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c-Src modulates ErbB2 and ErbB3 heterocomplex formation and function

R C Ishizawar1, T Miyake, S J Parsons

  • 1Department of Microbiology and Cancer Center, University of Virginia Health System, Charlottesville, VA 22908, USA.

Oncogene
|December 19, 2006
PubMed

Insights

The study reveals that c-Src kinase enhances the interaction between ErbB2 and ErbB3 receptors, boosting breast cancer cell growth and motility. Inhibiting c-Src disrupts this oncogenic signaling pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Overexpression of c-Src and epidermal growth factor receptor (EGFR/ErbB) family members is linked to breast cancer development.
  • EGFR/ErbB family members form heterocomplexes, and c-Src physically interacts with them in breast cancer.
  • The ErbB2/ErbB3 heterocomplex exhibits significant oncogenic potential.

Purpose of the Study:

  • To investigate the role of c-Src in modulating the physical and functional interaction between ErbB2 and ErbB3.
  • To determine if c-Src acts upstream or downstream of ErbB2/ErbB3 signaling.
  • To elucidate the impact of c-Src on the oncogenic functions mediated by the ErbB2/ErbB3 heterocomplex.

Main Methods:

  • Overexpression of wild-type and kinase-inactive c-Src (K(-) c-Src) in breast cancer cells.
  • Pharmacological inhibition of c-Src using PP2.
  • Assessment of ErbB2/ErbB3 heterocomplex formation and receptor activation.
  • Evaluation of downstream signaling pathways and cellular functions like motility and anchorage-independent growth.

Main Results:

  • Overexpressed wild-type c-Src enhances ErbB2/ErbB3 heterocomplex formation.
  • This enhancement leads to increased basal and heregulin-induced activation of ErbB2/ErbB3 and downstream effectors.
  • Inhibition or inactivation of c-Src abrogates ErbB2/ErbB3-mediated cellular motility and anchorage-independent growth.
  • c-Src positively modulates ErbB2/ErbB3 association, suggesting an upstream role.

Conclusions:

  • c-Src plays a critical upstream role in enhancing ErbB2/ErbB3 signaling and oncogenic functions in breast cancer.
  • Modulation of ErbB2/ErbB3 association by c-Src is a key mechanism driving tumor progression.
  • Targeting c-Src may represent a therapeutic strategy for breast cancers driven by ErbB2/ErbB3 signaling.

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