Grb2相关结合蛋白-1介导磷脂酰肌醇3激酶的激活以及神经生长因子对细胞存活的促进作用。
Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor.
作者信息
Holgado-Madruga M, Moscatello D K, Emlet D R, Dieterich R, Wong A J
机构信息
Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, 233 South 10th Street, Bluemle Life Science Building 1002, Philadelphia, PA 19107, USA.
出版信息
Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12419-24. doi: 10.1073/pnas.94.23.12419.
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.
神经生长因子（NGF）通过刺激TrkA受体蛋白酪氨酸激酶来防止细胞凋亡。磷脂酰肌醇3激酶（PI 3激酶）的下游激活对于抑制细胞凋亡至关重要，尽管该酶不与TrkA结合且不会被TrkA直接激活。我们发现，向PC-12细胞中添加NGF会导致Grb2相关结合蛋白-1（Gab1）对接蛋白磷酸化，并诱导包括PI 3激酶在内的几种含SH2结构域的蛋白发生结合。细胞总PI 3激酶活性的很大一部分与Gab1相关。过表达Gab1的PC-12细胞对抑制细胞凋亡所需的NGF量的需求降低。缺乏PI 3激酶结合位点的Gab1突变体的表达会增强细胞凋亡，并减弱NGF的保护作用。因此，Gab1在将TrkA与PI 3激酶激活相联系以及NGF促进细胞存活方面起着主要作用。
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