CAPRI regulates Ca2+-dependent inactivation of the Ras-MAPK pathway

Ca2+ is a universal second messenger that is critical for cell growth and i s intimately associated with many Pas-dependent cellular processes such as proliferation and differentiation [1]. Pas is a small GTP binding protein t hat operates as a molecular switch regulating the control of gene expressio n, cell growth, and differentiation through a pathway from receptors to mit ogen-activated protein kinases (MAPKs) [2]. A role for intracellular Ca2+ i n the activation of Pas has been previously demonstrated, e.g., via the non receptor tyrosine kinase PYK2 [3] and by Ca2+/calmodulin-dependent guanine nucleotide exchange factors (GEFs) such as Ras-GRF [4]; however, there is n o Ca2+-dependent mechanism for direct inactivation. An important advance to ward greater understanding of the complex coordination within the Ras-signa ling network is the spatio-temporal analysis of signaling events in vivo. H ere, we describe the identification of CAPRI (Ca2+-promoted Pas inactivator ), a Ca2+-dependent Pas GTPase-activating protein (GAP) that switches off t he Pas-MAPK pathway following a stimulus that elevates intracellular Ca2+, Analysis of the spatiotemporal dynamics of CAPRI indicates that Ca2+ regula tes the GAP by a fast C2 domain-dependent translocation mechanism. (C) 2001 Elsevier Science Ltd. All rights reserved.