Essential roles of PI(3)K-p110 beta in cell growth, metabolism and tumorigenesis

Article

关键词: TUMOR-SUPPRESSOR GENE;    PHOSPHOINOSITIDE 3-KINASE;    PHOSPHATIDYLINOSITOL 3-KINASES;    LYSOPHOSPHATIDIC ACID;    EMBRYONIC LETHALITY;    P110-ALPHA SUBUNIT;    CATALYTIC SUBUNIT;    PROSTATE-CANCER;    PI 3-KINASE;    BETA-GAMMA;   

DOI  :  10.1038/nature07091

来源: SCIE

【 摘 要 】

On activation by receptors, the ubiquitously expressed class IA isoforms (p110 alpha and p110 beta) of phosphatidylinositol-3-OH kinase (PI(3)K) generate lipid second messengers, which initiate multiple signal transduction cascades(1-5). Recent studies have demonstrated specific functions for p110 alpha in growth factor and insulin signalling(6-8). To probe for distinct functions of p110 beta, we constructed conditional knockout mice. Here we show that ablation of p110 beta 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 p110 beta in insulin metabolic action. Using established mouse embryonic fibroblasts, we found that removal of p110 beta 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 p110 beta-null cells with a wild-type or kinase-dead allele of p110 beta demonstrated that p110 beta possesses kinase-independent functions in regulating cell proliferation and trafficking. However, the kinase activity of p110 beta 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 p110 beta (also known as Pik3cb), but not that of p110 alpha (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 p110 beta, and strongly indicate the kinase-dependent functions of p110 beta as a promising target in cancer therapy.

【 授权许可】

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