Document Detail


Galpha12 stimulates c-Jun NH2-terminal kinase through the small G proteins Ras and Rac.
MedLine Citation:
PMID:  8663428     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The pertussis toxin (PTX) insensitive heterotrimeric G protein G12 has been implicated in mitogenesis and transformation, but its direct effectors remain unknown. To define potential signaling pathways utilized by G12, we expressed an activated mutant of its alpha subunit, Galpha12(Q229L), in HEK293 cells and examined its effects on Ras and mitogen-activated protein kinases (MAPKs). Transient expression of activated Galpha12 increased the percentage of Ras in the active, GTP-bound state, stimulated c-Jun NH2-terminal kinase (JNK) activity, and enhanced the transcriptional activity of c-Jun. Dominant negative Ras (N17Ras) inhibited Galpha12-mediated JNK activation in NIH3T3 cells but failed to do so in HEK293 cells. In contrast, dominant negative Rac (N17Rac1) inhibited JNK activation by Galpha12 in HEK293 cells as well as three other cell lines. In 1321N1 cells, where thrombin stimulates G12-dependent mitogenesis, coexpression of N17Rac1 or a dominant negative mutant of MEKK1 (MEKKDelta(K432M)) inhibits c-Jun/AP-1 sensitive reporter gene expression stimulated by thrombin or Galpha12. These data demonstrate that the alpha subunit of the heterotrimeric G protein G12, like tyrosine kinase growth factor receptors, activates Ras and recruits a signal transduction pathway involving the small GTP-binding protein Rac that leads to JNK activation.
Authors:
L R Collins; A Minden; M Karin; J H Brown
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  271     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1996 Jul 
Date Detail:
Created Date:  1996-09-12     Completed Date:  1996-09-12     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  17349-53     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, University of California at San Diego, La Jolla, California 92093-0636, USA.
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MeSH Terms
Descriptor/Qualifier:
3T3 Cells
Animals
Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
Cell Division
Cell Line
Cercopithecus aethiops
Enzyme Activation
GTP-Binding Proteins / biosynthesis,  metabolism*
Hela Cells
Humans
JNK Mitogen-Activated Protein Kinases
Kidney
MAP Kinase Kinase Kinase 1*
Mice
Mitogen-Activated Protein Kinases / biosynthesis,  metabolism
Mutagenesis, Site-Directed
Nerve Tissue Proteins / biosynthesis,  metabolism
Point Mutation
Protein-Serine-Threonine Kinases / metabolism
Recombinant Proteins / biosynthesis,  metabolism
Transfection
rac GTP-Binding Proteins
ras Proteins / metabolism*
Grant Support
ID/Acronym/Agency:
GM17277/GM/NIGMS NIH HHS; GM36927/GM/NIGMS NIH HHS; HL35018/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Nerve Tissue Proteins; 0/Recombinant Proteins; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinases; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 2.7.11.25/MAP Kinase Kinase Kinase 1; EC 2.7.11.25/MAP3K1 protein, human; EC 2.7.11.25/Map3k1 protein, mouse; EC 3.6.1.-/GTP-Binding Proteins; EC 3.6.5.2/rac GTP-Binding Proteins; EC 3.6.5.2/ras Proteins

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