Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins

The docking protein FRS2 is a major downstream effector that links fibrobla st growth factor (FGF) and nerve growth factor receptors with the Ras/mitog en-activated protein kinase signaling cascade. In this report, we demonstra te that FRS2 also plays a pivotal role in FCF-induced recruitment and activ ation of phosphatidylinositol 3-kinase (PI3-kinase). We demonstrate that ty rosine phosphorylation of FRS2 alpha leads to Grb2-mediated complex formati on with the docking protein Gab1 and its tyrosine phosphorylation. resultin g in the recruitment and activation of PI3-kinase. Furthermore, Grb2 bound to tyrosine-phosphorylated FRS2 through its SH2 domain interacts primarily via its carboxyl-terminal SH3 domain with a proline-rich region in Gab1 and via its amino-terminal SH3 domain with the nucleotide exchange factor Sos1 . Assembly of FRS2 alpha :Grb2:Gab1 complex induced by FGF stimulation resu lts in activation of PI3-kinase and downstream effector proteins such as th e S/T kinase Akt, whose cellular localization and activity are regulated by products of PI3-kinase. These experiments reveal a unique mechanism for ge neration of signal diversity by growth factor-induced coordinated assembly of a multidocking protein complex that can activate the Ras/mitogen-activat ed protein kinase cascade to induce cell proliferation and differentiation, and PI3-kinase to activate a mediator of a cell survival pathway.