ID:INSR_HUMAN DESCRIPTION: RecName: Full=Insulin receptor; Short=IR; EC=2.7.10.1; AltName: CD_antigen=CD220; Contains: RecName: Full=Insulin receptor subunit alpha; Contains: RecName: Full=Insulin receptor subunit beta; Flags: Precursor; 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. CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. ENZYME REGULATION: Activated in response to insulin. Autophosphorylation activates the kinase activity. PTP1B dephosphorylates important tyrosine residues, thereby reducing INSR activity. Inhibited by ENPP1. GRB10 and GRB14 inhibit the catalytic activity of the INSR, they block access of substrates to the activated receptor. SOCS1 and SOCS3 act as negative regulators of INSR activity, they bind to the activated INRS and interfere with the phosphorylation of INSR substrates. SUBUNIT: Tetramer of 2 alpha and 2 beta chains linked by disulfide bonds. The alpha chains contribute to the formation of the ligand- binding domain, while the beta chains carry the kinase domain. Forms a hybrid receptor with IGF1R, the hybrid is a tetramer consisting of 1 alpha chain and 1 beta chain of INSR and 1 alpha chain and 1 beta chain of IGF1R. Interacts with SORBS1 but dissociates from it following insulin stimulation. Binds SH2B2. Activated form of INSR interacts (via Tyr-999) with the PTB/PID domains of IRS1 and SHC1. The sequences surrounding the phosphorylated NPXY motif contribute differentially to either IRS1 or SHC1 recognition. Interacts (via tyrosines in the C-terminus) with IRS2 (via PTB domain and 591-786 AA); the 591-786 would be the primary anchor of IRS2 to INSR while the PTB domain would have a stabilizing action on the interaction with INSR. Interacts with the SH2 domains of the 85 kDa regulatory subunit of PI3K (PIK3R1) in vitro, when autophosphorylated on tyrosine residues. Interacts with SOCS7. Interacts (via the phosphorylated Tyr-999), with SOCS3. Interacts (via the phosphorylated Tyr-1185, Tyr-1189, Tyr- 1190) with SOCS1. Interacts with CAV2 (tyrosine-phosphorylated form); the interaction is increased with 'Tyr-27'phosphorylation of CAV2 (By similarity). Interacts with ARRB2 (By similarity). Interacts with GRB10; this interaction blocks the association between IRS1/IRS2 and INSR, significantly reduces insulin- stimulated tyrosine phosphorylation of IRS1 and IRS2 and thus decreases insulin signaling. Interacts with GRB7 (By similarity). Interacts with PDPK1. Interacts (via Tyr-1190) with GRB14 (via BPS domain); this interaction protects the tyrosines in the activation loop from dephosphorylation, but promotes dephosphorylation of Tyr-999, this results in decreased interaction with, and phosphorylation of, IRS1. Interacts (via subunit alpha) with ENPP1 (via 485-599 AA); this interaction blocks autophosphorylation. Interacts with PTPRE; this interaction is dependent of Tyr-1185, Tyr-1189 and Tyr-1190 of the INSR. Interacts with STAT5B (via SH2 domain). Interacts with PTPRF. SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane protein. 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. PTM: After being transported from the endoplasmic reticulum to the Golgi apparatus, the single glycosylated precursor is further glycosylated and then cleaved, followed by its transport to the plasma membrane. PTM: Autophosphorylated on tyrosine residues in response to insulin. Phosphorylation of Tyr-999 is required for IRS1-, SHC1-, and STAT5B-binding. Dephosphorylated by PTPRE on Tyr-999, Tyr- 1185, Tyr-1189 and Tyr-1190 residues. Dephosphorylated by PTPRF. DISEASE: Defects in INSR are the cause of Rabson-Mendenhall syndrome (RMS) [MIM:262190]; also known as Mendenhall syndrome. RMS is a 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. DISEASE: Defects in INSR are the cause of leprechaunism (LEPRCH) [MIM:246200]; also known as Donohue syndrome. Leprechaunism 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. DISEASE: Defects in INSR may be associated with noninsulin- dependent diabetes mellitus (NIDDM) [MIM:125853]; also known as diabetes mellitus type 2. DISEASE: Defects in INSR are the cause of familial hyperinsulinemic hypoglycemia type 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. DISEASE: Defects in INSR are the cause of insulin-resistant diabetes mellitus with acanthosis nigricans type A (IRAN type A) [MIM:610549]. This syndrome is 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. SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily. SIMILARITY: Contains 3 fibronectin type-III domains. SIMILARITY: Contains 1 protein kinase domain. WEB RESOURCE: Name=Wikipedia; Note=Insulin receptor entry; URL="http://en.wikipedia.org/wiki/Insulin_receptor"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/INSR";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P06213
