CYTOSKELETAL REGULATION BY RHO GTPASES AND ACTIN NUCLEATION FACTORS. Rho GTPases play a central role in diverse biological processes including reorganization of the actin cytoskeleton and microtubule dynamics. We are characterizing the Rho1 small GTPase and three of its downstream effectors: the linear actin nucleation factors Capu and Spire, which act downstream of Rho1 to regulate the onset of ooplasmic streaming during oogenesis, and WASH, a new Wiskott-Aldrich Syndrome family protein that activates the Arp2/3 complex and functions to remodel actin structures to elicit changes in cell shape/movement. Our current efforts are focused on identifying and analyzing the components, pathways, and regulatory mechanism(s) associated with these proteins.
MECHANISMS OF SINGLE CELL AND MULTICELLULAR WOUND REPAIR. Epithelial wound repair shares many similarities with the tissue movements that occur during normal embryo epithelial morphogenesis: both require cell shape changes and cell migrations that are dependent on the actin cytoskeleton. We are investigating the cellular and molecular mechanisms of single cell and multicellular wound repair and their ensuing biological manifestations within the context of a whole organism. We are particularly interested in the regulation of the actin cytoskeleton and in the role of the Rho family of small GTPases in these processes.
NUCLEAR ARCHITECTURE AND ORGANIZATION. The nucleus is highly organized and contains a cytoskeletal-like matrix or nucleoskeleton that provides overall structural integrity, as well as the internal infrastructure that allows the movement of components, complexes, and machineries within the nucleus. The nuclear envelope is a key component in the organization and structure of the nucleus, and is the site for signal sensing, molecule trafficking, and inter- and intra-nuclear attachments. In addition to their cytoplasmic roles, WAS proteins have recently been implicated in nuclear processes. Our preliminary data shows that WASH is present in the nucleus, associates with polytene chromosomes, and importantly, that its removal by RNAi in cells leads to altered nuclear morphology. Consistent with this, before WASH was appreciated as a WAS family protein, it was identified in a chromatin-remodeling complex along with ISWI and TRF2. We are investigating the effect of Wash on nuclear architecture and organization using a combination of comparative bioinformatic, proteomic, cell biological, and high-resolution microscopic approaches.
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Fred Hutch | University of Washington
Institute for Systems Biology (ISB)| Center for Infectious Disease Research