Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2
Mdm2 is involved in the ubiquitination and degradation of G-protein-coupled receptor kinase 2
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DOI：
10.1038/sj.emboj.7601351
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发表时间：
2006-10-18
期刊：
影响因子：
11.4
通讯作者：
Penela, Petronila
中科院分区：
文献类型：
--
作者：
Salcedo, Alicia;Mayor, Federico, Jr.;Penela, Petronila
g蛋白偶联受体激酶2 （GRK2）是g蛋白偶联受体信号传导的中心调节因子。我们报道了参与细胞生长和凋亡控制的e3泛素连接酶Mdm2在GRK2降解中起关键作用。β(2)-肾上腺素能受体刺激和β -抑制素可增强Mdm2和GRK2的关联。Mdm2表达的增加加速了GRK2蛋白水解，促进了特定残基上的激酶泛素化，而在Mdm2缺乏的细胞中，GRK2的周转明显受损。此外，我们发现胰岛素样生长因子-1激活PI3K/Akt通路可改变mdm2介导的GRK2降解，从而增强GRK2的稳定性和增加激酶水平。这些数据提出了在生理和病理条件下控制GRK2表达的新机制。
G-protein-coupled receptor kinase 2 (GRK2) is a central regulator of G-protein-coupled receptor signaling. We report that Mdm2, an E3-ubiquitin ligase involved in the control of cell growth and apoptosis, plays a key role in GRK2 degradation. Mdm2 and GRK2 association is enhanced by beta(2)-adrenergic receptor stimulation and beta-arrestin. Increased Mdm2 expression accelerates GRK2 proteolysis and promotes kinase ubiquitination at defined residues, whereas GRK2 turnover is markedly impaired in Mdm2-deficient cells. Moreover, we find that activation of the PI3K/Akt pathway by insulin-like growth factor-1 alters Mdm2-mediated GRK2 degradation, leading to enhanced GRK2 stability and increased kinase levels. These data put forward a novel mechanism for controlling GRK2 expression in physiological and pathological conditions.