The insulin receptor and signal transduction

The insulin receptor is a tetrameric integral membrane glycoprotein consisting of two 735 amino acid a-chains and two 620 amino acid P-chains. These are held together by disulfide linkages (Figure 11.2). The a-chain resides entirely on the extracellular side of the plasma membrane and contains the cysteine-rich insulin-binding domain.

Each P-subunit is composed of three regions: the extracellular domain, the transmembrane domain and a large cytoplasmic domain that displays tyrosine kinase activity. In the absence of bovine insulin, tyrosine kinase activity is very weak. Proteolytic digestion of the a-subunit results in activation of this kinase activity. It is believed that the intact a-subunit exerts a negative influence on the endogenous kinase of the P-subunit and that binding of insulin, by causing a confor-mational shift in a-subunits, relieves this negative influence.

The cytoplasmic domain of the P-subunit displays three distinct sub-domains: (a) the 'juxtam-embrane domain', implicated in recognition/binding of intracellular substrate molecules; (b) the tyrosine kinase domain, which (upon receptor activation) displays tyrosine kinase activity; (c) the C-terminal domain, whose exact function is less clear, although site-directed mutagenesis studies implicate it promoting insulin's mitogenic effects.

The molecular mechanisms central to insulin signal transduction are complex and have yet to be fully elucidated. However, considerable progress in this regard has been made over the last decade. Binding of insulin to its receptor promotes the autophosphorylation of three specific tyrosine residues in the tyrosine kinase domain (Figure 11.2b). This, in turn, promotes an alteration in the conformational state of the entire P-subunit, unmasking adenosine triphosphate (the phosphate donor) binding sites and substrate docking sites and activating its tyrosine kinase activity. Depending upon which specific intracellular substrates are then phosphorylated, at least two different signal transduction pathways are initiated (Figure 11.2c). Activation of the 'mitogen-activated protein kinase' pathway is ultimately responsible for triggering insulin's mitogenic effects, whereas activation of the PI-3 kinase pathway apparently mediates the majority of insulin's metabolic effects. Many of these effects, in particular the mitogenic effects, are promoted via transcriptional regulation of insulin-sensitive genes, of which there are probably in excess of 100 (Table 11.2).

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Supplements For Diabetics

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