Rho GTPase-Activating Proteins in Cancer
Principal Investigator: Yi Zheng
Abstract: Rho family small GTPases are molecular switches involved in the regulation of diverse cellular functions including various cytoskeleton related events and gene transcription. They may act as critical links to many aspects of cancer development. The Rho GTPase-activating proteins (RhoGAPs) are one of the major classes of regulators of Rho GTPases found in all eukaryotes that are essential in cell cytoskeletal organization, growth, differentiation, and neuronal development, and in certain cases may behave as tumor suppressors. Recent studies have implicated them as specific negative regulators of Rho protein pathways and provided clues on how the RhoGAP-catalyzed GTPase-activating reaction might proceed. The primary purposes of this study are to delineate the mechanism of substrate specificity and efficacy, to understand the mode of regulation, and to investigate the signaling roles of RhoGAP members. In addition, the possible use of RhoGAPs as downregulators of specific Rho GTPases in reversing cancer cell phenotypes will be explored. In specific aim 1 we propose to dissect the mechanism of specificity and efficiency of RhoGAP domain based on the available structure-function information of RhoGAPs. In specific aim 2 we will attempt to determine how various intracellular signals, through kinases and/or SH3 domain, might converge on RhoGAPs leading to their tight regulation, in specific aim 3 we will examine the normal function of two RhoGAPs, Cdc42GAP and p200RhoGAP, by expression, RNAi knockdown and gene targeting knockout approaches. Finally, we will develop a set of novel, RhoGAP-based molecular tools that can be utilized for specific downregulation of individual Rho GTPase activities and test their anti-tumorigenic potential in a variety of cancer cells in which Rho GTPase signaling is altered. These studies will provide mechanistic insights into the regulatory function of RhoGAPs in cell signaling and may generate therapeutic reagents targeting Rho GTPase pathways in human cancers.
Funding Period: 2004-03-01 - 2010-02-28
more information: NIH RePORT
- Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftmentLei Wang
Division of Experimental Hematology, Children s Hospital Medical Center, University of Cincinnati, OH 45229, USA
Blood 107:98-105. 2006..These results provide evidence that Cdc42 activity is important for erythropoiesis and for multiple HSP functions, including survival, adhesion, and engraftment...
- Gene targeting of Cdc42 and Cdc42GAP affirms the critical involvement of Cdc42 in filopodia induction, directed migration, and proliferation in primary mouse embryonic fibroblastsLinda Yang
Division of Experimental Hematology, Children s Hospital Medical Center, Molecular Developmental Biology Graduate Program, University of Cincinnati, Cincinnati, OH 45229, USA
Mol Biol Cell 17:4675-85. 2006..These results demonstrate a different requirement of Cdc42 activity in primary MEFs from ES or ES-derived clonal fibroblastoid cells and suggest that Cdc42 plays cell-type-specific signaling roles...
- Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephalyLei Chen
Division of Experimental Hematology, Cincinnati Children s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
Proc Natl Acad Sci U S A 103:16520-5. 2006..Taken together, these results indicate that Cdc42 has an essential role in establishing the apical-basal polarity of the telencephalic NE, which is needed for the expansion and bifurcation of cerebral hemispheres...
- Cdc42 GTPase-activating protein deficiency promotes genomic instability and premature aging-like phenotypesLei Wang
Division of Experimental Hematology, Molecular Developmental Biology Graduate Program, Children s Hospital Research Foundation, University of Cincinnati, Cincinnati, OH 45229, USA
Proc Natl Acad Sci U S A 104:1248-53. 2007..Furthermore, Cdc42 activation is sufficient to promote a premature cellular senescence phenotype that depends on p53. These results suggest a role of Cdc42 activity in regulating mammalian genomic stability and aging-related physiology...
- p200 RhoGAP promotes cell proliferation by mediating cross-talk between Ras and Rho signaling pathwaysXun Shang
Division of Experimental Hematology, Children s Hospital Research Foundation, University of Cincinnati, Cincinnati, Ohio 45229, USA
J Biol Chem 282:8801-11. 2007....
- Rac1 controls the formation of midline commissures and the competency of tangential migration in ventral telencephalic neuronsLei Chen
Division of Experimental Hematology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229, USA
J Neurosci 27:3884-93. 2007..Moreover, they indicate that Rac1 has a critical role in axon guidance and in acquisition of migratory competency during differentiation of the progenitors for the ventral telencephalon-derived interneurons...
- Cdc42 critically regulates the balance between myelopoiesis and erythropoiesisLinda Yang
Division of Experimental Hematology, Children s Hospital Medical Center, Cincinnati, OH 45229, USA
Blood 110:3853-61. 2007..Thus, Cdc42 is an essential regulator of the balance between myelopoiesis and erythropoiesis...
- Rho GTPase Cdc42 is essential for B-lymphocyte development and activationFukun Guo
Division of Experimental Hematology, Children s Hospital Research Foundation, University of Cincinnati, OH 45229, USA
Blood 114:2909-16. 2009..These results reveal multifaceted roles of Cdc42 in B-cell development and activation...