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c-Src associates with ErbB2 through an interaction between catalytic domains and confers enhanced transforming

Richard Marcotte1, Lixin Zhou, Harold Kim

  • 1Goodman Cancer Center, Department of Biochemistry, McGill University, Montreal, Quebec, Canada.

Molecular and Cellular Biology
|August 26, 2009
PubMed

Insights

The epidermal growth factor receptor (EGFR) Y877 motif binds c-Src tyrosine kinase, driving cancer cell transformation. This interaction is crucial for understanding EGFR inhibitor resistance and implicates c-Src in mutant EGFR-driven cancers.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncology

Background:

  • c-Src tyrosine kinase specifically interacts with ErbB2, a member of the epidermal growth factor receptor (EGFR) family.
  • Previous research identified the kinase region of ErbB2 as necessary for c-Src binding using a chimeric receptor approach.

Purpose of the Study:

  • To pinpoint the specific amino acid motif within EGFR responsible for c-Src binding.
  • To investigate the functional consequences of c-Src binding to EGFR, including cellular transformation.
  • To explore the role of c-Src in EGFR inhibitor resistance, particularly in lung cancer.

Main Methods:

  • Utilized chimeric EGFR/ErbB2 receptors to map the c-Src interaction site.
  • Introduced specific mutations, including the Y877 motif (EGFR(YHAD)), into EGFR constructs.
  • Assessed in vitro and in vivo transformation assays following ligand stimulation.
  • Investigated the role of Stat3 activation and Src inhibitors in EGFR-mediated transformation.
  • Examined EGFR mutants found in lung cancer for their capacity to bind c-Src and their sensitivity to kinase inhibitors.

Main Results:

  • The conserved amino acid motif surrounding tyrosine 877 (EGFR(YHAD)) is sufficient for c-Src binding, independent of Src domains or kinase activity.
  • Chimeric EGFRs with the Y877 motif induced transformation in vitro and in vivo, partially dependent on Stat3 activation.
  • EGFR mutants conferring sensitivity to gefitinib and erlotinib gained the ability to bind c-Src.
  • Src inhibitors blocked transformation by these EGFR mutants, irrespective of their sensitivity to EGFR inhibitors.

Conclusions:

  • The EGFR Y877 motif is a key determinant for c-Src interaction and subsequent cellular transformation.
  • c-Src plays a critical role in mediating transformation induced by EGFR mutants, including those resistant to EGFR inhibitors.
  • Targeting c-Src may offer a therapeutic strategy for cancers driven by EGFR mutants, especially in cases of acquired resistance to EGFR-targeted therapies.

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