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  current news   Press   selected story    
     
  27 October 2015  
 
Dual-faced SH3BGRL: oncogenic in mice, tumor suppressive in humans
 
 




Authors
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: wanghaih@mail.sysu.edu.cn or mcbzengq@imcb.a-star.edu.sg

Published online ahead of print in Oncogene on 12 October 2015.

Abstract
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:

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.

For more information on Qi ZENG’s laboratory, please click here.