The docking protein Gab1 is the primary mediator of EGF-stimulated activation of the PI-3K/Akt cell survival pathway.
The docking protein Gab1 is the primary mediator of EGF-stimulated activation of the PI-3K/Akt cell survival pathway.
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DOI：
10.1186/1741-7007-2-24
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发表时间：
2004-11-18
期刊：
影响因子：
5.4
通讯作者：
Schlessinger J
中科院分区：
文献类型：
--
作者：
Mattoon DR;Lamothe B;Lax I;Schlessinger J
Gab 1是一种对接蛋白，其响应于许多受体酪氨酸激酶（RTK）的活化而募集磷脂酰肌醇-3激酶（PI-3激酶）和其它效应蛋白。由于EGF受体（EGFR）上的自磷酸化位点不包括典型的PI-3激酶结合位点，因此认为EGF对PI-3激酶及其下游效应物Akt的刺激是通过间接机制介导的。我们使用从Gab 1-/-小鼠胚胎中分离的成纤维细胞来探讨EGF刺激PI-3激酶/Akt抗凋亡细胞信号通路的机制。我们表明，Gab 1是必不可少的EGF刺激PI-3激酶和Akt在这些细胞中，这些反应介导的复合物形成之间的p85，PI-3激酶的调节亚基，和Gab 1上的三个典型的酪氨酸磷酸化位点。此外，Gab 1和蛋白酪氨酸磷酸酶Shp 2之间的复合物形成负调节Gab 1介导的PI-3激酶和Akt激活EGF受体刺激后。我们还证明，ErbB 3的酪氨酸磷酸化可能导致招募和激活PI-3激酶和Akt在Gab 1-/- MEFs。EGF诱导的PI-3激酶/Akt抗凋亡途径的刺激的主要机制通过对接蛋白Gab 1发生。然而，在表达ErbB 3的细胞中，EGF和neuroregulin可以刺激PI-3激酶和Akt以Gab 1依赖或Gab 1非依赖的方式激活。
Gab1 is a docking protein that recruits phosphatidylinositol-3 kinase (PI-3 kinase) and other effector proteins in response to the activation of many receptor tyrosine kinases (RTKs). As the autophosphorylation sites on EGF-receptor (EGFR) do not include canonical PI-3 kinase binding sites, it is thought that EGF stimulation of PI-3 kinase and its downstream effector Akt is mediated by an indirect mechanism. We used fibroblasts isolated from Gab1-/- mouse embryos to explore the mechanism of EGF stimulation of the PI-3 kinase/Akt anti-apoptotic cell signaling pathway. We demonstrate that Gab1 is essential for EGF stimulation of PI-3 kinase and Akt in these cells and that these responses are mediated by complex formation between p85, the regulatory subunit of PI-3 kinase, and three canonical tyrosine phosphorylation sites on Gab1. Furthermore, complex formation between Gab1 and the protein tyrosine phosphatase Shp2 negatively regulates Gab1 mediated PI-3 kinase and Akt activation following EGF-receptor stimulation. We also demonstrate that tyrosine phosphorylation of ErbB3 may lead to recruitment and activation of PI-3 kinase and Akt in Gab1-/- MEFs. The primary mechanism of EGF-induced stimulation of the PI-3 kinase/Akt anti-apoptotic pathway occurs via the docking protein Gab1. However, in cells expressing ErbB3, EGF and neuroregulin can stimulate PI-3 kinase and Akt activation in a Gab1-dependent or Gab1-independent manner.
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影响因子：
5.3
作者：
SOLTOFF, SP;CARRAWAY, KL;CANTLEY, LC
通讯作者：
CANTLEY, LC
影响因子：
5.3
作者：
Shi, ZQ;Yu, DH;Feng, GS
通讯作者：
Feng, GS
影响因子：
4.8
作者：
Lock, LS;Royal, I;Park, M
通讯作者：
Park, M
影响因子：
3.5
作者：
HELLYER, NJ;KIM, HH;KOLAND, JG
通讯作者：
KOLAND, JG
DOI：
10.1073/pnas.87.10.3816
发表时间：
1990-05-01
影响因子：
11.1
作者：
BJORGE, JD;CHAN, TO;FUJITA, DJ
通讯作者：
FUJITA, DJ