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
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:0007612 learning GO:0007613 memory GO:0008284 positive regulation of cell proliferation GO:0008286 insulin receptor signaling pathway GO:0008544 epidermis development GO:0008584 male gonad development GO:0009887 animal organ morphogenesis GO:0016310 phosphorylation GO:0018108 peptidyl-tyrosine phosphorylation GO:0019087 transformation of host cell by virus GO:0030238 male sex determination GO:0030325 adrenal gland development 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:0043243 positive regulation of protein complex disassembly 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:0045821 positive regulation of glycolytic process GO:0045840 positive regulation of mitotic nuclear division GO:0045893 positive regulation of transcription, DNA-templated 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:0051446 positive regulation of meiotic cell cycle GO:0051897 positive regulation of protein kinase B signaling GO:0060267 positive regulation of respiratory burst GO:0071363 cellular response to growth factor stimulus GO:0097062 dendritic spine maintenance GO:0097242 beta-amyloid clearance GO:1990535 neuron projection maintenance GO:2000194 regulation of female gonad development
LF384322 - JP 2014500723-A/191825: Polycomb-Associated Non-Coding RNAs. E00999 - cDNA encoding human insulin receptor. X02160 - Human mRNA for insulin receptor precursor. A18657 - cDNA sequence for human insulin receptor. M10051 - Human insulin receptor mRNA, complete cds. BC117172 - Homo sapiens insulin receptor, mRNA (cDNA clone MGC:150781 IMAGE:40125723), complete cds. E11271 - Human cDNA encoding insulin receptor. BC047591 - Homo sapiens insulin receptor, mRNA (cDNA clone IMAGE:4823710), partial cds. MA619899 - JP 2018138019-A/191825: Polycomb-Associated Non-Coding RNAs. AL365454 - Homo sapiens mRNA full length insert cDNA clone EUROIMAGE 926491. AK025527 - Homo sapiens cDNA: FLJ21874 fis, clone HEP02488. AB208861 - Homo sapiens mRNA for insulin receptor variant protein. JD174662 - Sequence 155686 from Patent EP1572962. FW339964 - Screening. AK300332 - Homo sapiens cDNA FLJ56779 complete cds, highly similar to Insulin receptor precursor (EC 2.7.10.1). JD272620 - Sequence 253644 from Patent EP1572962. JD490205 - Sequence 471229 from Patent EP1572962. JD540969 - Sequence 521993 from Patent EP1572962. JD158185 - Sequence 139209 from Patent EP1572962. JD243366 - Sequence 224390 from Patent EP1572962. JD258296 - Sequence 239320 from Patent EP1572962. JD524492 - Sequence 505516 from Patent EP1572962. JD490277 - Sequence 471301 from Patent EP1572962. JD166918 - Sequence 147942 from Patent EP1572962. JD252872 - Sequence 233896 from Patent EP1572962. JD220963 - Sequence 201987 from Patent EP1572962. M24555 - Human insulin receptor (INSR) mRNA, partial cds. S70454 - insulin receptor [human, familial insulin resistance patient, mRNA Partial Mutant, 66 nt]. JD140448 - Sequence 121472 from Patent EP1572962.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_insulinPathway - Insulin Signaling Pathway h_hdacPathway - Control of skeletal myogenesis by HDAC & calcium/calmodulin-dependent kinase (CaMK) h_ghPathway - Growth Hormone Signaling Pathway
Reactome (by CSHL, EBI, and GO)
Protein P06213 (Reactome details) participates in the following event(s):
R-HSA-74716 Insulin binds the insulin receptor R-HSA-74733 Insulin receptor de-phosphorylation R-HSA-74726 Dissociation of insulin from insulin receptor R-HSA-74707 Binding of IRS to insulin receptor R-HSA-74740 Binding of SHC1 to insulin receptor R-HSA-110011 Binding of Grb10 to the insulin receptor R-HSA-74712 Dissociation of IRS-P from insulin receptor R-HSA-74715 Autophosphorylation of insulin receptor R-HSA-74743 Dissociation of p-Y427-SHC1 from insulin receptor R-HSA-74742 Phosphorylation of SHC1 R-HSA-74711 Phosphorylation of IRS R-HSA-8857925 Inhibition of PP2A activity by phosphorylation of the catalytic subunit at tyrosine Y307 R-HSA-74752 Signaling by Insulin receptor R-HSA-77387 Insulin receptor recycling R-HSA-74713 IRS activation R-HSA-74751 Insulin receptor signalling cascade R-HSA-74749 Signal attenuation R-HSA-9006934 Signaling by Receptor Tyrosine Kinases R-HSA-162582 Signal Transduction R-HSA-6811558 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling R-HSA-199418 Negative regulation of the PI3K/AKT network R-HSA-1257604 PIP3 activates AKT signaling R-HSA-9006925 Intracellular signaling by second messengers
GeneReviews article(s) related to gene INSR: hi (Nonsyndromic Genetic Hyperinsulinism Overview) insr-ir (INSR-Related Severe Insulin Resistance Syndrome)
Gene Model Information
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Common Gene Haplotype Alleles 
