Document Detail


RAC1P29S is a spontaneously activating cancer-associated GTPase.
MedLine Citation:
PMID:  23284172     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Matthew J Davis; Byung Hak Ha; Edna C Holman; Ruth Halaban; Joseph Schlessinger; Titus J Boggon
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     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:  2013-01-16     Completed Date:  2013-03-14     Revised Date:  2013-08-01    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  912-7     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Data Bank Information
Bank Name/Acc. No.:
PDB/4GZL;  4GZM
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MeSH Terms
Descriptor/Qualifier:
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:
CA121974/CA/NCI NIH HHS; GM102262/GM/NIGMS NIH HHS; P30 EB009998/EB/NIBIB NIH HHS; R01 GM102262/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/RAC1 protein, human; 0/Recombinant Fusion Proteins; 86-01-1/Guanosine Triphosphate; EC 3.6.5.2/rac1 GTP-Binding Protein
Comments/Corrections

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