Surfing the insulin signaling web

The diverse biological actions of insulin and insulin-like growth factor I (IGF-I) are initiated by binding of the polypeptides to their respective ce ll surface tyrosine kinase receptors. These activated receptors phosphoryla te a series of endogenous substrates on tyrosine, amongst which the insulin receptor substrate (IRS) proteins are the best characterized. Their phosph otyrosine-containing motifs become binding sites for Src homology 2 (SH2) d omains on proteins such as SH2 domain-containing protein-tyrosine-phosphata se (SHP)-2/Syp, growth factor receptor bound-2 protien, (Grb-2), and phosph atidyl inositol 3 kinase (PI3 kinase), which participate in activation of s pecific signaling cascades. However, the IRS molecules are not only platfor ms for signaling molecules, they also orchestrate the generation of signal specificity integration of signals induced by several extracellular stimuli , and signal termination and modulation. An extensive review is beyond the scope of the present article, which will be centered on our own contributio n and reflect our biases.