (Europe PMC)	NA	BioGRID
PRKCD	Affinity Capture-Western, Biochemical Activity	physical	12031982, 15516986, (Europe PMC)	NA	BioGRID
PTK2	Affinity Capture-Western, Two-hybrid	physical	9822703, (Europe PMC)	NA	BioGRID
PTPN1	Affinity Capture-Western, Reconstituted Complex, phosphatase assay	dephosphorylation reaction, physical	10660596, 11579209, (Europe PMC)	0.44	BioGRID, IntAct, MINT
PTPN11	Affinity Capture-Western, Biochemical Activity, Protein-peptide, Reconstituted Complex, surface plasmon resonance	association, physical	11781100, 22974441, 7513703, 8505282, 9756938, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PTPRU	Biochemical Activity	physical	11781100, (Europe PMC)	NA	BioGRID
RPS6KB1	Biochemical Activity, Reconstituted Complex	physical	18498745, 23045529, (Europe PMC)	NA	BioGRID
RPTOR	Affinity Capture-Western, Reconstituted Complex	physical	16354680, 19561084, (Europe PMC)	NA	BioGRID
SFN	Affinity Capture-MS, tandem affinity purification	physical, physical association	15778465, (Europe PMC)	0.40	BioGRID, IntAct, MINT
SH2B1	Protein-peptide	physical	22974441, (Europe PMC)	NA	BioGRID
SIRT1	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	17901049, 21241768, (Europe PMC)	0.40	BioGRID, IntAct
SMAD3	Affinity Capture-MS, tandem affinity purification	physical, physical association	18729074, (Europe PMC)	0.40	BioGRID, IntAct
SOCS1	Affinity Capture-Western	physical	12228220, 17276034, (Europe PMC)	NA	BioGRID
SOCS3	Affinity Capture-Western	physical	15514089, (Europe PMC)	NA	BioGRID
UBC	Reconstituted Complex	physical	23045529, (Europe PMC)	NA	BioGRID
UBTF	Affinity Capture-Western	physical	12554758, 17332342, (Europe PMC)	NA	BioGRID
YWHAB	Reconstituted Complex	physical	9422753, (Europe PMC)	NA	BioGRID
YWHAE	Reconstituted Complex, Two-hybrid, competition binding, pull down, two hybrid	association, direct interaction, physical, physical association	9111084, 9312143, (Europe PMC)	0.68	BioGRID, IntAct, MINT
YWHAH	Affinity Capture-Western	physical	11969417, (Europe PMC)	NA	BioGRID

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
CYTH2	anti bait coimmunoprecipitation	association	17167487, (Europe PMC)	0.35	IntAct
CYTH3	anti bait coimmunoprecipitation	association	17167487, (Europe PMC)	0.35	IntAct
DDR1	protein kinase assay	phosphorylation reaction	17721511, (Europe PMC)	0.44	IntAct
EBI-1108795	anti bait coimmunoprecipitation	physical association	14968112, (Europe PMC)	0.40	IntAct
EGFR	Protein-peptide, protein array	direct interaction, physical	16273093, (Europe PMC)	0.44	BioGRID, IntAct, MINT
EGLN3	anti tag coimmunoprecipitation	association	26972000, (Europe PMC)	0.35	IntAct
EIF4E	anti bait coimmunoprecipitation	association	23770097, (Europe PMC)	0.35	IntAct, MINT
ERBB2	Protein-peptide, protein array	direct interaction, physical	16273093, (Europe PMC)	0.44	BioGRID, IntAct, MINT
GRB2	Affinity Capture-MS, Affinity Capture-Western, Protein-peptide, Reconstituted Complex, anti tag coimmunoprecipitation	association, physical	12173038, 21706016, 22974441, 8491186, 8536716, (Europe PMC)	0.35	BioGRID, IntAct
IGF1R	Affinity Capture-Western, Two-hybrid, two hybrid	physical, physical association	10082579, 7541045, 7559507, 8776723, (Europe PMC)	0.37	BioGRID, IntAct
