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Essential roles of PI(3)K–p110β in cell growth, metabolism and tumorigenesis

A Corrigendum to this article was published on 27 January 2016

This article has been updated


On activation by receptors, the ubiquitously expressed class IA isoforms (p110α and p110β) of phosphatidylinositol-3-OH kinase (PI(3)K) generate lipid second messengers, which initiate multiple signal transduction cascades1,2,3,4,5. Recent studies have demonstrated specific functions for p110α in growth factor and insulin signalling6,7,8. To probe for distinct functions of p110β, we constructed conditional knockout mice. Here we show that ablation of p110β in the livers of the resulting mice leads to impaired insulin sensitivity and glucose homeostasis, while having little effect on phosphorylation of Akt, suggesting the involvement of a kinase-independent role of p110β in insulin metabolic action. Using established mouse embryonic fibroblasts, we found that removal of p110β also had little effect on Akt phosphorylation in response to stimulation by insulin and epidermal growth factor, but resulted in retarded cell proliferation. Reconstitution of p110β-null cells with a wild-type or kinase-dead allele of p110β demonstrated that p110β possesses kinase-independent functions in regulating cell proliferation and trafficking. However, the kinase activity of p110β was required for G-protein-coupled receptor signalling triggered by lysophosphatidic acid and had a function in oncogenic transformation. Most strikingly, in an animal model of prostate tumour formation induced by Pten loss, ablation of p110β (also known as Pik3cb), but not that of p110α (also known as Pik3ca), impeded tumorigenesis with a concomitant diminution of Akt phosphorylation. Taken together, our findings demonstrate both kinase-dependent and kinase-independent functions for p110β, and strongly indicate the kinase-dependent functions of p110β as a promising target in cancer therapy.

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Figure 1: Mice with liver-specific deletion of p110β show resistance to insulin and intolerance of glucose.
Figure 2: Analyses of the effects of p110β deletion on cell growth and signalling.
Figure 3: Kinase activity of p110β contributes to transformation both in vitro and in vivo.

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We thank C. D. Stiles and J. D. Iglehart for advice, and H. Wu for providing floxed PTEN mice. This work was supported by grants from the National Institutes of Health (M.L., T.M.R. and J.J.Z.,), the Department of Defense for Cancer Research (J.J.Z.), the V Foundation (J.J.Z.) and the Claudia Barr Program (J.J.Z.). In compliance with Harvard Medical School guidelines, we disclose the consulting relationships: Novartis Pharmaceuticals, Inc. (M.L., T.M.R. and J.J.Z.).

Author Contributions Z.L., S.Z. and S.L. generated the floxed p110β mouse. S.J. carried out mouse tumorigenesis studies. Z.L and S.Z. performed MEF studies. P.L. performed in vivo metabolic studies. L.Z. performed transferrin uptake assays. J.Z. assisted in focus formation and BrdU incorporation experiments. S.S. and M.L. performed and interpreted pathological analyses of mouse prostate tumors. T.M.R. and J.J.Z. supervised the research, interpreted the data and wrote the paper. S.J., Z.L., S.Z., P.L., L.Z., S.L. and M.L. participated in the writing of the paper.

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Correspondence to Thomas M. Roberts or Jean J. Zhao.

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Supplementary Figures

The file contains Supplementary Figures 1-12 and Legends. The Supplementary Figures and Legends show additional data to support the kinase-dependent and -independent functions of PI3K-p110:β in cell growth, metabolism and tumorigenesis. (PDF 2415 kb)

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Jia, S., Liu, Z., Zhang, S. et al. Essential roles of PI(3)K–p110β in cell growth, metabolism and tumorigenesis. Nature 454, 776–779 (2008).

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