The Insulin Receptor: Transduction through Tyrosine Kinase

An understanding of insulin resistance requires knowledge of the mechanisms of
insulin action in target tissues, such as liver, muscle and adipose tissue. The net
responses to this hormone include short-term metabolic effects, such as a rapid
increase in the uptake of glucose, and longer-term effects on cellular differentiation and growth [12]. The -subunits of the insulin receptor are located extracellularly and are the insulin-binding sites. Ligand binding promotes autophosphorylation of multiple tyrosine residues located in the cytoplasmic portions of -subunits. This autophosphorylation facilitates binding of cytosolic substrate proteins, such as IRS-1. When phosphorylated, this substrate acts as a docking protein for proteins mediating insulin action. Although the insulin receptor becomes autophosphorylated on tyrosines and phosphorylates tyrosines of IRS-1, other mediators are phosphorylated predominantly on serine and threonine residues. An insulin second messenger, possibly a glycoinositol derivative that stimulates phosphoprotein phosphatases, may be released at the cell membrane to account for the short-term metabolic effects of insulin. The activated -subunit also catalyzes the phosphorylation of other members of the IRS family, such as Shc and Cbl. Upon tyrosine phosphorylation, these proteins interact with other signaling molecules (such as p85, and Grb2-Sos and SHP-2) through their SH2 (Src-homolog-2) domains, which bind to a distinct sequence of amino acids surrounding a phosphotyrosine residue. Several diverse pathways are activated, and those include activation of phosphatidylinositol 3-OH kinase (PI3K), the small GTP-binding protein Ras, the mitogen-activated protein (MAP) kinase cascade, and the small GTP-binding protein TC10. Formation of the IRS-1/p85 complex activates PI3 kinase (class 1A), which transmits the major metabolic actions of insulin via downstream effectors such as phosphoinositide-dependent kinase 1 (PDK1), Akt and mTOR. The IRS-l/Grb2-Sos complex and SHP-2 transmit mitogenic signals through the activation of Ras to activate MAP kinase. Once activated via an exchange of GTP for GDP, TC10 promotes translocation of GLUT4 vesicles to the plasma membrane of muscle and fat cells, perhaps by stabilizing cortical actin filaments.

These pathways coordinate the regulation of vesicle trafficking (incorporation
of GLUT4 into the plasma membrane), protein synthesis, enzyme activation and
inactivation, and gene expression [for further details, see 12, 13]. The net result of these diverse pathways is regulation of glucose, lipid, and protein metabolism as well as cell growth and differentiation.