title: Identification of a specific Ins(1,3,4,5)P4-binding protein as a member of the GAP1 family.
abstract: Inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4) is produced rapidly from inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) in stimulated cells. Despite extensive experimentation, no clearly defined cellular function has yet been described for this inositol phosphate. Binding sites specific for Ins(1,3,4,5)P4 have been identified in several tissues, and we have purified one such protein to homogeneity. Its high affinity for Ins(1,3,4,5)P4, and its exquisite specificity for this isomeric configuration, suggest it may be an Ins(1,3,4,5)P4 receptor. Here we report the cloning and characterization of this protein as a GTPase-activating protein, specifically a member of the GAP1 family. In vitro it shows GAP activity against both Rap and Ras, but only the Ras GAP activity is inhibited by phospholipids and is specifically stimulated by Ins(1,3,4,5)P4.
authors.affiliation: Inositide Laboratory, Babraham Institute, Cambridge, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Cullen
authors.forename: J J
authors.initials: JJ
authors.lastname: Hsuan
authors.forename: O
authors.initials: O
authors.lastname: Truong
authors.forename: A J
authors.initials: AJ
authors.lastname: Letcher
authors.forename: T R
authors.initials: TR
authors.lastname: Jackson
authors.forename: A P
authors.initials: AP
authors.lastname: Dawson
authors.forename: R F
authors.initials: RF
authors.lastname: Irvine
mesh_terms: D000595:Amino Acid Sequence; D026905:Amino Acid Transport Systems; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D020690:GTPase-Activating Proteins; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000737:chemistry; D008969:Molecular Sequence Data; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D020668:rap GTP-Binding Proteins; D020703:ras GTPase-Activating Proteins; D018631:ras Proteins / Q000378:metabolism
chemical_list: D026905:Amino Acid Transport Systems; D020690:GTPase-Activating Proteins; D007295:Inositol Phosphates; D026901:Membrane Transport Proteins; D010743:Phospholipids; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C061107:inositol-1,3,4,5-tetrakisphosphate receptor; D020703:ras GTPase-Activating Proteins; C081655:inositol-1,3,4,5-tetrakisphosphate; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020668:rap GTP-Binding Proteins; D018631:ras Proteins