Dual-faced SH3BGRL: oncogenic in mice, tumor suppressive in humans.
Dual-faced SH3BGRL: oncogenic in mice, tumor suppressive in humans.
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双面 SH3BGRL：小鼠致癌，人类肿瘤抑制
DOI：
10.1038/onc.2015.391
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发表时间：
2016-06-23
期刊：
影响因子：
8
通讯作者：
Zeng Q
中科院分区：
文献类型：
--
作者：
Wang H;Liu B;Al-Aidaroos AQ;Shi H;Li L;Guo K;Li J;Tan BC;Loo JM;Tang JP;Thura M;Zeng Q
尽管有大量数据支持c - Src是一种促进转移的癌基因，但c - Src的激活突变却很罕见。这表明反式相互作用蛋白可能在调节c - Src激活中起关键作用。在此，我们首次报道了Src同源3（SH3）结构域结合的富含谷氨酸样蛋白（SH3BGRL）的发现，它是小鼠体内一种新型的c - Src激活剂。小鼠SH3BGRL（mSH3BGRL）的异位表达强烈促进肿瘤细胞侵袭和肺转移。在分子水平上，mSH3BGRL特异性结合在Tyr527位点磷酸化的无活性形式的c - Src，促进c - Src的Tyr416磷酸化以及随后由FAK介导的ERK和AKT信号通路的激活。仅靶向内源性c - Src就足以消除体内mSH3BGRL诱导的癌症转移。出乎意料的是，人源SH3BGRL（hSH3BGRL）反过来在本质上抑制肿瘤发生和转移。我们尝试将hSH3BGRL氨基酸序列进行位点特异性回复为mSH3BGRL，发现V108A替换足以恢复SH3BGRL作为c - Src激活剂和转移促进剂的功能。值得注意的是，hSH3BGRL的体细胞突变R76C在肿瘤发生和转移中可与hSH3BGRL - V108A和mSH3BGRL类似地起作用。我们的研究结果揭示了SH3BGRL在通过c - Src激活驱动肿瘤转移方面存在进化上有争议的作用，并表明hSH3BGRL的突变状态可能与癌症诊断和治疗相关。
Despite abundant data supporting c-Src as a metastasis-promoting oncogene, activating mutations of c-Src are rare. This suggests that trans-interacting proteins may have a critical role in regulating c-Src activation. Here, we first report the discovery of Src homology 3 (SH3) domain-binding glutamic acid-rich-like protein (SH3BGRL), a novel c-Src activator in mice. Ectopic expression of murine SH3BGRL (mSH3BGRL) strongly promoted both tumor cell invasion and lung metastasis. Molecularly, mSH3BGRL specifically bound the inactive form of c-Src phosphorylated at Tyr527, promoting Tyr416 phosphorylation of c-Src and subsequent FAK-mediated activation of ERK and AKT signaling pathways. Targeting endogenous c-Src alone was sufficient to abolish mSH3BGRL-induced cancer metastasis in vivo. Unexpectedly, human SH3BGRL (hSH3BGRL) in turn suppressed tumorigenesis and metastasis in nature. We attempted site-specific reversion of hSH3BGRL amino-acid sequence to mSH3BGRL and found V108A substitution sufficient to restore SH3BGRL function as a c-Src activator and metastasis promoter. Notably, the somatic mutation R76C of hSH3BGRL can similarly act as hSH3BGRL-V108A and mSH3BGRL in tumorigenesis and metastasis. Our results uncover an evolutionarily controversial role of SH3BGRL in driving tumor metastasis through c-Src activation, and suggests that hSH3BGRL mutation status could be relevant to cancer diagnosis and therapy.