GRB2-ASSOCIATED BINDER-1 MEDIATES PHOSPHATIDYLINOSITOL 3-KINASE ACTIVATION AND THE PROMOTION OF CELL-SURVIVAL BY NERVE GROWTH-FACTOR

Nerve growth factor (NGF) prevents apoptosis through stimulation of th e TrkA receptor protein tyrosine kinase, The downstream activation of phosphatidylinositol 3-kinase (PI 3-kinase) is essential for the inhib ition of apoptosis, although this enzyme does not bind to and is not d irectly activated by TrkA. We have found that the addition of NGF to P C-12 cells resulted in the phosphorylation of the Grb2-associated bind er-1 (Gab1) docking protein and induced the association of several SH2 domain-containing proteins, including PI 3-kinase, A substantial frac tion of the total cellular PI 3-kinase activity was associated with Ga b1. PC-12 cells that overexpressed Gab1 show a decreased requirement f or the amount of NGF necessary to inhibit apoptosis, The expression of a Gab1 mutant that lacked the binding sites for PI 3-kinase enhanced apoptosis and diminished the protective effect of NGF, Hence, Gab1 has a major role in connecting TrkA with PI 3-kinase activation and for t he promotion of cell survival by NGF.