The migratory and invasive properties of tumor cells are critical for metastasis, which is the main cause of treatment failure for cancer patients. The signaling mechanisms that control cell migration and invasion largely remain to be elucidated however. The long-term goal of this proposal is to elucidate the signaling pathways that are activated by the small GTPase Rac1 in the control of cell migration and invasion and to use this information to identify novel drug targets for cancer therapy. The phosphatidylinositol phosphatase synaptojanin 2 (SJ2) is a novel Rac effector that is required for the formation of lamellipodia and invadopodia and for tumor cell migration and invasion. Furthermore, SJ2 binds to Grb2 and cortactin, two proteins that have been implicated in the control of the actin cytoskeleton. Grb2 activates N-WASP, which stimulates actin nucleation, whereas cortactin promotes actin filament branch formation. The objective of this application is to determine the molecular mechanisms that underlie the role of SJ2 in lamellipodia and invadopodia formation and tumor cell migration and invasion. The central hypothesis of this proposal is that SJ2 contributes to tumor cell migration and invasion by acting downstream of Rac1 to coordinate the activities of N-WASP and cortactin. To accomplish the goals of this application, the following specific aims will be pursued: 1) To determine whether Rac1 regulates SJ2 by localizing SJ2 to lamellipodia and invadopodia. 2) To test the hypothesis that SJ2 regulates cell migration and invasion and the formation of lamellipodia and invadopodia by stimulating cortactin-dependent actin filament branching. 3) To test the hypothesis that synaptojanin 2 regulates cell migration and invasion and the formation of lamellipodia and invadopodia by regulating Grb2/N-WASP-dependent actin nucleation. The molecular analysis of the functions of SJ2 in the formation of lamellipodia and invadopodia and tumor cell migration and invasion will significantly expand our current understanding of the role of Rac1 in malignant transformation. ? ?
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