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Molecular and Cellular Biology, November 2009, p. 5858-5871, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.01731-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

c-Src Associates with ErbB2 through an Interaction between Catalytic Domains and Confers Enhanced Transforming Potential{triangledown} ,{dagger}

Richard Marcotte,1,2 Lixin Zhou,3 Harold Kim,4 Calvin D. Roskelly,3 and William J. Muller1,2*

Goodman Cancer Center, Departments of Biochemistry,1 Medicine, McGill University, Montreal, Quebec, Canada,2 Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada,3 Department of Biophysics, University of Toronto, Toronto, Ontario, Canada4

Received 11 November 2008/ Returned for modification 2 February 2009/ Accepted 14 August 2009

Previous studies have demonstrated that c-Src tyrosine kinase interacts specifically with ErbB2, but not with other members of the epidermal growth factor receptor (EGFR) family. To identify the site of interaction, we recently used a chimeric EGFR/ErbB2 receptor approach to show that c-Src requires the kinase region of ErbB2 for binding. Here, we demonstrate that retention of a conserved amino acid motif surrounding tyrosine 877 (referred to here as EGFRYHAD) is sufficient to confer binding to c-Src. Surprisingly the association of c-Src was not dependent on its SH2 or SH3 domain or on the phosphorylation or kinase activity of the receptor. We further show that the chimeric EGFRs that contain the Y877 motif are transforming in vitro and in vivo following ligand stimulation. Transformation was also partially dependent on sustained activation of Stat3. Finally, we demonstrate that EGFRs with mutations in the catalytic domain, originally identified in lung cancer and conferring increased sensitivity to gefitinib and erlotinib, two EGFR kinase inhibitors, gained the capacity to bind c-Src. Moreover, transformation by these EGFR mutants was inhibited by Src inhibitors regardless of their sensitivities to gefitinib and erlotinib. These observations have important implications for understanding the molecular basis for resistance to EGFR inhibitors and implicate c-Src as a critical signaling molecule in EGFR mutant-induced transformation.

* Corresponding author. Mailing address: Molecular Oncology Group, Biochemistry Department, 1160 Ave. des Pins Ouest, Room 509, Montreal, Quebec, Canada H3G 0B1. Phone: (514) 934-1934, ext. 36383. Fax: (514) 843-1478. E-mail: william.muller{at}mcgill.ca

{triangledown} Published ahead of print on 24 August 2009.

{dagger} Supplemental material for this article can be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2009, p. 5858-5871, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.01731-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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