Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)
Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)
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DOI：
10.1128/mcb.21.3.952-965.2001
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发表时间：
2001-02-01
影响因子：
5.3
通讯作者：
Greenberg, ME
中科院分区：
文献类型：
--
作者：
Brunet, A;Park, J;Greenberg, ME
血清和糖皮质激素诱导型激酶（SGK）形成了一个新型的丝氨酸/苏氨酸激酶家族，它们会响应各种细胞外刺激而被激活。SGK与Akt（也称为PKB）相关，Akt是一种丝氨酸/苏氨酸激酶，在促进细胞存活方面起着至关重要的作用。与Akt一样，SGK被磷酸肌醇-3激酶（PI 3 K）激活，并在生长因子刺激后转运至细胞核。然而，SGKs的生理底物和细胞功能仍有待确定。我们假设SGKs通过磷酸化细胞核内的共同靶点与Akt一起调节细胞功能。Akt最具特征的核底物是Forkhead家族的转录因子。Akt磷酸化Forkhead转录因子，如FKHRL 1，导致FKHRL 1从细胞核中退出，从而关闭FKHRL 1靶基因。我们在这里表明，SGK 1，像Akt，促进细胞存活，它这样做的一部分是通过磷酸化和灭活FKHRL 1。然而，SGK和Akt在磷酸化FKHRL 1上的三个调节位点的功效方面显示出差异。虽然这两种激酶都可以磷酸化Thr-32，但SGK显示出对Ser-315的明显偏好，而Akt则偏好Ser-253。这些结果表明，SGK和Akt可能协调调节FKHRL 1的功能，通过磷酸化这个转录因子在不同的网站。SGK和Akt对FKHRL 1上这三个位点的有效磷酸化似乎对生长因子抑制FKHRL 1依赖性转录的能力至关重要，从而防止FKHRL 1诱导细胞周期停滞和凋亡。这些发现表明，SGK与Akt协同作用，在细胞核内传播PI 3 K活化的效果，并介导PI 3 K信号传导的生物输出，包括细胞存活和细胞周期进展。
Serum- and glucocorticoid-inducible kinases (SGKs) form a novel family of serine/threonine kinases that are activated in response to a variety of extracellular stimuli. SGKs are related to Akt (also called PKB), a serine/threonine kinase that plays a crucial role in promoting cell survival. Like Akt, SGKs are activated by the phosphoinositide-3 kinase (PI3K) and translocate to the nucleus upon growth factor stimulation. However the physiological substrates and cellular functions of SGKs remained to be identified. We hypothesized that SGKs regulate cellular functions in concert with Akt by phosphorylating common targets within the nucleus. The best-characterized nuclear substrates of Akt are transcription factors of the Forkhead family. Akt phosphorylates Forkhead transcription factors such as FKHRL1, leading to FKHRL1's exit from the nucleus and the consequent shutoff of FKHRL1 target genes. We show here that SGK1, like Akt, promotes cell survival and that it does so in part by phosphorylating and inactivating FKHRL1. However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis. These findings indicate that SGK acts in concert with Akt to propagate the effects of PI3K activation within the nucleus and to mediate the biological outputs of PI3K signaling, including cell survival and cell cycle progression.