Molecular dissection of the complex and overlapping network of interactions between GTPases is currently a major challenge. Dozens of GTPases have been identified, many of which contain highly related amino acid sequences. Each species of GTPase much interact with regulatory and effector molecules to appropriately transduce specific external stimuli, leading to specific cellular responses. The long term goal of this Program Project is to gain insight into this regulatory network by studying one sub-family of GTPases, the RAC proteins. Rac1 and Rac2 proteins are highly similar (92% identical), yet disruption of the Rac2 gene, which is specifically expressed in hematopoietic cells, leads to multiple defects of blood cell development and function of phenotypes has recently been identified in a human patient carrying a dominant-mutant Rac2 allele. The specific goals of this Program Project include elucidation of the networks of upstream signaling molecules and downstream effector molecules that are utilized by Rac2 in hematopoietic cells, as well as gaining insight into the molecular controls responsible for coordinate expression of Rac GTPases. Each project within the questions of Rac2 function, including cross-talk between expression of Rac proteins; the molecular basis of tissue restricted expression of the Rac2 gene; the functional intersection of Rac2 with proteins such as BCR-ABL and Nf-1 that are involved in the control of hematopoietic cell proliferation; the unique role of Rac2 in the control of phagocyte function; the role of Rac2 in transducing integrin- mediated signals associated with inflammation and angiogenesis; and the role of Rac2 in the control of cytoskeletal structure and function. On a broader level, completion of these highly integrated studies will not only provide significant new information on the functional relationships and regulation of Rac1 and Rac2 GTPases in hematopoietic cells, but will also likely provide insights into GTPase regulation that will be relevant to other small molecular weight GTPases.
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