a receptor tyrosine kinase that 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 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. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). The holoenzyme is cleaved into two chains, the alpha and beta subunits. The active complex is a tetramer containing 2 alpha and 2 beta chains linked by disulfide bonds. The alpha chains constitute the ligand- binding domain, while the beta chains carry the kinase domain. Interacts with SORBS1 but dissociates from it following insulin stimulation. Familial mutations associated with insulin resistant diabetes, acanthosis nigricans, pineal hyperplasia, and polycystic ovary syndrome. SNP variants may be associated with polycystic ovary syndrome, atypical migraine and diabetic hyperlipidemia. Mutations also cause leprechaunism, a severe insulin resistance syndrome causing growth retardation and death in early infancy. Two isoforms of the human protein are produced by alternative splicing. The Short isoform has a higher affinity for insulin than the longer. 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. Overexpressed in several tumors, including breast, colon, lung, ovary, and thyroid carcinomas. Note: This description may include information from UniProtKB.
Protein type: EC 220.127.116.11; Protein kinase, tyrosine (receptor); Protein kinase, TK; Kinase, protein; Membrane protein, integral; TK group; InsR family
Cellular Component: intracellular membrane-bound organelle; membrane; integral to plasma membrane; plasma membrane; integral to membrane; synapse; caveola; nucleus; cytosol; receptor complex; endosome
Molecular Function: protein domain specific binding; GTP binding; PTB domain binding; transmembrane receptor protein tyrosine kinase activity; receptor signaling protein tyrosine kinase activity; protein phosphatase binding; insulin-like growth factor II binding; protein kinase binding; lipoic acid binding; protein kinase activity; insulin binding; insulin-like growth factor receptor binding; protein binding; insulin-like growth factor I binding; protein-tyrosine kinase activity; insulin receptor substrate binding; 3-phosphoinositide-dependent protein kinase binding; protein complex binding; phosphoinositide 3-kinase binding; ATP binding; insulin receptor activity
Biological Process: fat cell differentiation; heart morphogenesis; epidermis development; peptidyl-tyrosine phosphorylation; positive regulation of nitric oxide biosynthetic process; activation of MAPK activity; protein amino acid autophosphorylation; response to glucocorticoid stimulus; regulation of embryonic development; positive regulation of glycogen biosynthetic process; response to hormone stimulus; exocrine pancreas development; glucose homeostasis; protein amino acid phosphorylation; response to estradiol stimulus; response to insulin stimulus; positive regulation of glucose import; response to vitamin D; negative regulation of protein amino acid phosphorylation; positive regulation of MAPKKK cascade; regulation of transcription, DNA-dependent; male sex determination; positive regulation of cell proliferation; response to glucose stimulus; protein heterotetramerization; regulation of hydrogen peroxide metabolic process; response to nutrient levels; positive regulation of developmental growth; positive regulation of mitosis; activation of protein kinase B; response to testosterone stimulus; response to manganese ion; G-protein coupled receptor protein signaling pathway; positive regulation of protein kinase B signaling cascade; organ morphogenesis; response to ethanol; cellular response to insulin stimulus; positive regulation of glycolysis; insulin receptor signaling pathway; activation of protein kinase activity; response to activity; positive regulation of protein amino acid phosphorylation; negative regulation of transporter activity; transmembrane receptor protein tyrosine kinase signaling pathway; positive regulation of phosphorylation; positive regulation of DNA replication; positive regulation of cell migration; transformation of host cell by virus
SS: The number of records in which this modification site was determined using site-specific methods. SS methods include amino acid sequencing, site-directed mutagenesis, modification site-specific antibodies, specific MS strategies, etc.