The Ras-related GTPase Cdc42 plays important roles in a wide range of cellular processes including the establishment of cell polarity and the control of cell growth and migration. The proper regulation of Cdc42- coupled signaling activities is crucial for its cellular functions, as evidenced by the hyper-activation of Cdc42 by oncogenic guanine nucleotide exchange factors (GEFs), or mutations that give rise to an accelerated exchange of GDP for GTP, resulting in cellular transformation and tumor formation in nude mice. During the past funding period, we established how Cdc42 and its regulatory protein Cool-1 (for Cloned-out of library), which functions both as a GEF and a target/effector for Cdc42, regulate cell growth by helping to maintain proper EGF receptor (EGFR) homeostasis. We also discovered that the phosphorylation-dephosphorylation cycle of Cool-1 influences cell migration, raising the interesting possibility that Cdc42 and its signaling partners may coordinate cell growth control with the regulation of cell motility. Moreover, our studies with different cell and genetic model systems have highlighted a role for Cdc42 in cellular differentiation and cell fate determination. In the coming funding period, we will continue to combine biochemical and structural biology-based studies with genetic approaches to extend these findings and better establish how Cdc42 and its regulatory proteins impact three fundamentally important cellular processes, namely cell growth, migration, and differentiation. These studies will constitute 3 specific lines of investigation. 1) Determine how Cdc42 and its signaling partners work together to maintain proper EGFR homeostasis. In these studies, we will be particularly interested in determining the regulatory cues that set the timing for the Cdc42- mediated signals that establish the proper balance between EGFR-coupled mitogenic signaling versus receptor down-regulation and degradation. 2.) Examine how Cool-1 and its binding partners regulate cell migration. Here, we will follow-up recent clues suggesting that the phosphorylation of Cool-1 stimulates its dissociation from Cat (for Cool-associated tyrosine kinase substrate) and helps trigger the disassembly of focal complexes. We also will want to see whether the Cdc42-GEF activity of Cool-1, which is triggered by its phosphorylation, confers important regulatory effects on cell migration. 3.) Examine the roles of Cdc42 and its signaling partners in cellular differentiation. We will explore the possible involvement of Cdc42 in ensuring the proper lifetime for signaling activities necessary for neuronal differentiation. In addition, we will build on our recent studies in mouse embryonic (P19) cells that suggest Cdc42 and a dual function Cdc42- GEF/target-effector that we recently discovered, play important roles in neurogenesis. We expect that these studies will yield new insights into how Cdc42 is able to mediate a diversity of cellular responses that are necessary for normal biological outcomes and, when de-regulated, gives rise to a variety of disease states including cancer and neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM047458-19
Application #
7817131
Study Section
Intercellular Interactions (ICI)
Program Officer
Maas, Stefan
Project Start
1992-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
19
Fiscal Year
2010
Total Cost
$320,166
Indirect Cost
Name
Cornell University
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
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Katt, William P; Lukey, Michael J; Cerione, Richard A (2017) A tale of two glutaminases: homologous enzymes with distinct roles in tumorigenesis. Future Med Chem 9:223-243
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Lukey, Michael J; Greene, Kai Su; Erickson, Jon W et al. (2016) The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy. Nat Commun 7:11321
Druso, Joseph E; Endo, Makoto; Lin, Miao-Chong Joy et al. (2016) An Essential Role for Cdc42 in the Functioning of the Adult Mammary Gland. J Biol Chem 291:8886-95
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Desrochers, Laura M; Bordeleau, Fran├žois; Reinhart-King, Cynthia A et al. (2016) Microvesicles provide a mechanism for intercellular communication by embryonic stem cells during embryo implantation. Nat Commun 7:11958
Stalnecker, Clint A; Ulrich, Scott M; Li, Yunxing et al. (2015) Mechanism by which a recently discovered allosteric inhibitor blocks glutamine metabolism in transformed cells. Proc Natl Acad Sci U S A 112:394-9

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