Homo sapiens Protein: INSR
InnateDB Protein IDBP-22533.6
Last Modified 2014-10-13 [Report errors or provide feedback]
Gene Symbol INSR
Protein Name insulin receptor
Synonyms CD220; HHF5;
Species Homo sapiens
Ensembl Protein ENSP00000303830
InnateDB Gene IDBG-22529 (INSR)
Protein Structure
UniProt Annotation
Function Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src- homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti- apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K- AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. {ECO:0000269PubMed:12138094, ECO:0000269PubMed:16314505, ECO:0000269PubMed:16831875, ECO:0000269PubMed:8257688, ECO:0000269PubMed:8276809, ECO:0000269PubMed:8452530, ECO:0000269PubMed:9428692}.
Subcellular Localization Cell membrane; Single-pass type I membrane protein.
Disease Associations Rabson-Mendenhall syndrome (RMS) [MIM:262190]: Severe insulin resistance syndrome characterized by insulin-resistant diabetes mellitus with pineal hyperplasia and somatic abnormalities. Typical features include coarse, senile-appearing facies, dental and skin abnormalities, abdominal distension, and phallic enlargement. Inheritance is autosomal recessive. {ECO:0000269PubMed:10443650, ECO:0000269PubMed:12023989, ECO:0000269PubMed:17201797, ECO:0000269PubMed:2365819, ECO:0000269PubMed:8314008}. Note=The disease is caused by mutations affecting the gene represented in this entry.Leprechaunism (LEPRCH) [MIM:246200]: Represents the most severe form of insulin resistance syndrome, characterized by intrauterine and postnatal growth retardation and death in early infancy. Inheritance is autosomal recessive. {ECO:0000269PubMed:12538626, ECO:0000269PubMed:12970295, ECO:0000269PubMed:1607067, ECO:0000269PubMed:1730625, ECO:0000269PubMed:2365819, ECO:0000269PubMed:2479553, ECO:0000269PubMed:2834824, ECO:0000269PubMed:7538143, ECO:0000269PubMed:7815442, ECO:0000269PubMed:8188715, ECO:0000269PubMed:8326490, ECO:0000269PubMed:8419945, ECO:0000269PubMed:8636294, ECO:0000269PubMed:9249867, ECO:0000269PubMed:9703342}. Note=The disease is caused by mutations affecting the gene represented in this entry.Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269PubMed:1470163, ECO:0000269PubMed:1607076, ECO:0000269PubMed:7657032}. Note=The gene represented in this entry may be involved in disease pathogenesis.Familial hyperinsulinemic hypoglycemia 5 (HHF5) [MIM:609968]: Familial hyperinsulinemic hypoglycemia [MIM:256450], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. {ECO:0000269PubMed:15161766}. Note=The disease is caused by mutations affecting the gene represented in this entry.Insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:610549]: Characterized by the association of severe insulin resistance (manifested by marked hyperinsulinemia and a failure to respond to exogenous insulin) with the skin lesion acanthosis nigricans and ovarian hyperandrogenism in adolescent female subjects. Women frequently present with hirsutism, acne, amenorrhea or oligomenorrhea, and virilization. This syndrome is different from the type B that has been demonstrated to be secondary to the presence of circulating autoantibodies against the insulin receptor. {ECO:0000269PubMed:10733238, ECO:0000269PubMed:11260230, ECO:0000269PubMed:12107746, ECO:0000269PubMed:12970295, ECO:0000269PubMed:1563582, ECO:0000269PubMed:1963473, ECO:0000269PubMed:2002058, ECO:0000269PubMed:2168397, ECO:0000269PubMed:2365819, ECO:0000269PubMed:2544998, ECO:0000269PubMed:3283938, ECO:0000269PubMed:8243830, ECO:0000269PubMed:8288049, ECO:0000269PubMed:8314008, ECO:0000269PubMed:8388389, ECO:0000269PubMed:9175790}. Note=The disease is caused by mutations affecting the gene represented in this entry.
Tissue Specificity Isoform Long and isoform Short are predominantly expressed in tissue targets of insulin metabolic effects: liver, adipose tissue and skeletal muscle but are also expressed in the peripheral nerve, kidney, pulmonary alveoli, pancreatic acini, placenta vascular endothelium, fibroblasts, monocytes, granulocytes, erythrocytes and skin. Isoform Short is preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney. Found as a hybrid receptor with IGF1R in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Overexpressed in several tumors, including breast, colon, lung, ovary, and thyroid carcinomas. {ECO:0000269PubMed:10207053, ECO:0000269PubMed:2369896, ECO:0000269PubMed:9202395, ECO:0000269PubMed:9355755}.
Number of Interactions This gene and/or its encoded proteins are associated with 135 experimentally validated interaction(s) in this database.
They are also associated with 12 interaction(s) predicted by orthology.
