Src phosphorylates Grb2-associated binder 1 upon hepatocyte growth factor stimulation
Src phosphorylates Grb2-associated binder 1 upon hepatocyte growth factor stimulation
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DOI：
10.1074/jbc.m305745200
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发表时间：
2003-11-07
影响因子：
4.8
通讯作者：
Chen, HC
中科院分区：
文献类型：
--
作者：
Chan, PC;Chen, YL;Chen, HC
已知Grb 2相关结合物1（Gab 1）在肝细胞生长因子（HGF）信号传导中起重要作用，其在HGF刺激后迅速变得酪氨酸磷酸化。在本研究中，我们发现在HGF刺激下，Src/Yes/Fyn敲除小鼠胚胎细胞中的Gab 1酪氨酸磷酸化水平比野生型小鼠胚胎细胞低40%。野生型Src的表达增加增强了HGF诱导的Gab 1磷酸化，相反，Src激酶缺陷突变体的表达或特异性Src抑制剂PP 1的治疗抑制了它。组成型活性Src突变体（Y 527 F）或致癌v-Src的表达导致Gab 1磷酸化的显著增加，而不依赖于HGF刺激。此外，Src通过其Src同源2和3结构域与Gab 1相互作用，并且能够在体外磷酸化纯化的Gab 1。最后，由Src增加的Gab 1的磷酸化选择性地增强HGF诱导的ERK和AKT的激活。总之，我们的研究结果建立了一个新的作用，Src在HGF诱导的Gab 1磷酸化。
Grb2-associated binder 1 (Gab1) is known to play an important role in hepatocyte growth factor (HGF) signaling, which rapidly becomes tyrosine-phosphorylated upon HGF stimulation. In this study, we found that the tyrosine phosphorylation of Gab1 in the cells derived from Src/Yes/Fyn null mouse embryos was similar to40% lower than that in their wild type counterparts upon HGF stimulation. Increased expression of wild-type Src enhanced HGF-induced phosphorylation of Gab1, and, in contrast, expression of the Src kinase-deficient mutant or treatment of the specific Src inhibitor PP1 suppressed it. Expression of a constitutively active Src mutant (Y527F) or oncogenic v-Src led to a prominent increase in Gab1 phosphorylation independent of HGF stimulation. Moreover, Src interacted with Gab1 via both its Src homology 2 and 3 domains and was capable of phosphorylating purified Gab1 in vitro. Finally, the increased phosphorylation of Gab1 by Src selectively potentiated HGF-induced activation of ERK and AKT. Taken together, our results establish a new role for Src in HGF-induced Gab1 phosphorylation.