Molecular mechanism for the Shp-2 tyrosine phosphatase function in promoting growth factor stimulation of Erk activity

We have previously shown that activation of extracellular signal-regulated kinase (Erk) by epidermal growth factor (EGF) treatment was significantly d ecreased in mouse fibroblast cells expressing a mutant Shp-2 molecule lacki ng 65 amino acids in the SH2-N domain, Shp-2(Delta 46-110). To address the molecular mechanism for the positive role of Shp-2 in mediating Erk inducti on, we evaluated the activation of signaling components upstream of Erk in Shp-2 mutant cells, EGF-stimulated Ras, Raf, and Mek activation was signifi cantly attenuated in Shp-2 mutant cells, suggesting that Shp-2 acts to prom ote Ras activation or to suppress the down-regulation of activated Ras. Bio chemical analyses indicate that upon EGF stimulation, Shp-2 is recruited in to a multiprotein complex assembled on the Gab1 docking molecule and that S hp-2 seems to exert its biological function by specifically dephosphorylati ng an unidentified molecule of 90 kDa in the complex. The mutant Shp-2(Delt a 46-110) molecule failed to participate in the Gab1-organized complex for dephosphorylation of p90, correlating with a defective activation of the Ra s-Raf-Mek-Erk cascade in EGF-treated Shp-2 mutant cells. Evidence is also p resented that Shp-2 does not appear to modulate the signal relay from EGF r eceptor to Ras through the Shc, Grb2, and Sos proteins. These results begin to elucidate the mechanism of Shp-2 function downstream of a receptor tyro sine kinase to promote the activation of the Ras-Erk pathway, with potentia l therapeutic applications in cancer treatment.