title: SHIP2: Structure, Function and Inhibition.
abstract: SHIP2 is a phosphatase that acts at the 5-position of phosphatidylinositol 3,4,5-trisphosphate. It is one of several enzymes that catalyse dephosphorylation at the 5-position of phosphoinositides or inositol phosphates. SHIP2 has a confirmed role in opsismodysplasia, a disease of bone development, but also interacts with proteins involved in insulin signalling, cytoskeletal function (thus having an impact on endocytosis, adhesion, proliferation and apoptosis) and immune system function. The structure of three domains (constituting about 38 % of the protein) is known. Inhibitors of SHIP2 activity have been designed to interact with the catalytic domain with sub-micromolar IC50values: these come from a range of structural classes and have been shown to have in vivo effects consistent with SHIP2 inhibition. Much remains unknown about the roles of SHIP2, and possible future directions for research are indicated.
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
authors.forename: Mark P
authors.identifier: 0000-0002-7648-2400
authors.initials: MP
authors.lastname: Thomas
authors.affiliation: I.R.I.B.H.M., Université Libre de Bruxelles, Campus Erasme, 808 Route de Lennik, 1070, Brussels, Belgium.
authors.forename: Christophe
authors.identifier: 0000-0002-0773-8206
authors.initials: C
authors.lastname: Erneux
authors.affiliation: Drug Discovery and Medicinal Chemistry, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
authors.forename: Barry V L
authors.identifier: 0000-0003-3255-9135
authors.initials: BV
authors.lastname: Potter
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D006801:Humans; D007107:Immune System / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008024:Ligands; D010009:Osteochondrodysplasias / Q000378:metabolism / Q000473:pathology; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007328:Insulin; D008024:Ligands; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
keywords: enzymes; inhibitors; phosphatases; phospholipids; structure