| Breast cancer is a leading cause of mortality among North American women. Hepatocyte growth factor (HGF) and its tyrosine kinase receptor, Met, are often over-expressed in breast cancers, with inappropriate sustained activation of Met contributing to tumorgenesis and metastasis. Aberrant signaling through integrin-mediated cell-matrix adhesion has been shown to act in concert with receptor tyrosine kinases (RTKs) in manifesting a malignant phenotype. Cell-matrix adhesions have also been shown to facilitate ligand-independent activation of RTKs, though the mechanism remains unclear. Since elevated c-Src kinase activity is frequent in human breast cancers, the role of c-Src in regulating HGF/Met activation and function was investigated. HGF and fibronectin (FN) exhibit a co-operative effect in mammary carcinoma cell motility, and this process requires c-Src. Moreover, both intracellular localization of c-Src, as well as its activation status, are important. Elevated c-Src activity during non-adherent conditions still requires integrin engagement and formation of focal adhesion complexes in order to phosphorylate focal adhesion kinase (FAK) (even in the context of activated c-Src). However, activated c-Src does enhance basal Met activation, while Met is co-localized to alpha5beta 1 integrin in focal adhesion complexes. These findings suggest a novel mechanism by which c-Src links signals from integrin-based adhesion to promote activation of Met. |
