The Role of the Exocyst in Cell Migration

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DESCRIPTION (provided by applicant): Cell migration is important for a wide range of physiological processes from chemotaxis and wound healing, to neuron development and embryogenesis. Cell migration requires the dynamic assembly of the actin network and remodeling of the membrane. How actin dynamics and membrane activities are coordinated during cell migration is a fundamental question in the field. The exocyst, a multiprotein complex consisting of Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70 and Exo84, mediates exocytosis and polarized cell surface expansion. Recently, the exocyst emerges as an important player in cell migration. The exocyst component Exo70 directly interacts with, and kinetically stimulates, the Arp2/3 complex for actin polymerization and branching. In addition, Exo70 induces membrane curvature to generate surface protrusions. Exo70 therefore couples actin dynamics with membrane remodeling for protrusion formation and cell migration. Here we propose to examine the molecular mechanisms by which Exo70 promotes membrane curvature induction and the Arp2/3 complex-mediated actin remodeling. Furthermore, we will investigate the coordinated actions of the exocyst complex, the Arp2/3 complex, and the EHD family of "pinchases" in the generation of secretory vesicles from the sorting endosome that mediates integrins recycling to the leading edge for migration. We take a multi-disciplinary approach combining biochemistry, biophysics, microscopic imaging, and molecular dynamics simulation to address important emerging questions in the field. These studies will help us to elucidate the molecular mechanisms of cell migration, and contribute t our understanding of a number of diseases such neurological disorders and cancer.