ISOPRENYLATION IN REGULATION OF SIGNAL TRANSDUCTION BY G-PROTEIN-COUPLED RECEPTOR KINASES
ISOPRENYLATION IN REGULATION OF SIGNAL TRANSDUCTION BY G-PROTEIN-COUPLED RECEPTOR KINASES
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DOI：
10.1038/359147a0
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发表时间：
1992-09-10
期刊：
影响因子：
64.8
通讯作者：
LEFKOWITZ, RJ
中科院分区：
文献类型：
--
作者：
INGLESE, J;KOCH, WJ;LEFKOWITZ, RJ
视紫红质激酶 1 和 β-肾上腺素受体激酶 (β-ARK)2 是丝氨酸/苏氨酸激酶家族的相关成员，专门启动 G 蛋白偶联受体的失活。刺激介导的受体激活后，这些细胞质激酶易位至质膜3,4。在这里，我们表明该事件的分子基础涉及一类称为类异戊二烯的不饱和脂质。 15-C（法呢基）类异戊二烯对视紫红质激酶进行体内共价修饰，使该激酶能够锚定到光子激活的视紫质上。改变或消除类异戊二烯的突变会完全禁用光特异性视紫红质激酶易位。其他缺乏内在脂质的受体激酶（如 β-ARK）在接触信号转导 G 蛋白的大脑 β-γ 亚基时被激活 6，该亚基带有 20-C（香叶基香叶基）类异戊二烯 7,8。 使用在体外进行异戊二烯化的嵌合β-ARK，我们证明这些激酶的膜缔合和激活可以在不存在β-γ的情况下发生。这些结果表明，视紫红质激酶（通过完整的类异戊二烯）和 β-ARK（通过其与 β-γ 的结合）都依赖于异戊二烯基部分的功能来实现其易位和活性，说明了受体功能的生物调节的不同但相关的模式。
RHODOPSIN kinase1 and beta-adrenergic receptor kinase (beta-ARK)2 are related members of a serine/threonine kinase family that specifically initiate deactivation of G-protein-coupled receptors. After stimulus-mediated receptor activation, these cytoplasmic kinases translocate to the plasma membrane3,4. Here we show that the molecular basis for this event involves a class of unsaturated lipids called isoprenoids. Covalent modification in vivo of rhodopsin kinase by a 15-C (farnesyl) isoprenoid5 enables the kinase to anchor to photon-activated rhodopsin. Mutations that alter or eliminate the isoprenoid, fully disable light-specific Rhodopsin kinase translocation. Other receptor kinases (such as beta-ARK), which lack an intrinsic lipid, are activated6 on exposure to brain beta-gamma-subunits of the signal-transducing G proteins, the gamma-subunit of which bears a 20-C (geranylgeranyl) isoprenoid7,8. Using chimaeric beta-ARKs that undergo isoprenylation in vitro, we demonstrate that membrane association and activation of these kinases can occur in the absence of beta-gamma. These results indicate that rhodopsin kinase (by means of an integral isoprenoid) and beta-ARK (through its association with beta-gamma) both rely on the function of isoprenyl moieties for their translocation and activity, illustrating distinct, though related, modes of biological regulation of receptor function.