Experimentally validated
Total 135 [view]
Protein-Protein 132 [view]
Protein-DNA 2 [view]
Protein-RNA 0
DNA-DNA 1 [view]
Predicted by orthology
Total 12 [view]
Gene Ontology

Molecular Function
Accession GO Term
GO:0004672 protein kinase activity
GO:0004713 protein tyrosine kinase activity
GO:0004714 transmembrane receptor protein tyrosine kinase activity
GO:0004716 receptor signaling protein tyrosine kinase activity
GO:0005009 insulin-activated receptor activity
GO:0005159 insulin-like growth factor receptor binding
GO:0005515 protein binding
GO:0005524 ATP binding
GO:0005525 GTP binding
GO:0016772 transferase activity, transferring phosphorus-containing groups
GO:0031994 insulin-like growth factor I binding
GO:0031995 insulin-like growth factor II binding
GO:0043548 phosphatidylinositol 3-kinase binding
GO:0043559 insulin binding
GO:0043560 insulin receptor substrate binding
GO:0051425 PTB domain binding
Biological Process
GO:0000187 activation of MAPK activity
GO:0001934 positive regulation of protein phosphorylation
GO:0003007 heart morphogenesis
GO:0005975 carbohydrate metabolic process
GO:0006355 regulation of transcription, DNA-templated
GO:0006468 protein phosphorylation
GO:0007169 transmembrane receptor protein tyrosine kinase signaling pathway
GO:0007186 G-protein coupled receptor signaling pathway
GO:0008284 positive regulation of cell proliferation
GO:0008286 insulin receptor signaling pathway
GO:0008544 epidermis development
GO:0009887 organ morphogenesis
GO:0018108 peptidyl-tyrosine phosphorylation
GO:0019087 transformation of host cell by virus
GO:0023014 signal transduction by phosphorylation
GO:0030238 male sex determination
GO:0030335 positive regulation of cell migration
GO:0031017 exocrine pancreas development
GO:0032147 activation of protein kinase activity
GO:0032148 activation of protein kinase B activity
GO:0032869 cellular response to insulin stimulus
GO:0038083 peptidyl-tyrosine autophosphorylation
GO:0042593 glucose homeostasis
GO:0043410 positive regulation of MAPK cascade
GO:0045429 positive regulation of nitric oxide biosynthetic process
GO:0045725 positive regulation of glycogen biosynthetic process
GO:0045740 positive regulation of DNA replication
GO:0045821 positive regulation of glycolytic process
GO:0045840 positive regulation of mitosis
GO:0045995 regulation of embryonic development
GO:0046326 positive regulation of glucose import
GO:0046777 protein autophosphorylation
GO:0048639 positive regulation of developmental growth
GO:0051290 protein heterotetramerization
GO:0051897 positive regulation of protein kinase B signaling
GO:0060267 positive regulation of respiratory burst
GO:0071363 cellular response to growth factor stimulus
Cellular Component
GO:0005886 plasma membrane
GO:0005887 integral component of plasma membrane
GO:0005899 insulin receptor complex
GO:0005901 caveola
GO:0010008 endosome membrane
GO:0016020 membrane
GO:0016021 integral component of membrane
GO:0043235 receptor complex
GO:0070062 extracellular vesicular exosome
Protein Structure and Domains
InterPro IPR000494 EGF receptor, L domain
IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR003961 Fibronectin, type III
IPR006211 Furin-like cysteine-rich domain
IPR006212 Furin-like repeat
IPR009030 Insulin-like growth factor binding protein, N-terminal
IPR011009 Protein kinase-like domain
IPR016246 Tyrosine-protein kinase, insulin-like receptor
IPR020635 Tyrosine-protein kinase, catalytic domain
PFAM PF01030
Post-translational Modifications
SwissProt P06213
PhosphoSite PhosphoSite-P06213
UniProt Splice Variant
Entrez Gene 3643
UniGene Hs.694195
RefSeq NP_000199
OMIM 147670
HPRD 00975
EMBL AB208861 AC010311 AC010526 AC010606 AC125387 AK300332 BC117172 DQ021481 DQ311687 DQ333191 DQ333192 DQ333193 DQ333194 DQ333196 EF207604 EF207607 EF207609 EF207611 EF207612 J03466 J05043 M10051 M23100 M24555 M27195 M27197 M29929 M29930 M32823 M32824 M32825 M32826 M32827 M32828 M32829 M32830 M32831 M32832 M32833 M32834 M32835 M32836 M32837 M32838 M32839 M32840 M32841 M32842 M32972 M76592 X02160
GenPept AAA59174 AAA59175 AAA59176 AAA59177 AAA59178 AAA59190 AAA59452 AAA86791 AAC37604 AAI17173 AAY44085 ABC46548 ABC46549 ABC46550 ABC46551 ABC46553 ABC55359 ABP68900 ABP68903 ABP68905 ABP68907 ABP73389 BAD92098 BAG62079 CAA26096