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

机译：PI（3）K-p110β在细胞生长，代谢和肿瘤发生中的重要作用

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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.
机译：受体激活后，磷脂酰肌醇3-OH激酶（PI（3）K）普遍表达的IA类同工型（p110α和p110β）产生脂质第二信使，从而启动多个信号转导级联反应。最近的研究表明p110α在生长因子和胰岛素信号传导中具有特定功能。为了探测p110β的不同功能，我们构建了条件敲除小鼠。在这里，我们显示消融所得小鼠肝脏中的p110β会导致胰岛素敏感性和葡萄糖稳态受损，而对Akt的磷酸化影响很小，这表明p110β的激酶非依赖性作用与胰岛素代谢有关。使用已建立的小鼠胚胎成纤维细胞，我们发现去除p110β对胰岛素和表皮生长因子刺激的反应，对Akt磷酸化的影响也很小，但导致细胞增殖受阻。用p110β的野生型或激酶死亡的等位基因重建p110β无效的细胞表明，p110β在调节细胞增殖和运输中具有激酶非依赖性功能。然而，溶血磷脂酸触发的G蛋白偶联受体信号传导需要p110β的激酶活性，并在致癌转化中起作用。最引人注目的是，在由Pten缺失引起的前列腺肿瘤形成的动物模型中，p110β（也称为Pik3cb）的消融，而不是p110α（也称为Pik3ca）的消融，阻止了肿瘤的发生，同时伴随着Akt磷酸化的减少。综上所述，我们的发现证明了p110β的激酶依赖性和激酶非依赖性功能，并强烈表明p110β的激酶依赖性功能是癌症治疗中有希望的靶标。

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