Regulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes
Regulation of Akt/PKB activity by P21-activated kinase in cardiomyocytes
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DOI：
10.1016/j.yjmcc.2007.10.016
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发表时间：
2008-02-01
影响因子：
5
通讯作者：
Liang, Qiangrong
中科院分区：
文献类型：
--
作者：
Mao, Kai;Kobayashi, Satoru;Liang, Qiangrong
AKT/PKB是心脏功能和形态的重要调节因子，其活性受活性环(Thr308)和羧基末端疏水基序(Ser473)的双重磷酸化调控，活性环(Thr308)由磷酸肌醇依赖的蛋白激酶-1(PDK1)控制。P21-激活的蛋白-1(PAK-1)是一种丝氨酸/苏氨酸蛋白激酶，参与心肌肥大和收缩的调节，先前发现通过一种未知的机制激活Akt。在这里，我们报告了PAK1是一种潜在的PDK2，对心肌细胞中Akt的活性是必不可少的。Ak1和Akt都可以被多种肥大刺激或生长因子以磷脂酰肌醇-3-激酶(PI3K)依赖的方式激活。PAK1过表达可诱导心肌细胞Ser473和Thr308处Akt的磷酸化。相反，在体外和体内，沉默或失活pak1基因会减少Akt的磷酸化。纯化的Pak 1仅在Ser473位直接磷酸化Akt，提示Pak1可能是与心肌细胞AKT Ser473磷酸化有关的PDK2。此外，Ak1保护心肌细胞免于细胞死亡，Akt抑制可阻断这种作用。我们的结果连接了两个重要的细胞生理功能调节器，并为心肌细胞中的pak1信号提供了一个潜在的机制。(C)2007 Elsevier Inc.保留所有权利。
Akt/PKB is a critical regulator of cardiac function and morphology, and its activity is governed by dual phosphorylation at active loop (Thr308) by phosphoinositide-dependent protein kinase-1 (PDK1) and at carboxyl-terminal hydrophobic motif (Ser473) by a putative PDK2. P21-activated kinase-1 (Pak 1) is a serine/threonine protein kinase implicated in the regulation of cardiac hypertrophy and contractility and was shown previously to activate Akt through an undefined mechanism. Here we report Pak 1 as a potential PDK2 that is essential for Akt activity in cardiomyocytes. Both Pak1 and Akt can be activated by multiple hypertrophic stimuli or growth factors in a phosphatidylinositol-3-kinase (PI3K)-dependent manner. Pak1 overexpression induces Akt phosphorylation at both Ser473 and Thr308 in cardiomyocytes. Conversely, silencing or inactivating Pak1 gene diminishes Akt phosphorylation in vitro and in vivo. Purified Pak 1 can directly phosphorylate Akt only at Ser473, suggesting that Pak1 may be a relevant PDK2 responsible for AKT Ser473 phosphorylation in cardiomyocytes. In addition, Pak1 protects cardiomyocytes from cell death, which is blocked by Akt inhibition. Our results connect two important regulators of cellular physiological functions and provide a potential mechanism for Pak1 signaling in cardiomyocytes. (c) 2007 Elsevier Inc. All rights reserved.