INSR	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down, two hybrid	association, direct interaction, physical, physical association	11606564, 11781100, 16582879, 17167487, 25667086, 7499194, 7935368, 8626379, 8662806, (Europe PMC)	0.35, 0.70	BioGRID, IntAct, MINT
LRRK2	protein array	direct interaction	24947832, (Europe PMC)	0.44	IntAct
NUMB	two hybrid array, validated two hybrid	physical association	25814554, (Europe PMC)	0.49	IntAct
PABPC1	anti bait coimmunoprecipitation	association, physical association	23770097, (Europe PMC)	0.50	IntAct, MINT
PELI1	Two-hybrid, two hybrid array	physical, physical association	25814554, (Europe PMC)	0.37	BioGRID, IntAct
PIK3CA	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	association, direct interaction, physical, physical association	12933652, 14511371, 16150444, 16354680, 23604317, 23643389, (Europe PMC)	0.75	BioGRID, IntAct, MINT
PIK3R1	Affinity Capture-Luminescence, Affinity Capture-Western, Far Western, Protein-peptide, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, cross-linking study, enzymatic study, luminescence based mammalian interactome mapping, nuclear magnetic resonance, pull down, surface plasmon resonance, two hybrid, two hybrid array, validated two hybrid	association, physical, physical association	11403293, 11416002, 12107746, 12173038, 12730242, 1381348, 14511371, 14632132, 15514089, 16150444, 16230374, 16354680, 17640984, 19561084, 22974441, 23439647, 23643389, 25814554, 7680095, 7680644, 8175658, 8382612, 8628286, 9564850, (Europe PMC)	0.57, 0.92	BioGRID, IntAct, MINT
PIK3R3	Affinity Capture-Luminescence, Affinity Capture-Western, Two-hybrid, luminescence based mammalian interactome mapping, two hybrid array, validated two hybrid	physical, physical association	10417350, 25814554, 9415396, (Europe PMC)	0.57	BioGRID, IntAct
PTPN1	Affinity Capture-Western, Reconstituted Complex, phosphatase assay	dephosphorylation reaction, physical	10660596, 11579209, (Europe PMC)	0.44	BioGRID, IntAct, MINT
PTPN11	Affinity Capture-Western, Biochemical Activity, Protein-peptide, Reconstituted Complex, surface plasmon resonance	association, physical	11781100, 22974441, 7513703, 8505282, 9756938, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PTPRD	protein array	direct interaction	22305495, (Europe PMC)	0.44	IntAct, MINT
SFN	Affinity Capture-MS, tandem affinity purification	physical, physical association	15778465, (Europe PMC)	0.40	BioGRID, IntAct, MINT
SIRT1	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	17901049, 21241768, (Europe PMC)	0.40	BioGRID, IntAct
SMAD3	Affinity Capture-MS, tandem affinity purification	physical, physical association	18729074, (Europe PMC)	0.40	BioGRID, IntAct
YWHAE	Reconstituted Complex, Two-hybrid, competition binding, pull down, two hybrid	association, direct interaction, physical, physical association	9111084, 9312143, (Europe PMC)	0.68	BioGRID, IntAct, MINT

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
EIF4E	anti bait coimmunoprecipitation	association	23770097, (Europe PMC)	0.35	IntAct, MINT
ERBB2	Protein-peptide, protein array	direct interaction, physical	16273093, (Europe PMC)	0.44	BioGRID, IntAct, MINT
INSR	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down, two hybrid	association, direct interaction, physical, physical association	11606564, 11781100, 16582879, 17167487, 25667086, 7499194, 7935368, 8626379, 8662806, (Europe PMC)	0.35, 0.70	BioGRID, IntAct, MINT
