p66Shc links alpha1-adrenergic receptors to a reactive oxygen species-dependent AKT-FOXO3A phosphorylation pathway in cardiomyocytes.
p66Shc links alpha1-adrenergic receptors to a reactive oxygen species-dependent AKT-FOXO3A phosphorylation pathway in cardiomyocytes.
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DOI：
10.1161/circresaha.108.186288
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发表时间：
2009-03-13
影响因子：
20.1
通讯作者：
Steinberg SF
中科院分区：
文献类型：
--
作者：
Guo J;Gertsberg Z;Ozgen N;Steinberg SF
p66 Shc是一种由肥大刺激诱导的衔接蛋白，并且已经被认为是活性氧（ROS）产生和心血管氧化应激反应的主要调节剂。这项研究表明p66 Shc参与了α1-肾上腺素能受体（α1-AR）通路，该通路需要蛋白激酶（PK）Cε和PKCδ的协同作用，并导致心肌细胞中AKT-FOXO 3a磷酸化。α1-AR通过ROS依赖性机制促进p66 Shc-YY 239/240磷酸化，该机制定位于小窝，需要表皮生长因子受体（EGFR）和PKCε活性。α1-AR还通过涉及PKCδ的EGFR反式激活途径增加p66 Shc-S36磷酸化。p66 Shc将α1-AR与AKT信号通路连接，该通路选择性磷酸化/失活FOXO转录因子并下调ROS清除蛋白锰超氧化物歧化酶（MnSOD）;涉及AKT的α1-AR-p66 Shc依赖性通路不调节GSK 3。其他研究表明，RNA干扰介导的内源性p66 Shc下调导致FOXO 3a调节基因如MnSOD、p27 Kip 1和BIM-1的去抑制。p66 Shc下调也增加增殖细胞核抗原的表达和诱导心肌细胞肥大，表明p66 Shc在新生心肌细胞中发挥抗肥大作用。本研究中发现的涉及p66 Shc的新的α1-AR和ROS依赖性通路可能有助于心肌细胞重塑和心力衰竭的演变。
p66Shc is an adapter protein that is induced by hypertrophic stimuli and has been implicated as a major regulator of reactive oxygen species (ROS) production and cardiovascular oxidative stress responses. This study implicates p66Shc in an α1-adrenergtic receptor (α1-AR) pathway that requires the cooperative effects of protein kinase (PK)Cε and PKCδ and leads to AKT-FOXO3a phosphorylation in cardiomyocytes. α1-ARs promote p66Shc-YY239/240 phosphorylation via a ROS-dependent mechanism that is localized to caveolae and requires epidermal growth factor receptor (EGFR) and PKCε activity. α1-ARs also increase p66Shc-S36 phosphorylation via an EGFR transactivation pathway involving PKCδ. p66Shc links α1-ARs to an AKT signaling pathway that selectively phosphorylates/inactivates FOXO transcription factors and downregulates the ROS-scavenging protein manganese superoxide dismutase (MnSOD); the α1-AR-p66Shc-dependent pathway involving AKT does not regulate GSK3. Additional studies show that RNA interference–mediated downregulation of endogenous p66Shc leads to the derepression of FOXO3a-regulated genes such as MnSOD, p27Kip1, and BIM-1. p66Shc downregulation also increases proliferating cell nuclear antigen expression and induces cardiomyocyte hypertrophy, suggesting that p66Shc exerts an antihypertrophic action in neonatal cardiomyocytes. The novel α1-AR– and ROS-dependent pathway involving p66Shc identified in this study is likely to contribute to cardiomyocyte remodeling and the evolution of heart failure.