A Rac1 effector site controlling mitogenesis through superoxide production.
The Rac GTP-binding protein controls signal transduction pathways that are critical for mitogenesis and oncogenesis (1,2). The biochemical nature of these signaling pathways is presently unknown. Here we report that a region in Rac1 (residues 124-135), previously defined as the insert region (3), is essential for its mitogenic activity. Deletion of this region does not interfere with the ability of Rac1 to induce cytoskeletal changes or to activate the Jun kinase mitogen-activated protein kinase cascade but abrogates Rac1-induced stimulation of DNA synthesis and Rac1-mediated superoxide production in quiescent fibroblasts. Treatment of cells with agents that abolish superoxide generation inhibits specifically the mitogenic effect of Rac1. Our results identify an effector site in Rac1 that is necessary for mitogenic signaling and implicate superoxide generation as a candidate effector pathway of Rac1-dependent cell growth.
Joneson
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T
Department of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, New York 11794-5222, USA.
Bar-Sagi
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D
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004261:DNA Replication; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D008938:Mitosis; D016254:Mutagenesis, Insertional; D019255:NADPH Oxidases / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D020744:rac GTP-Binding Proteins
D013481:Superoxides; D019255:NADPH Oxidases; D019908:Proto-Oncogene Proteins c-raf; 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