RAC regulation of actin polymerization and proliferation by a pathway distinct from Jun kinase.
The RAC guanine nucleotide binding proteins regulate multiple biological activities, including actin polymerization, activation of the Jun kinase (JNK) cascade, and cell proliferation. RAC effector loop mutants were identified that separate the ability of RAC to interact with different downstream effectors. One mutant of activated human RAC protein, RACV12H40 (with valine and histidine substituted at position 12 and 40, respectively), was defective in binding to PAK3, a Ste20-related p21-activated kinase (PAK), but bound to POR1, a RAC-binding protein. This mutant failed to stimulate PAK and JNK activity but still induced membrane ruffling and mediated transformation. A second mutant, RACV12L37 (with leucine substituted at position 37), which bound PAK but not POR1, induced JNK activation but was defective in inducing membrane ruffling and transformation. These results indicate that the effects of RAC on the JNK cascade and on actin polymerization and cell proliferation are mediated by distinct effector pathways that diverge at the level of RAC itself.
Department of Molecular Genetics and Microbiology, State University of New York, Stony Brook, NY 11794, USA.
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Joneson
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McDonough
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Bar-Sagi
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Van Aelst
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000648:ultrastructure; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D016296:Mutagenesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D014162:Transfection; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins
C101158:ARFIP2 protein, human; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C515903:PAK1 protein, human; C515911:PAK3 protein, human; C515905:Pak1 protein, mouse; C515906:Pak1 protein, rat; C515912:Pak3 protein, mouse; C515913:Pak3 protein, rat; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins