Ca(2+) is a universal second messenger that is critical for cell growth and is intimately associated with many Ras-dependent cellular processes such as proliferation and differentiation. Ras is a small GTP binding protein that operates as a molecular switch regulating the control of gene expression, cell growth, and differentiation through a pathway from receptors to mitogen-activated protein kinases (MAPKs). A role for intracellular Ca(2+) in the activation of Ras has been previously demonstrated, e.g., via the nonreceptor tyrosine kinase PYK2 and by Ca(2+)/calmodulin-dependent guanine nucleotide exchange factors (GEFs) such as Ras-GRF; however, there is no Ca(2+)-dependent mechanism for direct inactivation. An important advance toward greater understanding of the complex coordination within the Ras-signaling network is the spatio-temporal analysis of signaling events in vivo. Here, we describe the identification of CAPRI (Ca(2+)-promoted Ras inactivator), a Ca(2+)-dependent Ras GTPase-activating protein (GAP) that switches off the Ras-MAPK pathway following a stimulus that elevates intracellular Ca(2+). Analysis of the spatio-temporal dynamics of CAPRI indicates that Ca(2+) regulates the GAP by a fast C2 domain-dependent translocation mechanism.
Pubmed ID: 11448776 RIS Download
Mesh terms: Adenosine Triphosphate | Amino Acid Sequence | Animals | Calcium | Cell Line | Culture Media, Serum-Free | GTP Phosphohydrolase Activators | Genes, Reporter | Histamine | Humans | Immunoblotting | Ionomycin | Ionophores | MAP Kinase Signaling System | Molecular Sequence Data | Protein Structure, Tertiary | Recombinant Fusion Proteins | Sequence Alignment | ras GTPase-Activating Proteins | ras Proteins
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