Metastasis involves the expression of different proteins involved in cell motility along with homing receptors, their ligands, and extracellular matrix degrading proteases. Recent studies have identified that the signaling pathways regulated by lysophosphatidic acid (LPA) play a critical role in ovarian cell growth and metastasis. Based on our preliminary findings that G?13 (which can be activated by LPA) and Hax-1 interaction is required for cell motility, we hypothesize here that G?13-HAX-1-cortactin interaction is critically involved in the metastasis of LPA-responsive ovarian cancer cells. This hypothesis will be tested under the following specific aims:
Aim 1 : Characterization of G?13-Hax-1 interaction. Hax-1 interaction sites with G?13 and cortactin will be defined by site-directed mutagenesis approach;
Aim 2 : Analysis of G?13-Hax-1-cortactin complex. The interrelationship of Hax-1, G?13, Cortactin, and Rac in forming the quadnary complex and the role of Hax-1 and G?13 in cortactin-phosphorylation will be defined;
Aim 3 : Analysis of other Hax-1 interacting signaling components. The target pathways regulated by G?13-Hax-1 complex will be identified by the analysis for specific GEFs and regulation of uPA and/or MMP2;
Aim 4 : Effect of Hax-1 on the oncogenic activity of G?13: We will investigate whether G?13-Hax-1 association is involved in neoplastic growth of ovarian cancer cells;
and Aim 5 : Role of G?13-Hax in tumor cell migration and metastasis. The role of Hax-1 or G?13 on the migration and invasive potentials of ovarian cancer cells will be analyzed using the novel mouse model system developed by Dr. Sandra Orsulic (Co-P.I) at Massachusetts General Hospital, Boston. We hope that the identification of a signaling locus involved in tumor cell motility, as proposed here, will define newer targets for therapeutic intervention.
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