| RAC1P29S is a spontaneously activating cancer-associated GTPase. | |
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MedLine Citation:
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PMID: 23284172 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RAC1 is a small, Ras-related GTPase that was recently reported to harbor a recurrent UV-induced signature mutation in melanoma, resulting in substitution of P29 to serine (RAC1(P29S)), ranking this the third most frequently occurring gain-of-function mutation in melanoma. Although the Ras family GTPases are mutated in about 30% of all cancers, mutations in the Rho family GTPases have rarely been observed. In this study, we demonstrate that unlike oncogenic Ras proteins, which are primarily activated by mutations that eliminate GTPase activity, the activated melanoma RAC1(P29S) protein maintains intrinsic GTP hydrolysis and is spontaneously activated by substantially increased inherent GDP/GTP nucleotide exchange. Determination and comparison of crystal structures for activated RAC1 GTPases suggest that RAC1(F28L)--a known spontaneously activated RAC1 mutant--and RAC1(P29S) are self-activated in distinct fashions. Moreover, the mechanism of RAC1(P29S) and RAC1(F28L) activation differs from the common oncogenic mutations found in Ras-like GTPases that abrogate GTP hydrolysis. The melanoma RAC1(P29S) gain-of-function point mutation therefore represents a previously undescribed class of cancer-related GTPase activity. |
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Authors:
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Matthew J Davis; Byung Hak Ha; Edna C Holman; Ruth Halaban; Joseph Schlessinger; Titus J Boggon |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2013-01-02 |
Journal Detail:
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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:
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Created Date: 2013-01-16 Completed Date: 2013-03-14 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 912-7 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA. |
| Data Bank Information | |
Bank Name/Acc. No.:
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PDB/4GZL; 4GZM |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Substitution Animals COS Cells Cell Surface Extensions / enzymology Cercopithecus aethiops Crystallography, X-Ray Enzyme Activation / genetics Genetic Association Studies Guanosine Triphosphate / metabolism Humans Hydrolysis Kinetics Melanoma / enzymology*, genetics* Mice Microscopy, Fluorescence Models, Molecular Mutation, Missense* NIH 3T3 Cells Oncogenes* Recombinant Fusion Proteins / chemistry, genetics, metabolism Signal Transduction Static Electricity rac1 GTP-Binding Protein / chemistry, genetics*, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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CA121974/CA/NCI NIH HHS; GM102262/GM/NIGMS NIH HHS; R01 GM102262/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/RAC1 protein, human; 0/Recombinant Fusion Proteins; 86-01-1/Guanosine Triphosphate; EC 3.6.5.2/rac1 GTP-Binding Protein |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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