Grant: Operating Grant

DOCK180, an evolutionarily conserved protein, acts in concert with ELMO in regulating the activity of the small GTPases of the Rac family. Work in model organisms uncovered a role for these proteins in crucial developmental processes such as cell migration, myoblast fusion and phagocytosis of apoptotic cells. Yet, the mechanisms governing their activities and their biological functions in mammalian systems are poorly understood. As such, the long-term objectives of this proposal are to (i) uncover the biological functions of DOCK180/ELMO complex in mice and (ii) decipher the molecular mechanisms underlying the regulation of the signaling activity of the DOCK180/ELMO complex. We recently uncovered a central role for DOCK180 in mammalian myoblast fusion. The podocyte, a specialized cell type of the kidney, shares remarkable similarities to myoblasts. In our first aim, we will study the biological functions of two signaling pathways involving DOCK180 in the orchestration of the formation/maintenance of the kidney filtration barrier. In addition, we will pursue our studies on myoblast fusion by characterizing a putative mammalian fusion receptor. In the second aim, we propose to test the hypothesis that intramolecular constraints in ELMO maintain the protein in a "dormant" state and that activation by small GTPases is needed to permit DOCK180-mediated Rac signaling. Finally, in aim 3, we will investigate the molecular mechanisms of cell polarity and leading edge formation by DOCK180/ELMO. In summary, this work will help define the contribution of the DOCK180/ELMO/Rac signaling axis on biological events such as myoblast fusion, kidney filtration and cell polarity that require precise spatiotemporal remodeling of the cytoskeleton.