Src and FAK mediate cell-matrix adhesion-dependent activation of met during transformation of breast epithelial cells
| Autor: | Angela Y. Hui, Jalna Meens, Colleen Schick, Shawna L. Organ, Eric Tremblay, Bruce E. Elliott, Shashi Uniyal, Erik Schaeffer, Bosco M.C. Chan, Hui Qiao |
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| Rok vydání: | 2009 |
| Předmět: |
Integrins
Integrin Mammary Neoplasms Animal Biochemistry Stress fiber assembly Focal adhesion Mice Cell-matrix adhesion Cell Line Tumor Cell Adhesion Animals Pseudopodia Phosphorylation Cell adhesion Cell Shape Molecular Biology biology Chemistry Epithelial Cells Cell Biology Proto-Oncogene Proteins c-met Vinculin Cell biology Cell Transformation Neoplastic src-Family Kinases Hepatocyte Growth Factor Receptor Focal Adhesion Protein-Tyrosine Kinases biology.protein Female Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Journal of Cellular Biochemistry. 107:1168-1181 |
| ISSN: | 1097-4644 0730-2312 |
| Popis: | Cell-matrix adhesion has been shown to promote activation of the hepatocyte growth factor receptor, Met, in a ligand-independent manner. This process has been linked to transformation and tumorigenesis in a variety of cancer types. In the present report, we describe a key role of integrin signaling via the Src/FAK axis in the activation of Met in breast epithelial and carcinoma cells. Expression of an activated Src mutant in non-neoplastic breast epithelial cells or in carcinoma cells was found to increase phosphorylation of Met at regulatory tyrosines in the auto-activation loop domain, correlating with increased cell spreading and filopodia extensions. Furthermore, phosphorylated Met is complexed with beta1 integrins and is co-localized with vinculin and FAK at focal adhesions in epithelial cells expressing activated Src. Conversely, genetic or pharmacological inhibition of Src abrogates constitutive Met phosphorylation in carcinoma cells or epithelial cells expressing activated Src, and inhibits filopodia formation. Interestingly, Src-dependent phosphorylation of Met requires cell-matrix adhesion, as well as actin stress fiber assembly. Phosphorylation of FAK by Src is also required for Src-induced Met phosphorylation, emphasizing the importance of the Src/FAK signaling pathway. However, stimulation of Met phosphorylation by addition of exogenous HGF in epithelial cells is refractory to inhibition of Src family kinases, indicating that HGF-dependent and Src/integrin-dependent Met activation occur via distinct mechanisms. Together these findings demonstrate a novel mechanism by which the Src/FAK axis links signals from the integrin adhesion complex to promote Met activation in breast epithelial cells. |
| Databáze: | OpenAIRE |
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