ins. These events trigger additional conformational changes that activate the receptor's tyrosine kinase function. The phosphotyrosine allow for the recruitment and subsequent phosphorylation of various receptor substrates including Irs1 and 2, Sh2b2 and Shc1; P-tyrosine 972, for instance is critical for binding the PTB (phosphotyrosine binding) domains of Irs1 and Shc1. Irs1 and 2 are widely expressed whereas Irs4 is restricted to thymus, kidney, beta cells and brain and Irs3 is only present in rodents with functions similar to Irs1. The phosphorylated substrates serve as docking sites for the binding of selected partners and the activation of downstream signaling cascades, primarily the PI3K-Akt and the Ras mediated Raf/Mek/Erk pathways. The SH2 (src homology 2) domains of p85 - the regulatory subunit of PI3K - and of Grb2 bind to phosphorylated insulin substrates and in the case of Grb2 to Shc1 as well. Via its N-terminal SH3 (src homology 3) domain, Grb2 associates with Sos (guanine nucleotide exchange factor for Ras), to activate Ras and the downstream Raf/Mek/Erk MAPK pathway. Both the autophosphorylation and the substrate driven kinase activities of the insulin receptor are very tightly regulated. The binding of Enpp1 to InsR is thought to block its autophosphorylation; dephopshorylation by tyrosine phosphatases deactivate it. Serine/threonine phosphorylation of both the receptor and Irs1 by members of protein kinase C inhibit the receptor's autophosphorylation and substrate kinase activity. As a note, increased PKC activity is believed to play a role in models of insulin resistance. The receptor's substrate activity is also inhibited by members of the Grb adaptor and Socs families of proteins. Socs protein bind to the insulin receptor, thus precluding the access of substrates and counteracting the kinase activity of the receptor. Socs proteins, in particular Socs1 and 3, have also been shown to interact with Irs1 and Irs2 and promote their ubiquitination leading to the subsequent degradation by the proteasome. Members of the Socs family also inhibit leptin pathway, particularly Socs3 whose expression is under the control of Stat3 acting downstream of the leptin activated Jak2. While PI3K is a main signaling pathway downstream of insulin and the particular Jak2-Stat3 combination is the main downstream effector of leptin, leptin mediated activation of Jak2 can also trigger PI3K via Irs phosphorylation by Jak2. In the brain, both leptin and insulin act to increase the expression of appetite-decreasing Pomc while decreasing the expression of appetite-stimulating Agrp genes albeit through different mechanisms. In the heart, skeletal muscle and adipose tissue, insulin signaling, via PI3K-Akt pathway, stimulates the exocytosis of Glut4 (Slc2a4 gene) containing vesicles to increase the presence of the transporter to the membrane and induce the uptake of glucose in these tissues. In the basal state, Slc2a4 is found in specialized vesicles. Elevated glucose levels trigger the secretion of insulin from the pancreatic beta cells of the islets of Langerhans. A number of miRNAs (micro-RNA) are involved in the insulin production and secretion and data show that miRNAs are also involved in the control of insulin action. To see the ontology report for annotations, GViewer and download, click here [click to see the ontology report for related GO term GO:0008286, KEGG map map04910 and entry at Reactome - REACT_498.5]

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