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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL069974-03
Application #
6726836
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Thomas, John
Project Start
2002-04-22
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
3
Fiscal Year
2004
Total Cost
$1,345,309
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Muthukrishnan, Rajarajeswari; Skalnik, David G (2009) Identification of a minimal cis-element and cognate trans-factor(s) required for induction of Rac2 gene expression during K562 cell differentiation. Gene 440:63-72
Allen, Jayme D; Jaffer, Zahara M; Park, Su-Jung et al. (2009) p21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics. Blood 113:2695-705
Ghiaur, Gabriel; Ferkowicz, Michael J; Milsom, Michael D et al. (2008) Rac1 is essential for intraembryonic hematopoiesis and for the initial seeding of fetal liver with definitive hematopoietic progenitor cells. Blood 111:3313-21
Muller, L U W; Schore, R J; Zheng, Y et al. (2008) Rac guanosine triphosphatases represent a potential target in AML. Leukemia 22:1803-6
Thomas, E K; Cancelas, J A; Zheng, Y et al. (2008) Rac GTPases as key regulators of p210-BCR-ABL-dependent leukemogenesis. Leukemia 22:898-904
Li, Yu; Yan, Jingliang; De, Pradip et al. (2007) Rap1a null mice have altered myeloid cell functions suggesting distinct roles for the closely related Rap1a and 1b proteins. J Immunol 179:8322-31
Cheng, Ni; He, Rong; Tian, Jun et al. (2007) A critical role of protein kinase C delta activation loop phosphorylation in formyl-methionyl-leucyl-phenylalanine-induced phosphorylation of p47(phox) and rapid activation of nicotinamide adenine dinucleotide phosphate oxidase. J Immunol 179:7720-8
Thomas, Emily K; Cancelas, Jose A; Chae, Hee-Don et al. (2007) Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR-ABL-induced myeloproliferative disease. Cancer Cell 12:467-78
Ming, Wenyu; Li, Shijun; Billadeau, Daniel D et al. (2007) The Rac effector p67phox regulates phagocyte NADPH oxidase by stimulating Vav1 guanine nucleotide exchange activity. Mol Cell Biol 27:312-23
Ghiaur, Gabriel; Lee, Andrew; Bailey, Jeff et al. (2006) Inhibition of RhoA GTPase activity enhances hematopoietic stem and progenitor cell proliferation and engraftment. Blood 108:2087-94

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