This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Division of a cell into two daughter cells, i.e. cytokinesis, is a fundamental process in biology. During cytokinesis, furrow ingression is believed to be powered by the mechanical force generated by the interaction between actin and myosin filaments, which form a contractile ring in anaphase and telophase cells. A body of evidence has implicated the central spindle as one of the important factors in positioning the contractile ring. However, the underlying mechanism is still unclear: how does myosin II concentrate at the cleavage furrow in response to the assembly of the central spindle, a set of antiparallel microtubules that become bundled in anaphase cells. We have identified a myosin-interacting GEF guanine nucleotide exchange factor (MyoGEF), which is capable of binding to nonmuscle myosin II, concentrating at the cleavage furrow, and activating the small GTPase protein RhoA. Additionally, MyoGEF interacts with another protein, called MyoGEF-interacting central spindle protein (MICSP), which concentrates at the central spindle in anaphase cells. We therefore hypothesize that MyoGEF, RhoA, and nonmuscle myosin II are assembled at the cleavage furrow as a functional unit, which is anchored to the central spindle via MyoGEF-MICSP interaction. To test this hypothesis, we will use a combination of biochemistry, cell biology, and molecular biology, with mammalian cells as a model, to: 1) Elucidate the interaction between MyoGEF and nonmuscle myosin II. 2) Elucidate the interaction between MyoGEF and MICSP. 3) Determine the importance of MyoGEF in the regulation of cytokinesis. 4) Define the structural basis for MICSP to concentrate at the central spindle. The successful completion of the research outlined in this proposal is expected to provide insights into how cell division goes awry in cancer as well as to provide potential molecular strategies for the prevention and treatment of cancer.
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