Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases
Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases
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DOI：
10.1074/jbc.m003597200
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发表时间：
2000-10-06
影响因子：
4.8
通讯作者：
Park, M
中科院分区：
文献类型：
--
作者：
Lock, LS;Royal, I;Park, M
对接蛋白的Gab家族响应于各种生长因子和细胞因子而被磷酸化，并且用于募集多种信号传导蛋白。Gab 1作用于Met-肝细胞生长因子受体的下游，并且Gab 1过表达促进上皮细胞的Met依赖性形态发生。招募Gab 1的Met或表皮生长因子（EGF）受体需要一个受体结合位点的Grb 2衔接蛋白和富含脯氨酸的结构域Gab 1，定义为Met结合结构域。为了确定需要Grb 2在Gab 1招聘，我们已经映射了两个Grb 2羧基末端SH 3结构域结合位点保守的Gab 1和相关蛋白Gab 2。一个对应于一个典型的Grb 2结合基序，而第二个，位于Gab 1 Met结合结构域内，需要脯氨酸和精氨酸残基的非典型PXXXR基序。PXXXR基序是Grb 2结合所必需的，但不足以结合Grb 2，而Gab蛋白中保守的扩展基序PX 3RX 2KPX 7 PLD以及Grb 2/Gads对接蛋白Slp-76有效地竞争Grb 2或Gads衔接蛋白的结合。Gab 1与Grb 2的结合是Gab 1募集到EGF受体而不是Met受体所必需的。因此，Gab 1募集的不同机制可能反映了EGF和Met受体下游Gab 1的不同生物学功能。
The Gab family of docking proteins is phosphorylated in response to various growth factors and cytokines and serves to recruit multiple signaling proteins. Gab1 acts downstream from the Met-hepatocyte growth factor receptor, and Gab1 overexpression promotes Met dependent morphogenesis of epithelial cells. Recruitment of Gab1 to Met or epidermal growth factor (EGF) receptors requires a receptor-binding site for the Grb2 adapter protein and a proline-rich domain in Gab1, defined as the Met-binding domain. To determine the requirement for Grb2 in Gab1 recruitment, we have mapped two Grb2 carboxyl-terminal SH3 domain binding sites conserved in Gab1 and related protein Gab2. One corresponds to a canonical Grb2-binding motif, whereas the second, located within the Gab1 Met-binding domain, requires the proline and arginine residues of an atypical PXXXR motif. The PXXXR motif is required but not sufficient for Grb2 binding, whereas an extended motif, PX3RX2KPX7PLD, conserved in Gab proteins as well as the Grb2/Gads-docking protein, Slp-76, efficiently competes binding of Grb2 or Gads adapter proteins. The association of Gab1 with Grb2 is required for Gab1 recruitment to the EGF receptor but not the Met receptor. Hence different mechanisms of Gab1 recruitment may reflect the distinct biological functions for Gab1 downstream from the EGF and Met receptors.