Rho GTPases are members of the Ras superfamily and have been shown to control actin cytoskeletal organization in eukaryotic cells. Studies primarily in fibroblasts, demonstrate that Rho GTPases control integrin receptor localization on the cell surface, adhesion and cell shape changes. In addition, one of the members of the Rho GTPase family, Rac, has been implicated in cell cycle progression and may be required for full transformation in fibroblasts. Little is known about the role of GTPases in hematopoietic cells. Since adhesion via integrin receptors appears has been shown to be important in hematopoietic stem cell localization, survival and proliferation, we have generated mice deficient in an hematopoietic-specific Rac, Rac2. We have recently reported that neutrophils and mast cells derived from Rac2-/- mice display a unique phenotype, characterized by abnormal actin-based functions such as adhesion, migration, phagocytosis and degranulation and abnormal cell survival with increased apoptosis after growth factor stimulation. In addition, we have recently identified a mutation of human Rac2 (aspartic acid to asparagine at position 57) associated with a phagocytic immunodeficiency demonstrating that Rac2 also plays a critical role in human blood cells. These abnormalities in differentiated blood cells occur in spite of the presence of the highly homologous Raci protein in Rac2-deficient cells. The focus of this grant proposal is to determine the role of Rac2 in hematopoietic stem and progenitor cell adhesion, migration and survival/proliferation and to determine the sequences in Rac2, which mediate specificity of these functions in hematopoietic cells. The proposed studies will utilize both Rac2-/-, Rac1+/- and conditional Rac1-/mice combined with retroviral-mediated gene transfer of mutants to study hematopoietic cells both in vitro and in vivo.
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