|Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2005: ¥700,000 (Direct Cost: ¥700,000)
Cytoskeleton reorganization regulates cell polarity, migration and signal transduction in various cells, but the precise role in hematopoietic cells is still unclear. In this study, we focused on several aspects of the regulation and function of cytoskeleton reorganization molecules, such as DOCK2,Vavl, and SLAT, in hematopoietic cell activation. We found that DOCK2 deficiency causes marked reduction of Val4 NKT cells in the thymus, liver, and spleen. Studies using bone marrow chimeras indicated that development of Val4 NKT cell requires DOCK2 expression in T cell precursors, but not in APCs. We also reported that DOCK2 regulates motility and polarity during neutrophil chemotaxis. In DOCK2-deficient neutrophils, chemoattractant-induced activation of both Rac1 and Rac2 were severely impaired, resulting in the loss of polarized accumulation of F-actin and phosphatidylinositol 3,4,5-triphosphate (PIP_3) at the leading edge. These results indicate that during neutrophil chemotaxis DOCK2 regulates leading edge formation through PIP_3-dependent membrane translocation and Rac activation. In addition, we showed that Vavl is selectively required for IL-4 and c-Maf expression, a requirement reflecting, at least in part, the dependence of c-Maf expression of Ca^<2+>/NFAT signaling. Finally, we found that SLAT regulates Th1 and Th2 lung inflammatory responses by controlling Ca^<2+>/NFAT signaling. Thus, we demonstrated several critical aspects for cytoskeleton reorganization in hematopoietic cells using a combination of biochemical and genetic approaches. Future work should be aimed at defining the precise mechanisms through which these molecules regulate the function of cytoskeleton reorganization.