Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor
Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor
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DOI：
10.1073/pnas.94.23.12419
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发表时间：
1997-11-11
影响因子：
11.1
通讯作者：
Wong, AJ
中科院分区：
文献类型：
--
作者：
HolgadoMadruga, M;Moscatello, DK;Wong, AJ
神经生长因子(NGF)通过刺激TrkA受体蛋白酪氨酸激酶来阻止细胞凋亡，磷脂酰肌醇3-激酶(PI-3-Kinase)的下游激活对于抑制细胞凋亡是必不可少的，尽管该酶不与TrkA结合，也不直接被TrkA激活。我们发现，在PC-12细胞中加入NGF导致Grb2相关结合蛋白1(GAB1)的磷酸化，并诱导几种含有SH2结构域的蛋白的结合，其中包括PI 3-K，细胞总PI 3-K的很大一部分与GAB1相关。高表达GAB1的PC-12细胞对抑制细胞凋亡所需的NGF的需求量减少，缺乏PI 3-激酶结合位点的GAB1突变体的表达促进了细胞的凋亡，减弱了NGF的保护作用，因此，GAB1在连接TrkA和PI 3-K激活以及促进NGF促进细胞存活方面具有重要作用。
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.