| Transforming activity of the Rho family GTPase, Wrch-1, a Wnt-regulated Cdc42 homolog, is dependent on a novel carboxyl-terminal palmitoylation motif. | |
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MedLine Citation:
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PMID: 16046391 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Wrch-1 is a Rho family GTPase that shares strong sequence and functional similarity with Cdc42. Like Cdc42, Wrch-1 can promote anchorage-independent growth transformation. We determined that activated Wrch-1 also promoted anchorage-dependent growth transformation of NIH 3T3 fibroblasts. Wrch-1 contains a distinct carboxyl-terminal extension not found in Cdc42, suggesting potential differences in subcellular location and function. Consistent with this, we found that Wrch-1 associated extensively with plasma membrane and endosomes, rather than with cytosol and perinuclear membranes like Cdc42. Like Cdc42, Wrch-1 terminates in a CAAX tetrapeptide (where C is cysteine, A is aliphatic amino acid, and X is any amino acid) motif (CCFV), suggesting that Wrch-1 may be prenylated similarly to Cdc42. Most surprisingly, unlike Cdc42, Wrch-1 did not incorporate isoprenoid moieties, and Wrch-1 membrane localization was not altered by inhibitors of protein prenylation. Instead, we showed that Wrch-1 is modified by the fatty acid palmitate, and pharmacologic inhibition of protein palmitoylation caused mislocalization of Wrch-1. Most interestingly, mutation of the second cysteine of the CCFV motif (CCFV > CSFV), but not the first, abrogated both Wrch-1 membrane localization and transformation. These results suggest that Wrch-1 membrane association, subcellular localization, and biological activity are mediated by a novel membrane-targeting mechanism distinct from that of Cdc42 and other isoprenylated Rho family GTPases. |
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Authors:
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Anastacia C Berzat; Janice E Buss; Emily J Chenette; Carolyn A Weinbaum; Adam Shutes; Channing J Der; Audrey Minden; Adrienne D Cox |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2005-07-26 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 280 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2005 Sep |
Date Detail:
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Created Date: 2005-09-19 Completed Date: 2005-11-28 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 33055-65 Citation Subset: IM |
Affiliation:
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Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, 27599-7512, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Motifs Amino Acid Sequence Animals Biotin / chemistry Blotting, Western Cell Adhesion Cell Membrane / metabolism Cell Proliferation Cysteine / chemistry Cytosol / metabolism Endosomes / metabolism Esters / chemistry Green Fluorescent Proteins / metabolism Mice Microscopy, Fluorescence Molecular Sequence Data Mutagenesis, Site-Directed Mutation NIH 3T3 Cells Palmitic Acid / chemistry Protein Binding Protein Structure, Tertiary Recombinant Proteins / chemistry Sequence Homology, Amino Acid Signal Transduction Transfection cdc42 GTP-Binding Protein / metabolism* rho GTP-Binding Proteins / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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CA103143/CA/NCI NIH HHS; CA109550/CA/NCI NIH HHS; CA51890/CA/NCI NIH HHS; CA63071/CA/NCI NIH HHS; CA67771/CA/NCI NIH HHS; GM46372/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Esters; 0/Recombinant Proteins; 147336-22-9/Green Fluorescent Proteins; 52-90-4/Cysteine; 57-10-3/Palmitic Acid; 58-85-5/Biotin; EC 3.6.1.-/RHOU protein, human; EC 3.6.5.2/cdc42 GTP-Binding Protein; EC 3.6.5.2/rho GTP-Binding Proteins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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