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Role of RAC GTPase in Tumor Motility and Metastasis
Final rept. 1 Jul 1996-30 Jun 1999
SCRIPPS RESEARCH INST LA JOLLA CA
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Metastasis of breast cancers contributes heavily to the severity and mortality of this disease. There is substantial evidence that integrins and small GTPases contribute to the metastatic properties of breast cancer cells enabling them to invade and migrate to distant sites throughout the body. This study provides evidence that Rac GTPase is required for both integrin and growth factor-mediated motility. Although Rac can activate JNK, not MAP kinase, we found it can interact with the RasMAP kinase pathway at the level of Raf kinase to regulate cell migration. One of the identified targets of Rac-GTP in cells are the p21-activated kinases PAKs. PAKs can mediate many of the cytoskeletal changes induced by Rac and Cdc42. We show that cell adhesion can activate PAK through an integrin-dependent manner and PAK mediates cell spread and motility on extracellular matrix.
APPROVED FOR PUBLIC RELEASE