H Wang1,2,6, B Liu1,2,6, AQO Al-Aidaroos3,6, H Shi1,2, L Li1,2, K Guo3, J Li3, BCP Tan3, JM Loo4, JP Tang3, M Thura3 and Q Zeng3,5
1 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China
2 Center for Stem Cell Biology and Tissue Engineering, Sun Yat-Sen University, Guangzhou, People's Republic of China
3 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
4 The Rockefeller University, New York, NY, USA
5 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
6 These authors contributed equally to this work.
Correspondence: email@example.com or firstname.lastname@example.org
Published online ahead of print in Oncogene on 12 October 2015.
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 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's and found V108A substitution sufficient to restore SH3BGRL function as a c-Src activator and metastasis promoter. Notably, the somatic mutation R76C of hSH3BGRL phenocopied 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.
Figure legend: Schematic model for SH3BGRL-mediated c-Src activation. The SH3-binding domain from SH3BGRL competes for and displaces the inhibitory SH3-binding SH2 kinase linker region in c-Src, triggering conformational changes that promote c-Src kinase activity.
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