Document Detail


Small molecule targeting Cdc42-intersectin interaction disrupts Golgi organization and suppresses cell motility.
MedLine Citation:
PMID:  23284167     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Signaling through the Rho family of small GTPases has been intensely investigated for its crucial roles in a wide variety of human diseases. Although RhoA and Rac1 signaling pathways are frequently exploited with the aid of effective small molecule modulators, studies of the Cdc42 subclass have lagged because of a lack of such means. We have applied high-throughput in silico screening and identified compounds that are able to fit into the surface groove of Cdc42, which is critical for guanine nucleotide exchange factor binding. Based on the interaction between Cdc42 and intersectin (ITSN), a specific Cdc42 guanine nucleotide exchange factor, we discovered compounds that rendered ITSN-like interactions in the binding pocket. By using in vitro binding and imaging as well as biochemical and cell-based assays, we demonstrated that ZCL278 has emerged as a selective Cdc42 small molecule modulator that directly binds to Cdc42 and inhibits its functions. In Swiss 3T3 fibroblast cultures, ZCL278 abolished microspike formation and disrupted GM130-docked Golgi structures, two of the most prominent Cdc42-mediated subcellular events. ZCL278 reduces the perinuclear accumulation of active Cdc42 in contrast to NSC23766, a selective Rac inhibitor. ZCL278 suppresses Cdc42-mediated neuronal branching and growth cone dynamics as well as actin-based motility and migration in a metastatic prostate cancer cell line (i.e., PC-3) without disrupting cell viability. Thus, ZCL278 is a small molecule that specifically targets Cdc42-ITSN interaction and inhibits Cdc42-mediated cellular processes, thus providing a powerful tool for research of Cdc42 subclass of Rho GTPases in human pathogenesis, such as those of cancer and neurological disorders.
Authors:
Amy Friesland; Yaxue Zhao; Yan-Hua Chen; Lie Wang; Huchen Zhou; Qun Lu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-02
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  110     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-23     Completed Date:  2013-03-21     Revised Date:  2013-07-24    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1261-6     Citation Subset:  IM    
Affiliation:
Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Vesicular Transport / antagonists & inhibitors*,  chemistry*,  physiology
Amino Acid Sequence
Animals
Binding Sites
Cell Movement / drug effects,  physiology
Cell Survival / drug effects
Cells, Cultured
Drug Evaluation, Preclinical
Golgi Apparatus / drug effects,  physiology
Humans
Mice
Models, Molecular
Molecular Sequence Data
Neurons / drug effects,  ultrastructure
Protein Interaction Domains and Motifs / drug effects
Sequence Homology, Amino Acid
Signal Transduction / drug effects
Swiss 3T3 Cells
User-Computer Interface
Wound Healing / drug effects
cdc42 GTP-Binding Protein / antagonists & inhibitors*,  chemistry*,  genetics,  physiology
Grant Support
ID/Acronym/Agency:
CA111891/CA/NCI NIH HHS; CA165202/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Vesicular Transport; 0/intersectin 1; EC 3.6.5.2/cdc42 GTP-Binding Protein
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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