CDC25(Mm)/Ras-GRF1 regulates both Ras and Rac signaling pathways.
The Ras-GRF1 exchange factor molecule contains in addition to the catalytic domain two pleckstrin homology (PH1 and PH2), one IQ and one Dbl homology (DH) domains. In this study we investigated the role of such additional domains. We found that a Ras-GRF1 mutant lacking PH1 and IQ domains is sufficient to activate c-fos promoter in response to lysophosphatidic acid (LPA). The same mutant did not increase external stimuli-regulated kinase (ERK) activity, suggesting an additional mechanism for the induction of gene transcription. Isolated DH-PH2 module activates c-Jun NH(2)-terminal kinase and the c-fos promoter in response to LPA, providing the basis for an ERK-independent mechanism. These results provide evidence that Ras-GRF1 acts as a bifunctional molecule on both ERK-dependent and independent pathways.
Innocenti
M
M
Department of General Physiology and Biochemistry, University of Milan, Via Celoria 26, 20133, Milano, Italy.
Zippel
R
R
Brambilla
R
R
Sturani
E
E
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D005786:Gene Expression Regulation; D048031:JNK Mitogen-Activated Protein Kinases; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008957:Models, Genetic; D016296:Mutagenesis; D010957:Plasmids; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*; D020666:ras-GRF1 / Q000235:genetics / Q000502:physiology*
D008246:Lysophospholipids; D016760:Proto-Oncogene Proteins c-fos; D020666:ras-GRF1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins; D018631:ras Proteins