c-Src modulates ErbB2 and ErbB3 heterocomplex formation and function.
Overexpression and/or gene amplification of c-Src and members of the epidermal growth factor receptor (EGFR/ErbB) family have been implicated in the pathogenesis of breast cancer. Although members of the EGFR family are known to form heterocomplexes with one another, c-Src has also been shown to physically interact with members of this family in breast cancer cell lines and tumors. This paper investigates the role of c-Src in modulating the physical and functional interaction between ErbB2 and ErbB3, two family members that preferentially associate with one another and together exhibit high oncogenic potential. We show that overexpressed wild-type c-Src enhances heterocomplex formation of ErbB2 and ErbB3 that results in increased basal and/or heregulin-induced activation of receptors, and their downstream intracellular effectors. Expression of a kinase-inactive form of c-Src (K(-) c-Src) or pharmacological inhibition of c-Src by PP2 negatively affects these events. Furthermore, cellular motility and anchorage-independent growth promoted by the ErbB2/ErbB3 heterocomplex are dependent upon c-Src, as demonstrated by the effects of K(-) c-Src overexpression or treatment with PP2. In contrast to previous studies that defined a role for c-Src downstream of ErbB2/ErbB3, the current work suggests an upstream mechanism, whereby c-Src enhances ErbB2/ErbB3 signaling and biological functions by positively modulating the association between ErbB2 and ErbB3.
Ishizawar
R C
RC
Department of Microbiology and Cancer Center, University of Virginia Health System, Charlottesville, VA 22908, USA.
Miyake
T
T
Parsons
S J
SJ
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D002465:Cell Movement; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes; D020890:Neuregulin-1 / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases
D000081247:CSK Tyrosine-Protein Kinase; D004791:Enzyme Inhibitors; D046912:Multiprotein Complexes; D020890:Neuregulin-1; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D014443:Tyrosine; D019061:src-Family Kinases; C412373:AG 1879; C000631346:CSK protein, human