Title |
Essential roles of PI(3)K–p110β in cell growth, metabolism and tumorigenesis
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Published in |
Nature, June 2008
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DOI | 10.1038/nature07091 |
Pubmed ID | |
Authors |
Shidong Jia, Zhenning Liu, Sen Zhang, Pixu Liu, Lei Zhang, Sang Hyun Lee, Jing Zhang, Sabina Signoretti, Massimo Loda, Thomas M. Roberts, Jean J. Zhao |
Abstract |
On activation by receptors, the ubiquitously expressed class IA isoforms (p110alpha and p110beta) 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 p110alpha in growth factor and insulin signalling. To probe for distinct functions of p110beta, we constructed conditional knockout mice. Here we show that ablation of p110beta 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 p110beta in insulin metabolic action. Using established mouse embryonic fibroblasts, we found that removal of p110beta 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 p110beta-null cells with a wild-type or kinase-dead allele of p110beta demonstrated that p110beta possesses kinase-independent functions in regulating cell proliferation and trafficking. However, the kinase activity of p110beta 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 p110beta (also known as Pik3cb), but not that of p110alpha (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 p110beta, and strongly indicate the kinase-dependent functions of p110beta as a promising target in cancer therapy. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 6 | 2% |
United Kingdom | 4 | 1% |
New Zealand | 2 | <1% |
Japan | 1 | <1% |
Germany | 1 | <1% |
Unknown | 289 | 95% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 71 | 23% |
Student > Ph. D. Student | 69 | 23% |
Professor > Associate Professor | 24 | 8% |
Student > Master | 24 | 8% |
Student > Bachelor | 20 | 7% |
Other | 55 | 18% |
Unknown | 40 | 13% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 113 | 37% |
Biochemistry, Genetics and Molecular Biology | 65 | 21% |
Medicine and Dentistry | 35 | 12% |
Chemistry | 17 | 6% |
Pharmacology, Toxicology and Pharmaceutical Science | 6 | 2% |
Other | 18 | 6% |
Unknown | 49 | 16% |