title: Inositol polyphosphate multikinase is a physiologic PI3-kinase that activates Akt/PKB.
abstract: The second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP(3)), formed by the p110 family of PI3-kinases, promotes cellular growth, proliferation, and survival, in large part by activating the protein kinase Akt/PKB. We show that inositol polyphosphate multikinase (IPMK) physiologically generates PIP(3) as well as water soluble inositol phosphates. IPMK deletion reduces growth factor-elicited Akt signaling and cell proliferation caused uniquely by loss of its PI3-kinase activity. Inhibition of p110 PI3-kinases by wortmannin prevents IPMK phosphorylation and activation. Thus, growth factor stimulation of Akt signaling involves PIP(3) generation through the sequential activations of the p110 PI3-kinases and IPMK. As inositol phosphates inhibit Akt signaling, IPMK appears to act as a molecular switch, inhibiting or stimulating Akt via its inositol phosphate kinase or PI3-kinase activities, respectively. Drugs regulating IPMK may have therapeutic relevance in influencing cell proliferation.
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: David
authors.initials: D
authors.lastname: Maag
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Maxwell
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Hardesty
authors.forename: Katie L
authors.initials: KL
authors.lastname: Boucher
authors.forename: Namrata
authors.initials: N
authors.lastname: Choudhari
authors.forename: Adam G
authors.initials: AG
authors.lastname: Hanno
authors.forename: Jenny F
authors.initials: JF
authors.lastname: Ma
authors.forename: Adele S
authors.initials: AS
authors.lastname: Snowman
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Pietropaoli
authors.forename: Risheng
authors.initials: R
authors.lastname: Xu
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Storm
authors.forename: Adolfo
authors.initials: A
authors.lastname: Saiardi
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
authors.forename: Adam C
authors.initials: AC
authors.lastname: Resnick
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007295:Inositol Phosphates / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D007295:Inositol Phosphates; D036341:Intercellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; C060974:phosphatidylinositol 3,4,5-triphosphate; C434257:inositol polyphosphate multikinase