Fig. 2.

Signaling pathway downstream of PI3K affect cell death and cell survival. Activation of growth factor receptor protein tyrosine kinases results in autophosphorylation on tyrosine residues and transphosphorylation of adaptor proteins such as IRS. PI3K can also be stimulated by integrin-dependent cell adhesion and by G-protein coupled receptors (not shown). PI3K is brought to the membrane and activated by directly binding to phosphotyrosine residues of growth factor receptors or adapters. The lipid products of PI3K, PI-3,4-P₂, or PI-3,4,5-P₃, recruit a subset of signaling proteins with pleckstrin homology (PH) domains to the membrane where they are activated. The proteins include protein serine-threonine kinases, protein tyrosine kinases, exchange factors, and adaptor proteins (downstream effectors). Ultimately these proteins initiate complex sets of events that control protein synthesis, actin polymerization, cell survival, and cell entry. PI3K, phosphoinositide 3-kinase; IRS, insulin receptor substrate; PH, pleckstrin homology.