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PMID: 18780892 Published · epublish English Journal Article

Phosphoinositide 3-kinase p110beta activity: key role in metabolism and mammary gland cancer but not development.

Science signaling ·Vol. 1 ·No. 36 ·2008-09-09 ·Pages ra3

Ciraolo E, Iezzi M, Marone R, Marengo S, Curcio C, Costa C, Azzolino O, Gonella C, Rubinetto C, Wu H, Dastrù W, Martin EL, Silengo L, Altruda F, Turco E, Lanzetti L, Musiani P, Rückle T, Rommel C, Backer JM, Forni G, Wymann MP, Hirsch E

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.

MeSH Terms
Aging/physiology Animals Cell Transformation, Neoplastic/metabolism,pathology Cells, Cultured Class I Phosphatidylinositol 3-Kinases Diabetes Mellitus, Experimental/enzymology Endocytosis Insulin Resistance/physiology Mammary Neoplasms, Experimental/enzymology,pathology Mice Mice, Mutant Strains Phosphatidylinositol 3-Kinases/genetics,physiology Receptor, ErbB-2/physiology Signal Transduction
Chemicals
Phosphatidylinositol 3-Kinases 1-phosphatidylinositol 3-kinase p110 subunit, mouse Class I Phosphatidylinositol 3-Kinases Erbb2 protein, mouse Receptor, ErbB-2
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Ciraolo Elisa
Department of Genetics, Biology and Biochemistry, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
Iezzi Manuela
Marone Romina
Marengo Stefano
Curcio Claudia
Costa Carlotta
Azzolino Ornella
Gonella Cristiano
Rubinetto Cristina
Wu Haiyan
Dastrù Walter
Martin Erica L
Silengo Lorenzo
Altruda Fiorella
Turco Emilia
Lanzetti Letizia
Musiani Piero
Rückle Thomas
Rommel Christian
Backer Jonathan M
Forni Guido
Wymann Matthias P
Hirsch Emilio
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Article Info
Journal
Science signaling
Abbr.
Sci Signal
ISSN
1937-9145
DOI
10.1126/scisignal.1161577
Published
2008-09-09
Epub
2008-00-09
Pages
ra3
Language
English
Region
United States
NLM ID
101465400
PMCID
PMC2694958
Subset
IM
Grants
Telethon · GGP05113 · Italy
NIGMS NIH HHS · R01 GM055692 · United States
NIGMS NIH HHS · R01 GM055692-11 · United States
External Links
PubMed source DOI: 10.1126/scisignal.1161577 PMC Full Text View journal details
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