CALCIUM ACTIVATION OF RAS MEDIATED BY NEURONAL EXCHANGE FACTOR RAS-GRF

TYROSINE kinase receptors stimulate the Ras signalling pathway by enha ncing the activity of the SOS nucleotide-exchange factor(1) This occur s, at least in part, by the recruitment of an SOS-GRB2 complex to Ras in the plasma membrane. Here we describe a different signalling pathwa y to Ras that involves activation of the Ras-GRF exchange factor(2-4) in response to Ca2+-influx, In particular, se show that the ability of Ras-CRF to activate Ras in vivo is markedly enhanced by raised Ca2+ c oncentrations. Activation is mediated by calmodulin binding to an IQ m otif(5) in Ras-GRF, because substitutions in conserved amino acids in this motif prevent both calmodulin binding to Ras-CRF and Ras-GRF acti vation in vivo, So far, full-length Ras-GRF has been detected only in brain neurons(2,6,7), Our findings implicate Ras-GRF in the regulation of neuronal functions that are influenced by Ca2+ signals.