The c-Src tyrosine kinase associates with the catalytic domain of ErbB-2: implications for ErbB-2 mediated signaling and transformation.
c-Src associates with and is activated by the ErbB-2 receptor tyrosine kinase, but is unable to bind the EGFR. Although c-Src has been found to interact directly and specifically with the ErbB-2 receptor, the significance of this interaction is unclear. Using both chimeric receptor and site-directed mutagenesis approaches, the region of interaction of c-Src on ErbB-2 was identified. Significantly, EGFR could be converted into a receptor capable of binding c-Src by replacement of a catalytic domain of ErbB-2. We further demonstrated that MDCK cells that express mutant EGFR that are competent in c-Src recruitment lose epithelial polarity in organoid cultures, whereas cells overexpressing the wild-type EGFR retain a polarized phenotype. ErbB-2-dependent activation of c-Src results in disruption of epithelial cell-cell contacts leading to cell dispersal that correlates with the re-localization of phospho-MAPK to focal adhesions. Taken together, these observations suggest that recruitment of c-Src to these closely related EGFR family members plays a critical role in modulating cell polarity.
Kim
Harold
H
Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada.
Chan
Richard
R
Dankort
David L
DL
Zuo
Dongmei
D
Najoukas
Monica
M
Park
Morag
M
Muller
William J
WJ
D000818:Animals; D001665:Binding Sites; D000081247:CSK Tyrosine-Protein Kinase; D020134:Catalytic Domain; D002454:Cell Differentiation; D002460:Cell Line; D016764:Cell Polarity / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D004285:Dogs; D066246:ErbB Receptors / Q000235:genetics* / Q000502:physiology; D022001:Focal Adhesions; D006801:Humans; D007668:Kidney / Q000166:cytology; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D019061:src-Family Kinases
D000081247:CSK Tyrosine-Protein Kinase; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D019061:src-Family Kinases; C000631346:CSK protein, human