PABPC1	anti bait coimmunoprecipitation	association, physical association	23770097, (Europe PMC)	0.50	IntAct, MINT
PIK3CA	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	association, direct interaction, physical, physical association	12933652, 14511371, 16150444, 16354680, 23604317, 23643389, (Europe PMC)	0.75	BioGRID, IntAct, MINT
PIK3R1	Affinity Capture-Luminescence, Affinity Capture-Western, Far Western, Protein-peptide, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, cross-linking study, enzymatic study, luminescence based mammalian interactome mapping, nuclear magnetic resonance, pull down, surface plasmon resonance, two hybrid, two hybrid array, validated two hybrid	association, physical, physical association	11403293, 11416002, 12107746, 12173038, 12730242, 1381348, 14511371, 14632132, 15514089, 16150444, 16230374, 16354680, 17640984, 19561084, 22974441, 23439647, 23643389, 25814554, 7680095, 7680644, 8175658, 8382612, 8628286, 9564850, (Europe PMC)	0.57, 0.92	BioGRID, IntAct, MINT
PTPN1	Affinity Capture-Western, Reconstituted Complex, phosphatase assay	dephosphorylation reaction, physical	10660596, 11579209, (Europe PMC)	0.44	BioGRID, IntAct, MINT
PTPN11	Affinity Capture-Western, Biochemical Activity, Protein-peptide, Reconstituted Complex, surface plasmon resonance	association, physical	11781100, 22974441, 7513703, 8505282, 9756938, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PTPRD	protein array	direct interaction	22305495, (Europe PMC)	0.44	IntAct, MINT
SFN	Affinity Capture-MS, tandem affinity purification	physical, physical association	15778465, (Europe PMC)	0.40	BioGRID, IntAct, MINT
YWHAE	Reconstituted Complex, Two-hybrid, competition binding, pull down, two hybrid	association, direct interaction, physical, physical association	9111084, 9312143, (Europe PMC)	0.68	BioGRID, IntAct, MINT

Visualize Download

Interacting partner	Detection method	Interaction type	PubMed IDs	Interaction Score	Source
ALK	Affinity Capture-Western	physical	14968112, (Europe PMC)	NA	BioGRID
AP3S1	Reconstituted Complex	physical	9792713, (Europe PMC)	NA	BioGRID
APP	Reconstituted Complex	physical	21832049, (Europe PMC)	NA	BioGRID
BCAR3	Affinity Capture-Luminescence, Two-hybrid, luminescence based mammalian interactome mapping, two hybrid array, validated two hybrid	physical, physical association	25814554, (Europe PMC)	0.57	BioGRID, IntAct
BCL2	Affinity Capture-Western	physical	10679027, (Europe PMC)	NA	BioGRID
BCL2L1	Affinity Capture-Western	physical	10679027, (Europe PMC)	NA	BioGRID
CBL	Affinity Capture-Western	physical	10854852, (Europe PMC)	NA	BioGRID
CBLB	Affinity Capture-Western	physical	16734387, (Europe PMC)	NA	BioGRID
CHUK	Affinity Capture-Western	physical	12351658, (Europe PMC)	NA	BioGRID
CUL7	Affinity Capture-Western	physical	18498745, (Europe PMC)	NA	BioGRID
CYTH2	anti bait coimmunoprecipitation	association	17167487, (Europe PMC)	0.35	IntAct
CYTH3	anti bait coimmunoprecipitation	association	17167487, (Europe PMC)	0.35	IntAct
DDR1	protein kinase assay	phosphorylation reaction	17721511, (Europe PMC)	0.44	IntAct
DVL2	Affinity Capture-Western	physical	24616100, (Europe PMC)	NA	BioGRID
EBI-1108795	anti bait coimmunoprecipitation	physical association	14968112, (Europe PMC)	0.40	IntAct
