Calcium Signals Stop Through CAPRI

Abstract

Lockyer et al. have identified and characterized a new member of the Ras guanosine triphosphatase (GTPase)-activating protein (GAP) family that is regulated by calcium and thus, named Ca 2+ -promoted Ras activator (CAPRI). Capri has structural similarity (a pleckstrin homology domain, a GAP-related domain, and a Bruton's tyrosine kinase motif) to members of the Ras GAP1 subfamily, but unlike other members of the subfamily, CAPRI has functional calcium-binding C2 domains. The redistribution of CAPRI to the plasma membrane in transfected cells was stimulated by increases in intracellular Ca 2+ (either by treatment with a calcium ionophore or activation of the purinergic G protein-coupled receptor that activates phospholipase C leading to increased intracellular Ca 2+ owing to production of inositol trisphosphate). Unlike other members of the GAP1 family, CAPRI was not sensitive to changes in phosphatidylinositol lipids in the membrane. Increases in intracellular Ca 2+ were required to activate the GAP activity of CAPRI. In transfected cells, activation of CAPRI attenuated calcium-induced activation of the Ras-mitogen-activated protein kinase (MAPK) pathway. Expression of a dominant negative form of CAPRI enhanced phosphorylation of the MAPKs ERK1 and ERK2. Thus, CAPRI may be an off switch that helps to regulate the output of calcium-mediated activation of the Ras-MAPK pathway. P. J. Lockyer, S. Kupzig, P. J. Cullen, CAPRI regulates the Ca 2+ -dependent inactivation of the Ras-MAPK pathway. Current Biol . 11 , 981-986 (2001). [Full Text]