Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2
Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2
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DOI：
10.1038/nature02158
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发表时间：
2003-12-04
期刊：
影响因子：
64.8
通讯作者：
Quitterer, U
中科院分区：
文献类型：
--
作者：
Lorenz, K;Lohse, MJ;Quitterer, U
反馈抑制是信号转导的基本原理，允许对不同刺激的快速适应。在哺乳动物细胞中，G蛋白偶联受体（GPCR）的主要反馈抑制剂是G蛋白偶联受体激酶2（GRK-2），其磷酸化活化的受体，使其与G蛋白解偶联并启动其内化（1，2）。GRK-2的功能不可或缺，需要严格控制（3）。失调会导致高血压（4）或心力衰竭（5）等疾病。在我们寻找这种重要激酶的控制机制时，我们发现Raf激酶抑制蛋白（6-8）（RKIP）是GRK-2的生理抑制剂。在刺激GPCR后，RKIP与其已知靶Raf-1解离（参考文献6 - 8），与GRK-2结合并阻断其活性。该开关由RKIP在丝氨酸153上的蛋白激酶C（PKC）依赖性磷酸化触发。这些数据描绘了信号转导的新原理：通过激活PKC，通过从Raf-1中去除抑制剂和阻断受体内化来增强传入的受体信号。该机制的生理作用在心肌细胞中显示，其中RKIP的下调抑制β-肾上腺素能信号传导和收缩活性。
Feedback inhibition is a fundamental principle in signal transduction allowing rapid adaptation to different stimuli. In mammalian cells, the major feedback inhibitor for G-protein-coupled receptors (GPCR) is G-protein-coupled receptor kinase 2 (GRK-2), which phosphorylates activated receptors, uncouples them from G proteins and initiates their internalization(1,2). The functions of GRK-2 are indispensable and need to be tightly controlled(3). Dysregulation promotes disorders such as hypertension(4) or heart failure(5). In our search for a control mechanism for this vital kinase, here we show that the Raf kinase inhibitor protein(6-8) (RKIP) is a physiological inhibitor of GRK-2. After stimulation of GPCR, RKIP dissociates from its known target, Raf-1 (refs 6 - 8), to associate with GRK-2 and block its activity. This switch is triggered by protein kinase C (PKC)- dependent phosphorylation of the RKIP on serine 153. The data delineate a new principle in signal transduction: by activating PKC, the incoming receptor signal is enhanced both by removing an inhibitor from Raf-1 and by blocking receptor internalization. A physiological role for this mechanism is shown in cardiomyocytes in which the downregulation of RKIP restrains beta-adrenergic signalling and contractile activity.