title: CAPRI regulates Ca(2+)-dependent inactivation of the Ras-MAPK pathway.
abstract: 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.
authors.affiliation: Department of Biochemistry, School of Medical Sciences, University of Bristol, BS8 1TD, Bristol, United Kingdom. P.J.Lockyer@bristol.ac.uk
authors.forename: P J
authors.initials: PJ
authors.lastname: Lockyer
authors.forename: S
authors.initials: S
authors.lastname: Kupzig
authors.forename: P J
authors.initials: PJ
authors.lastname: Cullen
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D016895:Culture Media, Serum-Free; D020549:GTP Phosphohydrolase Activators / Q000378:metabolism; D017930:Genes, Reporter; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D016895:Culture Media, Serum-Free; D020549:GTP Phosphohydrolase Activators; D007476:Ionophores; C491144:RASA4 protein, human; D011993:Recombinant Fusion Proteins; D020703:ras GTPase-Activating Proteins; D015759:Ionomycin; D006632:Histamine; D000255:Adenosine Triphosphate; D018631:ras Proteins; D002118:Calcium