title: Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor.
abstract: Nerve growth factor (NGF) prevents apoptosis through stimulation of the TrkA receptor protein tyrosine kinase. The downstream activation of phosphatidylinositol 3-kinase (PI 3-kinase) is essential for the inhibition of apoptosis, although this enzyme does not bind to and is not directly activated by TrkA. We have found that the addition of NGF to PC-12 cells resulted in the phosphorylation of the Grb2-associated binder-1 (Gab1) docking protein and induced the association of several SH2 domain-containing proteins, including PI 3-kinase. A substantial fraction of the total cellular PI 3-kinase activity was associated with Gab1. PC-12 cells that overexpressed Gab1 show a decreased requirement for 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 the promotion of cell survival by NGF.
authors.affiliation: Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, 233 South 10th Street, Bluemle Life Science Building 1002, Philadelphia, PA 19107, USA.
authors.forename: M
authors.initials: M
authors.lastname: Holgado-Madruga
authors.forename: D K
authors.initials: DK
authors.lastname: Moscatello
authors.forename: D R
authors.initials: DR
authors.lastname: Emlet
authors.forename: R
authors.initials: R
authors.lastname: Dieterich
authors.forename: A J
authors.initials: AJ
authors.lastname: Wong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D009154:Mutation; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C490896:Gab1 protein, rat; D009414:Nerve Growth Factors; D010750:Phosphoproteins; D019869:Phosphatidylinositol 3-Kinases