The insulin receptor belongs to a subfamily of receptor tyrosine kinases that also includes the IGF-1 receptor and an orphan receptor called the insulin receptor-related receptor (IRR). It is a tetrameric protein consisting of two α- and two β-subunits encoded by the IR gene. The two subunits derived from a single chain proreceptor undergo post translational processing including cleavage by a furin-like enzyme and glycosylation, forming a single α-β subunit complex. Two of the α-β dimers are then cross linked by disulfide bonds to form the tetramer.
Ligand (insulin or IGF-1) binding to the α-subunit leads to activation of the kinase activity in the β-subunit. Following this initial activation, phosphorylation of one β-subunit by the other (transphosphorylation), leads to a conformational change and a further increase in activity of the kinase domain. Activation of the tyrosine kinase domain leads to autophosphorylation of tyrosine residues in several regions of the intracellular β-subunit, including Tyr960 in the juxtamembrane region, creating an NPXpY recognition motif for the PTB domain of the IRS proteins, Tyr1146, Tyr1150 and Tyr1151 in the regulatory loop and Tyr1316 and Tyr1322 in the C-terminus.
The α-β heterodimers of the individual insulin, IGF-1 and the IRR receptors can form functional hybrids in which ligand binding to one receptor’s binding site leads to activation of the other receptor in the heterodimer by this transphosphorylation process.
Intracellular substrates of the insulin and IGF-1 receptor tyrosine kinases that have been identified include insulin receptor substrate (IRS) proteins 1-4, Gab-1, p62dok, Cbl, APS and the various isoforms of Shc. Following insulin stimulation, the receptor directly phosphorylates most of these substrates on multiple tyrosine residues. These phosphorylated tyrosines occur in specific sequence motifs, which once phosphorylated serve as ‘docking sites’ for intracellular molecules that contain the SH2 (Src-homology) domain, transmitting the insulin signal downstream. A few proteins that bind to phosphotyrosines in the IRS proteins do not contain known SH2 domains; these include the calcium ATPases SERCA 1 and 2, and the SV40 large T antigen.
Negative regulation of insulin receptor signaling has been demonstrated by the tyrosine phosphatase PTP1B, which dephosphorylates the phosphotyrosine residues in the insulin receptor kinase and also through direct association of the novel PIR domain of the Grb14 adaptor protein with the insulin receptor.
Alterations in the function of the insulin receptor, both genetic and acquired, can lead to several different disease states including insulin resistance, diabetes and growth retardation. Insulin resistance at the level of the receptor may be the result of genetic alterations in receptor expression or structure, secondary changes in receptor activity due to serine phosphorylation, or due to down-regulation of receptor concentration. Insulin resistance is also closely linked to other common health problems, including obesity, polycystic ovarian disease, hyperlipidemia, hypertension and atherosclerosis.
The insulin receptor is widely distributed throughout the body, found in tissues classically regarded as both insulin 'responsive', for example muscle, liver and fat, and 'non-responsive', for example brain and the vascular system. It signals through two major signaling pathways, the IRS/PI 3-kinase pathway and the Ras-MAP kinase pathway, controlling processes including glucose transport, uptake and storage, glycogen synthesis, cell growth and differentiation, protein synthesis and gene expression.
Tissue specific knockouts of the insulin receptor have helped to define the role of the receptor in the classical insulin sensitive tissues and identified novel functions in other tissues. The Muscle specific Insulin Receptor Knockout (MIRKO) mouse model exhibits increased insulin stimulated glucose uptake in the fat, suggesting 'cross-talk' between muscle and fat in insulin resistant states. Fat specific knockout (FIRKO) mice have decreased fat mass, are resistant to diet induced obesity and have an extended lifespan, suggesting an interesting role for the insulin receptor in regulating longevity. The neuron specific insulin receptor knockout (NIRKO) has confirmed the importance of the receptor in brain and highlighted a role for it in appetite regulation.
Defining the key steps that lead to specificity in insulin signaling should offer therapeutic approaches for patients suffering from insulin resistant states, including type 2 diabetes.
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