Phosphoinositide 3-kinase p110beta activity: key role in metabolism and mammary gland cancer but not development.
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.
Ciraolo
Elisa
E
Department of Genetics, Biology and Biochemistry, Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
Iezzi
Manuela
M
Marone
Romina
R
Marengo
Stefano
S
Curcio
Claudia
C
Costa
Carlotta
C
Azzolino
Ornella
O
Gonella
Cristiano
C
Rubinetto
Cristina
C
Wu
Haiyan
H
Dastrù
Walter
W
Martin
Erica L
EL
Silengo
Lorenzo
L
Altruda
Fiorella
F
Turco
Emilia
E
Lanzetti
Letizia
L
Musiani
Piero
P
Rückle
Thomas
T
Rommel
Christian
C
Backer
Jonathan M
JM
Forni
Guido
G
Wymann
Matthias P
MP
Hirsch
Emilio
E
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
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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