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

被引：566

作者：

Shidong Jia ^{[1
]}

Zhenning Liu ^{[3
]}

Sen Zhang ^{[1
]}

Pixu Liu ^{[3
]}

Lei Zhang ^{[1
]}

Sang Hyun Lee ^{[3
]}

Jing Zhang ^{[1
]}

Sabina Signoretti ^{[3
]}

Massimo Loda ^{[1
]}

Thomas M. Roberts ^{[3
]}

Jean J. Zhao ^{[1
]}

机构：

[1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston

[2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston

[3] Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston

[4] Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston

来源：

Nature | 2008年 / 454卷 / 7205期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1038/nature07091

中图分类号：

学科分类号：

摘要：

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 cascades. Recent studies have demonstrated specific functions for p110α in growth factor and insulin signalling. 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. ©2008 Macmillan Publishers Limited. All rights reserved.

引用

页码：776 / 779

页数：3

共 33 条

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