EGFR	Protein-peptide, protein array	direct interaction, physical	16273093, (Europe PMC)	0.44	BioGRID, IntAct, MINT
EGLN3	anti tag coimmunoprecipitation	association	26972000, (Europe PMC)	0.35	IntAct
EIF4E	anti bait coimmunoprecipitation	association	23770097, (Europe PMC)	0.35	IntAct, MINT
ERBB2	Protein-peptide, protein array	direct interaction, physical	16273093, (Europe PMC)	0.44	BioGRID, IntAct, MINT
ESR1	Affinity Capture-Western	physical	12821935, (Europe PMC)	NA	BioGRID
FBXO25	Biochemical Activity	physical	23940030, (Europe PMC)	NA	BioGRID
FBXW8	Affinity Capture-MS, Affinity Capture-Western, Biochemical Activity, Reconstituted Complex	physical	18498745, 23045529, (Europe PMC)	NA	BioGRID
GRB10	Affinity Capture-Western, Reconstituted Complex	physical	12783867, 8621530, (Europe PMC)	NA	BioGRID
GRB2	Affinity Capture-MS, Affinity Capture-Western, Protein-peptide, Reconstituted Complex, anti tag coimmunoprecipitation	association, physical	12173038, 21706016, 22974441, 8491186, 8536716, (Europe PMC)	0.35	BioGRID, IntAct
HDAC2	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	15522123, (Europe PMC)	NA	BioGRID
IGF1R	Affinity Capture-Western, Two-hybrid, two hybrid	physical, physical association	10082579, 7541045, 7559507, 8776723, (Europe PMC)	0.37	BioGRID, IntAct
IKBKB	Affinity Capture-Western	physical	12351658, (Europe PMC)	NA	BioGRID
INSR	Affinity Capture-Western, Biochemical Activity, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down, two hybrid	association, direct interaction, physical, physical association	11606564, 11781100, 16582879, 17167487, 25667086, 7499194, 7935368, 8626379, 8662806, (Europe PMC)	0.35, 0.70	BioGRID, IntAct, MINT
IRS2	Co-fractionation	physical	12554758, (Europe PMC)	NA	BioGRID
JAK1	Affinity Capture-Western, Biochemical Activity	physical	7499365, 9492017, (Europe PMC)	NA	BioGRID
JAK2	Affinity Capture-Western, Biochemical Activity	physical	11208867, 9492017, (Europe PMC)	NA	BioGRID
JAK3	Affinity Capture-Western	physical	7499365, (Europe PMC)	NA	BioGRID
KHDRBS1	Affinity Capture-Western	physical	11604231, 8175658, (Europe PMC)	NA	BioGRID
LRRK2	protein array	direct interaction	24947832, (Europe PMC)	0.44	IntAct
MAPK3	Biochemical Activity	physical	17640984, (Europe PMC)	NA	BioGRID
MAPK8	Affinity Capture-Western, Reconstituted Complex, Two-hybrid	physical	10722755, 11606564, (Europe PMC)	NA	BioGRID
MTOR	Affinity Capture-Western, Biochemical Activity	physical	11287630, 16354680, (Europe PMC)	NA	BioGRID
NCK2	Reconstituted Complex	physical	9843575, (Europe PMC)	NA	BioGRID
NEDD4	Reconstituted Complex	physical	19953087, (Europe PMC)	NA	BioGRID
NISCH	Affinity Capture-Western	physical	11912194, (Europe PMC)	NA	BioGRID
NUMB	Two-hybrid	physical	25814554, (Europe PMC)	NA	BioGRID
NUMB	two hybrid array, validated two hybrid	physical association	25814554, (Europe PMC)	0.49	IntAct
PABPC1	anti bait coimmunoprecipitation	association, physical association	23770097, (Europe PMC)	0.50	IntAct, MINT
PELI1	Two-hybrid, two hybrid array	physical, physical association	25814554, (Europe PMC)	0.37	BioGRID, IntAct
PIK3CA	Affinity Capture-Western, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, pull down	association, direct interaction, physical, physical association	12933652, 14511371, 16150444, 16354680, 23604317, 23643389, (Europe PMC)	0.75	BioGRID, IntAct, MINT
