title: Dual-faced SH3BGRL: oncogenic in mice, tumor suppressive in humans.
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 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.
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.|Center for Stem Cell Biology and Tissue Engineering, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.|Center for Stem Cell Biology and Tissue Engineering, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: A Q O
authors.initials: AQ
authors.lastname: Al-Aidaroos
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.|Center for Stem Cell Biology and Tissue Engineering, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.|Center for Stem Cell Biology and Tissue Engineering, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: K
authors.initials: K
authors.lastname: Guo
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: B C P
authors.initials: BC
authors.lastname: Tan
authors.affiliation: The Rockefeller University, New York, NY, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Loo
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: J P
authors.initials: JP
authors.lastname: Tang
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: M
authors.initials: M
authors.lastname: Thura
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Q
authors.initials: Q
authors.lastname: Zeng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D061986:MCF-7 Cells; D008819:Mice, Nude; D009154:Mutation; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes / Q000235:genetics*; D011485:Protein Binding; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D011506:Proteins; C113099:SH3BGRL protein, human; D025521:Tumor Suppressor Proteins; D016392:Proto-Oncogene Proteins pp60(c-src)