title: Phosphoinositide 3-kinase p110beta activity: key role in metabolism and mammary gland cancer but not development.
abstract: The phosphoinositide 3-kinase (PI3K) pathway crucially controls metabolism and cell growth. Although different PI3K catalytic subunits are known to play distinct roles, the specific in vivo function of p110beta (the product of the PIK3CB gene) is not clear. Here, we show that mouse mutants expressing a catalytically inactive PIK3CB(K805R) mutant survived to adulthood but showed growth retardation and developed mild insulin resistance with age. Pharmacological and genetic analyses of p110beta function revealed that p110beta catalytic activity is required for PI3K signaling downstream of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors as well as to sustain long-term insulin signaling. In addition, PIK3CB(K805R) mice were protected in a model of ERBB2-driven tumor development. These findings indicate an unexpected role for p110beta catalytic activity in diabetes and cancer, opening potential avenues for therapeutic intervention.
authors.affiliation: Department of Genetics, Biology and Biochemistry, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Ciraolo
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.forename: Romina
authors.initials: R
authors.lastname: Marone
authors.forename: Stefano
authors.initials: S
authors.lastname: Marengo
authors.forename: Claudia
authors.initials: C
authors.lastname: Curcio
authors.forename: Carlotta
authors.initials: C
authors.lastname: Costa
authors.forename: Ornella
authors.initials: O
authors.lastname: Azzolino
authors.forename: Cristiano
authors.initials: C
authors.lastname: Gonella
authors.forename: Cristina
authors.initials: C
authors.lastname: Rubinetto
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wu
authors.forename: Walter
authors.initials: W
authors.lastname: Dastrù
authors.forename: Erica L
authors.initials: EL
authors.lastname: Martin
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Silengo
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.forename: Emilia
authors.initials: E
authors.lastname: Turco
authors.forename: Letizia
authors.initials: L
authors.lastname: Lanzetti
authors.forename: Piero
authors.initials: P
authors.lastname: Musiani
authors.forename: Thomas
authors.initials: T
authors.lastname: Rückle
authors.forename: Christian
authors.initials: C
authors.lastname: Rommel
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Backer
authors.forename: Guido
authors.initials: G
authors.lastname: Forni
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Wymann
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004705:Endocytosis; D007333:Insulin Resistance / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology; D015398:Signal Transduction
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; C524056:Erbb2 protein, mouse
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