PIK3CB	Affinity Capture-Western	physical	23604317, (Europe PMC)	NA	BioGRID
PIK3R1	Affinity Capture-Luminescence, Affinity Capture-Western, Far Western, Protein-peptide, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, coimmunoprecipitation, cross-linking study, enzymatic study, luminescence based mammalian interactome mapping, nuclear magnetic resonance, pull down, surface plasmon resonance, two hybrid, two hybrid array, validated two hybrid	association, physical, physical association	11403293, 11416002, 12107746, 12173038, 12730242, 1381348, 14511371, 14632132, 15514089, 16150444, 16230374, 16354680, 17640984, 19561084, 22974441, 23439647, 23643389, 25814554, 7680095, 7680644, 8175658, 8382612, 8628286, 9564850, (Europe PMC)	0.57, 0.92	BioGRID, IntAct, MINT
PIK3R2	Affinity Capture-Western	physical	23604317, (Europe PMC)	NA	BioGRID
PIK3R3	Affinity Capture-Luminescence, Affinity Capture-Western, Two-hybrid, luminescence based mammalian interactome mapping, two hybrid array, validated two hybrid	physical, physical association	10417350, 25814554, 9415396, (Europe PMC)	0.57	BioGRID, IntAct
PLCG2	Protein-peptide	physical	22974441, (Europe PMC)	NA	BioGRID
PRKCD	Affinity Capture-Western, Biochemical Activity	physical	12031982, 15516986, (Europe PMC)	NA	BioGRID
PTK2	Affinity Capture-Western, Two-hybrid	physical	9822703, (Europe PMC)	NA	BioGRID
PTPN1	Affinity Capture-Western, Reconstituted Complex, phosphatase assay	dephosphorylation reaction, physical	10660596, 11579209, (Europe PMC)	0.44	BioGRID, IntAct, MINT
PTPN11	Affinity Capture-Western, Biochemical Activity, Protein-peptide, Reconstituted Complex, surface plasmon resonance	association, physical	11781100, 22974441, 7513703, 8505282, 9756938, (Europe PMC)	0.35	BioGRID, IntAct, MINT
PTPRD	protein array	direct interaction	22305495, (Europe PMC)	0.44	IntAct, MINT
PTPRU	Biochemical Activity	physical	11781100, (Europe PMC)	NA	BioGRID
RPS6KB1	Biochemical Activity, Reconstituted Complex	physical	18498745, 23045529, (Europe PMC)	NA	BioGRID
RPTOR	Affinity Capture-Western, Reconstituted Complex	physical	16354680, 19561084, (Europe PMC)	NA	BioGRID
SFN	Affinity Capture-MS, tandem affinity purification	physical, physical association	15778465, (Europe PMC)	0.40	BioGRID, IntAct, MINT
SH2B1	Protein-peptide	physical	22974441, (Europe PMC)	NA	BioGRID
SIRT1	Affinity Capture-Western, anti bait coimmunoprecipitation	physical, physical association	17901049, 21241768, (Europe PMC)	0.40	BioGRID, IntAct
SMAD3	Affinity Capture-MS, tandem affinity purification	physical, physical association	18729074, (Europe PMC)	0.40	BioGRID, IntAct
SOCS1	Affinity Capture-Western	physical	12228220, 17276034, (Europe PMC)	NA	BioGRID
SOCS3	Affinity Capture-Western	physical	15514089, (Europe PMC)	NA	BioGRID
UBC	Reconstituted Complex	physical	23045529, (Europe PMC)	NA	BioGRID
UBTF	Affinity Capture-Western	physical	12554758, 17332342, (Europe PMC)	NA	BioGRID
YWHAB	Reconstituted Complex	physical	9422753, (Europe PMC)	NA	BioGRID
YWHAE	Reconstituted Complex, Two-hybrid, competition binding, pull down, two hybrid	association, direct interaction, physical, physical association	9111084, 9312143, (Europe PMC)	0.68	BioGRID, IntAct, MINT
YWHAH	Affinity Capture-Western	physical	11969417, (Europe PMC)	NA	BioGRID

Top

IRS1