Integrins play a central role in facilitating the adhesive requirements of migration, and transmit outside in signals which regulate this process. Little is known of the signaling mechanisms that cause cell migration on ECM. Preliminary evidence indicates that formation of an adaptor protein complex between p130CAS and c-CrkII serve as a molecular switch causing a cell to migrate on ECM. Because CAS/Crk coupling is a necessary event for cytokine-dependent migration and is associated with tumor cell invasion and metastases in vivo. It is important to understand the molecular mechanisms that facilitate CAS/Crk association in migratory cells. Studies outlined in this proposal will test the hypothesis that two adhesion dependent tyr kinases, FAK and Src are critical upstream proteins that promote CAS phosphorylation leading to CAS/Crk coupling and migration. The relationship of Ras-MAPK signaling to CAS/Crk cell migration will also be investigated. Finally, experiments will test the ability of this signaling cascade to regulate cell migration in vitro and tumor cell invasion and metastasis in vivo. These studies should help to define the critical adhesion-dependent signal transduction events that regulate cell movement as it pertains to the invasive properties of tumor cells.
