title: A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system.
abstract: Phosphoinositide (PI) 3-kinases have been characterized as enzymes involved in receptor signal transduction in mammalian cells and in a complex which mediates protein trafficking in yeast. PI 3-kinases linked to receptors with intrinsic or associated tyrosine kinase activity are heterodimeric proteins, consisting of p85 adaptor and p110 catalytic subunits, which can generate the 3-phosphorylated forms of phosphatidylinositol (PtdIns), PtdIns4P and PtdIns(4,5)P2 as potential second messengers. Yeast Vps34p kinase, however, has a substrate specificity restricted to PtdIns and is a PtdIns 3-kinase. Here the molecular characterization of a new human PtdIns 3-kinase with extensive sequence homology to Vps34p is described. PtdIns 3-kinase does not associate with p85 and phosphorylates PtdIns, but not PtdIns4P or PtdIns(4,5)P2. In vivo PtdIns 3-kinase is in a complex with a cellular protein of 150 kDa, as detected by immunoprecipitation from human cells. Protein sequence analysis and cDNA cloning show that this 150 kDa protein is highly homologous to Vps15p, a 160 kDa protein serine/threonine kinase associated with yeast Vps34p. These results suggest that the major components of the yeast Vps intracellular trafficking complex are conserved in humans.
authors.affiliation: Ludwig Institute for Cancer Research, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Volinia
authors.forename: R
authors.initials: R
authors.lastname: Dhand
authors.forename: B
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: L K
authors.initials: LK
authors.lastname: MacDougall
authors.forename: R
authors.initials: R
authors.lastname: Stein
authors.forename: M J
authors.initials: MJ
authors.lastname: Zvelebil
authors.forename: J
authors.initials: J
authors.lastname: Domin
authors.forename: C
authors.initials: C
authors.lastname: Panaretou
authors.forename: M D
authors.initials: MD
authors.lastname: Waterfield
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004247:DNA; D056827:Endosomal Sorting Complexes Required for Transport; D006801:Humans; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D058571:Vacuolar Sorting Protein VPS15
chemical_list: D004247:DNA; D056827:Endosomal Sorting Complexes Required for Transport; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D058571:Vacuolar Sorting Protein VPS15; C094981:p150 protein kinase; C546851:PIK3R4 protein, human; C546854:VPS15 protein, S cerevisiae