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Article
Characterization of a Cdc42 Protein Inhibitor and Its Use as a Molecular Probe
The Journal of Biological Chemistry
  • Lin Hong, University of New Mexico
  • S. Ray Kenney, University of New Mexico
  • Genevieve K. Phillips, University of New Mexico
  • Denise S. Simpson, Cedarville University
  • Chad E. Schroeder, University of Kansas
  • Julica Nöth, University of Kansas
  • Elsa Romero, University of New Mexico
  • Scarlett Swanson, University of New Mexico
  • Anna Waller, University of New Mexico
  • J. Jacob Strouse, University of New Mexico
  • Mark Carter, University of New Mexico
  • Alexandre Chigaev, University of New Mexico
  • Oleg Ursu, University of New Mexico
  • Tudor Oprea, University of New Mexico
  • Brian Hjelle, University of New Mexico
  • Jennifer E. Golden, University of Kansas
  • Jeffrey Aubé, University of Kansas
  • Laurie G. Hudson, University of New Mexico
  • Tione Buranda, University of New Mexico
  • Larry A. Sklar, University of New Mexico
  • Angela Wandinger-Ness, University of New Mexico
Document Type
Article
Publication Date
3-22-2013
DOI
http://dx.doi.org/10.1074/jbc.m112.435941
PubMed ID
23382385
PubMed Central® ID
PMC3605667
Abstract
Cdc42 plays important roles in cytoskeleton organization, cell cycle progression, signal transduction, and vesicle trafficking. Overactive Cdc42 has been implicated in the pathology of cancers, immune diseases, and neuronal disorders. Therefore, Cdc42 inhibitors would be useful in probing molecular pathways and could have therapeutic potential. Previous inhibitors have lacked selectivity and trended toward toxicity. We report here the characterization of a Cdc42-selective guanine nucleotide binding lead inhibitor that was identified by high throughput screening. A second active analog was identified via structure-activity relationship studies. The compounds demonstrated excellent selectivity with no inhibition toward Rho and Rac in the same GTPase family. Biochemical characterization showed that the compounds act as noncompetitive allosteric inhibitors. When tested in cellular assays, the lead compound inhibited Cdc42-related filopodia formation and cell migration. The lead compound was also used to clarify the involvement of Cdc42 in the Sin Nombre virus internalization and the signaling pathway of integrin VLA-4. Together, these data present the characterization of a novel Cdc42-selective allosteric inhibitor and a related analog, the use of which will facilitate drug development targeting Cdc42-related diseases and molecular pathway studies that involve GTPases.
Keywords
  • Cdc42,
  • cytoskeleton,
  • GTPase,
  • integrin,
  • migration
Citation Information
Lin Hong, S. Ray Kenney, Genevieve K. Phillips, Denise S. Simpson, et al.. "Characterization of a Cdc42 Protein Inhibitor and Its Use as a Molecular Probe" The Journal of Biological Chemistry Vol. 288 Iss. 12 (2013) p. 8531 - 8543 ISSN: 1083-351X
Available at: http://works.bepress.com/denise_simpson/31/