title: Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF.
abstract: Tyrosine kinase receptors stimulate the Ras signalling pathway by enhancing the activity of the SOS nucleotide-exchange factor. This occurs, at least in part, by the recruitment of an SOS-GRB2 complex to Ras in the plasma membrane. Here we describe a different signalling pathway to Ras that involves activation of the Ras-GRF exchange factor in response to Ca2+ influx. In particular, we show that the ability of Ras-GRF to activate Ras in vivo is markedly enhanced by raised Ca2+ concentrations. Activation is mediated by calmodulin binding to an IQ motif in Ras-GRF, because substitutions in conserved amino acids in this motif prevent both calmodulin binding to Ras-GRF and Ras-GRF activation in vivo. So far, full-length Ras-GRF has been detected only in brain neurons. Our findings implicate Ras-GRF in the regulation of neuronal functions that are influenced by Ca2+ signals.
authors.affiliation: Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Farnsworth
authors.forename: N W
authors.initials: NW
authors.lastname: Freshney
authors.forename: L B
authors.initials: LB
authors.lastname: Rosen
authors.forename: A
authors.initials: A
authors.lastname: Ghosh
authors.forename: M E
authors.initials: ME
authors.lastname: Greenberg
authors.forename: L A
authors.initials: LA
authors.lastname: Feig
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor; D002118:Calcium / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors; D015759:Ionomycin / Q000494:pharmacology; D008564:Membrane Potentials; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D014162:Transfection; D020663:ras Guanine Nucleotide Exchange Factors; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D020666:ras-GRF1
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002147:Calmodulin; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D011506:Proteins; D020663:ras Guanine Nucleotide Exchange Factors; D020666:ras-GRF1; D015759:Ionomycin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D002118:Calcium