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Dual-faced SH3BGRL: oncogenic in mice, tumor suppressive in humans

H Wang1,2, B Liu1,2, A Q O Al-Aidaroos3

  • 1Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People's Republic of China.

Oncogene
|October 13, 2015
PubMed

Insights

A novel protein, Src homology 3 (SH3) domain-binding glutamic acid-rich-like protein (SH3BGRL), activates c-Src to promote cancer metastasis in mice. However, human SH3BGRL suppresses metastasis, with specific mutations restoring its oncogenic function.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • c-Src is a known oncogene promoting metastasis, but activating mutations are rare.
  • Trans-acting proteins are implicated in regulating c-Src activation.
  • The role of SH3BGRL in cancer has not been previously defined.

Purpose of the Study:

  • To identify novel regulators of c-Src activation.
  • To investigate the role of SH3BGRL in cancer metastasis.
  • To explore the differential functions of murine and human SH3BGRL.

Main Methods:

  • Discovery and characterization of murine SH3BGRL (mSH3BGRL).
  • Assays for tumor cell invasion and lung metastasis.
  • Molecular analysis of c-Src phosphorylation and downstream signaling pathways (FAK, ERK, AKT).
  • Site-specific mutation analysis of human SH3BGRL (hSH3BGRL).

Main Results:

  • Ectopic mSH3BGRL expression promoted tumor cell invasion and lung metastasis.
  • mSH3BGRL binds inactive c-Src, promoting its activation and downstream signaling.
  • Targeting c-Src abolished mSH3BGRL-induced metastasis.
  • hSH3BGRL suppressed tumorigenesis and metastasis.
  • A V108A substitution in hSH3BGRL restored its oncogenic function.
  • The somatic mutation R76C in hSH3BGRL also promoted tumorigenesis and metastasis.

Conclusions:

  • SH3BGRL has an evolutionarily divergent role in cancer metastasis via c-Src activation.
  • Murine SH3BGRL acts as a c-Src activator promoting metastasis.
  • Human SH3BGRL generally suppresses metastasis, but specific mutations confer oncogenic activity.
  • SH3BGRL mutation status may be relevant for cancer diagnosis and therapy.

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