Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor

被引:223
|
作者
HolgadoMadruga, M
Moscatello, DK
Emlet, DR
Dieterich, R
Wong, AJ
机构
[1] THOMAS JEFFERSON UNIV, KIMMEL CANC INST, DEPT MICROBIOL & IMMUNOL, PHILADELPHIA, PA 19107 USA
[2] THOMAS JEFFERSON UNIV, KIMMEL CANC INST, DEPT BIOCHEM & MOL PHARMACOL, PHILADELPHIA, PA 19107 USA
关键词
D O I
10.1073/pnas.94.23.12419
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:12419 / 12424
页数:6
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