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.

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

CIRAOLO, Elisa;MARENGO, Stefano;CURCIO, CLAUDIA;COSTA, Carlotta;AZZOLINO, Ornella;RUBINETTO, Cristina;DASTRU', Walter;MARTIN, ERICA LEANNE;SILENGO, Lorenzo;ALTRUDA, Fiorella;TURCO, Emilia;LANZETTI, Letizia;FORNI, Guido;HIRSCH, Emilio
2008-01-01

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.
2008
1
1
12
signal transduction; breast cancer; type 2 diabetes; phosphoinositide 3-kinase beta
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...espandi
File in questo prodotto:
File Dimensione Formato  
Ciraolo 2008.pdf

Accesso riservato

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 1.33 MB
Formato Adobe PDF
1.33 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/56211
Citazioni
  • ???jsp.display-item.citation.pmc??? 117
  • Scopus 213
  • ???jsp.display-item.citation.isi??? 198
social impact