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Sci. Signal., 9 September 2008
Vol. 1, Issue 36, p. ra3
[DOI: 10.1126/scisignal.1161577]

RESEARCH

Phosphoinositide 3-Kinase p110β Activity: Key Role in Metabolism and Mammary Gland Cancer but Not Development

Elisa Ciraolo1, Manuela Iezzi2, Romina Marone3, Stefano Marengo1, Claudia Curcio4, Carlotta Costa1, Ornella Azzolino1, Cristiano Gonella1, Cristina Rubinetto1, Haiyan Wu5, Walter Dastrù6, Erica L. Martin7, Lorenzo Silengo1, Fiorella Altruda1, Emilia Turco1, Letizia Lanzetti8, Piero Musiani2, Thomas Rückle9, Christian Rommel9, Jonathan M. Backer5, Guido Forni4, Matthias P. Wymann3, and Emilio Hirsch1*

1 Department of Genetics, Biology and Biochemistry, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
2 Aging Research Centre, G. d’Annunzio University Foundation, 66013 Chieti, Italy.
3 Department of Biomedicine, Institute of Biochemistry and Genetics, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland.
4 Department of Clinical and Biological Sciences, Molecular Biotechnology Center, University of Torino, via Nizza 52, 10126 Torino, Italy.
5 Department of Molecular Pharmacology, Albert Einstein College of Medicine, 10461 Bronx, NY, USA.
6 Department of Chemistry IFM, Molecular Imaging Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
7 Department of Anesthesia and Critical Care, University of Torino, Corso Dogliotti 14, 10126 Torino, Italy.
8 Dipartimento di Scienze Oncologiche, Istituto per la Ricerca e la Cura del Cancro, University of Torino, Strada Provinciale 142, 10060 Candiolo, Torino, Italy.
9 Merck Serono S.A., Geneva Research Center, CH-1202 Geneva, Switzerland.

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 p110β (the product of the PIK3CB gene) is not clear. Here, we show that mouse mutants expressing a catalytically inactive PIK3CBK805R mutant survived to adulthood but showed growth retardation and developed mild insulin resistance with age. Pharmacological and genetic analyses of p110β function revealed that p110β 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, PIK3CBK805R mice were protected in a model of ERBB2-driven tumor development. These findings indicate an unexpected role for p110β catalytic activity in diabetes and cancer, opening potential avenues for therapeutic intervention.

* To whom correspondence should be addressed. E-mail: emilio.hirsch{at}unito.it

Citation: E. Ciraolo, M. Iezzi, R. Marone, S. Marengo, C. Curcio, C. Costa, O. Azzolino, C. Gonella, C. Rubinetto, H. Wu, W. Dastrù, E. L. Martin, L. Silengo, F. Altruda, E. Turco, L. Lanzetti, P. Musiani, T. Rückle, C. Rommel, J. M. Backer, G. Forni, M. P. Wymann, E. Hirsch, Phosphoinositide 3-Kinase p110β Activity: Key Role in Metabolism and Mammary Gland Cancer but Not Development. Sci. Signal. 1, ra3 (2008).

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