Insulin Receptor

The insulin receptor is a member of the ligand-activated receptor and tyrosine kinase family of transmembrane signaling proteins that collectively are fundamentally important regulators of cell differentiation, growth, and metabolism. The insulin receptor has a number of unique physiological and biochemical properties that distinguish it from other members of this large well-studied receptor family. The main physiological role of the insulin receptor appears to be metabolic regulation, whereas all other receptor tyrosine kinases are engaged in regulating cell growth and/or differentiation.

1360433-93-7
KW-2450 Tosylate salt
1360433-93-7
1384426-12-3
NT-157
1384426-12-3
189224-48-4
KU14R
189224-48-4

Background


The insulin receptor is a member of the ligand-activated receptor and tyrosine kinase family of transmembrane signaling proteins that collectively are fundamentally important regulators of cell differentiation, growth, and metabolism. It is a heterotetramer of two α subunits and two β subunits. The insulin receptor shares similarities with the insulin-related receptor and the insulin-like growth factor-1 receptor. The α subunit serves as an allosteric inhibitor of the β subunit under basal conditions. Insulin stimulation activates tyrosine kinase activity through a conformational change that leads to transphosphorylation of specific β subunit tyrosine residues thereby relieving the repression of the β subunit.

The insulin receptor has a number of unique physiological and biochemical properties that distinguish it from other members of this large well-studied receptor family. The main physiological role of the insulin receptor appears to be metabolic regulation, whereas all other receptor tyrosine kinases are engaged in regulating cell growth and/or differentiation. The insulin receptor propagates insulin signaling via tyrosine phosphorylation of substrate proteins that form a scaffold for a myriad of signaling events.

The identification of mutations in the insulin receptor gene that leads to diabetes with a broad spectrum of cell biological defects is the strongest evidence for the insulin receptor mediating insulin signal transduction. There are three tyrosine residues (Tyr-1146, Tyr-1162 and Tyr-1163) that have been identified as critical in mediating insulin signaling within the β subunit. Tyr-1146 is the most critical among the three tyrosine residues. Mutation of Tyr-1146 results in an 80% reduction in tyrosine autophosphorylation and failure to detect endogenous substrates. There is some evidence that insulin and insulinrelated receptors form functional hybrids with each other and that an inhibitory mutation in one receptor monomer could inhibit the activity of the other. Whether this phenomenon occurs in vivo is not known.

In skeletal muscle, the insulin receptor substrate (IRS-1) serves as a major docking protein and undergoes tyrosine phosphorylation by the activated insulin receptor in regions containing specific amino acid sequence motifs. Mutations of these specific tyrosine residues in IRS-1 severely impair the ability of insulin to stimulate muscle glycogen synthesis, glucose uptake, oxidation and the growth promoting effects of insulin. The phosphorylated tyrosine residues of IRS-1 mediate an association with the regulatory subunit of phosphatidylinositol 3-kinase (PI3K), leading to its activation.

The ligands of the insulin family exert their physiological effects via their cellsurface receptors: insulin binds to the insulin receptor (IR), while IGFs bind to the type-1 insulin-like growth factor receptor (IGF1R). The entire sequence of IR and IGF1R precursors contains 1370 and 1367 amino acids, respectively. Both IR and IGF1R are highly homologous membrane-spanning glycoproteins of the receptor tyrosine kinase (RTK) superfamily. Both are also unique among RTKs due to their covalently-linked homo-dimeric architecture, which also means that these receptors need domain rearrangements rather than receptor dimerization for activation. Each subunit in the IR family has an extracellular L1-CR-L2 motif common to hormone receptors, linked to three fibronectin type-Ill repeats, Fl, F2, and F3, which connect through the plasma membrane via a single helix to the cytoplasmic kinase domain. The (Ll-CR) and (L2-F1-F2) domains of IGF1R form two distinct binding epitopes for growth factors, designated traditionally as site 1, and site 2, respectively. However, site 1 and site 2 of IR are limited only to LI and (F1-F2), respectively.

Reference: Harish Vashisth. Molecular Simulation Studies of the Insulin Receptor Family