title: Heterodimeric phosphoinositide 3-kinase consisting of p85 and p110beta is synergistically activated by the betagamma subunits of G proteins and phosphotyrosyl peptide.
abstract: Phosphoinositide 3-kinase (PI 3-kinase) is a key signaling enzyme implicated in variety of receptor-stimulated cell responses. Receptors with intrinsic or associated tyrosine kinase activity recruit heterodimeric PI 3-kinases consisting of a 110-kDa catalytic subunit (p110) and an 85-kDa regulatory subunit (p85). We separated a PI 3-kinase that could be stimulated by the betagamma subunits of G protein (Gbetagamma) from rat liver. The Gbetagamma-sensitive PI 3-kinase appeared to be a heterodimer consisting of p110beta and p85 (or their related subunits). The stimulation by Gbetagamma was inhibited by the GDP-bound alpha subunit of the inhibitory GTP-binding protein. Moreover, the stimulatory action of Gbetagamma was markedly enhanced by the simultaneous addition of a phosphotyrosyl peptide synthesized according to the amino acid sequence of the insulin receptor substrate-1. Such enzymic properties could be observed with a recombinant p110beta/p85alpha expressed in COS-7 cells with their cDNAs. In contrast, another heterodimeric PI 3-kinase consisting of p110alpha and p85 in the same rat liver, together with a recombinant p110alpha/p85alpha, was not activated by Gbetagamma, although their activities were stimulated by the phosphotyrosyl peptide. These results indicate that p110beta/p85 PI 3-kinase may be regulated in a cooperative manner by two different types of membrane receptors, one possessing tyrosine kinase activity and the other activating GTP-binding proteins.
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kurosu
authors.forename: T
authors.initials: T
authors.lastname: Maehama
authors.forename: T
authors.initials: T
authors.lastname: Okada
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.forename: S
authors.initials: S
authors.lastname: Hoshino
authors.forename: Y
authors.initials: Y
authors.lastname: Fukui
authors.forename: M
authors.initials: M
authors.lastname: Ui
authors.forename: O
authors.initials: O
authors.lastname: Hazeki
authors.forename: T
authors.initials: T
authors.lastname: Katada
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D018076:DNA, Complementary; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D011994:Recombinant Proteins; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D019204:GTP-Binding Proteins