INSULIN SIGNAL-TRANSDUCTION AND THE IRS PROTEINS

Insulin controls organismal and cellular physiology by initiating nume rous intracelluar signals. Insulin first binds the extracelluar domain of the insulin receptor, which activates the receptor's intracellular tyrosine kinase. Receptor-mediated phosphorylation of the IRS protein s is required for the propagation of signals for mitogenesis, glucose transport, and numerous other biological and biochemical events during insulin signaling. IRS proteins also mediate signaling by a subset of other growth factor and cytokine receptors; recognition and phosphory lation by specific receptors appears to be mediated by the PH and PTB domains of the IRS proteins. The best understood mechainsm of IRS-prot ein-mediated signaling is the binding of SH2 domain-containing signali ng molecules (such as PI 3'-kinase) by tyrosine phosphorylation sites on IRS proteins. Other paradigms of IRS-protein signaling are beginnin g to emerge, however, and these exciting molecules promise to teach us much in the next few years.