期刊
CANCER RESEARCH
卷 70, 期 4, 页码 1645-1655出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-09-2447
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资金
- Korea Healthcare Technology RD Project [A084250]
- Ministry for Health, Welfare and Family Affairs
- Korea Health Promotion Institute [A084250] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Aberrant adhesion signaling pathways in cancer cells underlie their deadly invasive capabilities. The adhesion-related PDZ adapter protein mda-9/syntenin is a positive regulator of cancer cell progression in breast cancer, melanoma, and other human cancers. In this study, we report that mda-9/syntenin mediates adhesion-mediated activation of protein kinase C alpha (PKC alpha) and focal adhesion kinase (FAK) by fibronectin (FN) in human breast cancer and melanoma cells. FN rapidly stimulated the expression of mda-9/syntenin and the activation of PKC alpha prior to activation of FAK. Inhibiting PKC alpha suppressed basal or FN-induced expression of mda-9/syntenin, as well as cell migration and invasion toward FN stimulated by mda-9/syntenin. Several lines of evidence suggested that activation of PKC alpha and expression of mda-9/syntenin were interdependent. First, mda-9/syntenin inhibition suppressed basal or FN-induced phosphorylation of PKC alpha at Thr(638/641), whereas PKC alpha inhibition suppressed basal or FN-induced expression of mda-9/syntenin. Second, inhibiting either mda-9/syntenin or PKC alpha suppressed FN-induced formation of integrin-beta(1)/FAK/c-Src signaling complexes. Third, inhibiting either mda-9/syntenin or PKC alpha suppressed FN-induced phosphorylation of FAK Tyr(397) and c-Src Tyr(416) and the induction of downstream effector signals to p38 and mitogen-activated protein kinase, Cdc42, and NF-kappa B. In summary, our findings offer evidence that mda-9/syntenin acts as a molecular adaptor linking PKC alpha and FAK activation in a pathway of FN adhesion by human breast cancer and melanoma cells. Cancer Res; 70(4); 1645-55. (C) 2010 AACR.
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