N-acetyl-l-cysteine fosters inactivation and transfer to endolysosomes of c-Src
N-acetyl-l-cysteine fosters inactivation and transfer to endolysosomes of c-Src
复制标题
DOI：
10.1016/j.freeradbiomed.2008.09.012
复制
发表时间：
2008-12-01
影响因子：
7.4
通讯作者：
Parasassi, Tiziana
中科院分区：
文献类型：
--
作者：
Krasnowska, Ewa K.;Pittalluga, Eugenia;Parasassi, Tiziana
非受体蛋白酪氨酸激酶c-Src在许多人类肿瘤中过表达和激活，与肿瘤的发生发展密切相关。典型的调节是通过酪氨酸残基的另一种磷酸化来发生的--Tyr419用于激活，Tyr530用于失活。还提出了一个涉及半胱氨酸残基的独立氧化还原调节机制，在该机制中，氧化激活了酶。本文对N-乙酰-L-半胱氨酸(NAC)对c-Src的作用进行了动力学分析，证明还原逆转了氧化驱动的激活。在癌细胞中，我们发现NAC治疗增加了c-Src半胱氨酸的特定标记的还原硫醇，从而证实了氧化还原转变。除了减少Tyr419的磷酸化外，这还导致c-Src从其活性形式所在的质膜大量转移到溶酶体内室。为了破译c-Src调控的复杂问题，并设计新的策略来逆转其在癌症中的激活，氧化还原调控因此成为一个有前途的研究领域。(C)2008 Elsevier Inc.保留所有权利。
The non-receptor-protein tyrosine kinase c-Src is overexpressed and activated in a large number of human cancers, in which it is associated with tumor development and progression. Canonical regulation takes place by means of an alternative phosphorylation of tyrosine residues-Tyr419 for activation and Tyr530 for inactivation. An independent redox regulation mechanism, involving cysteine residues, has also been proposed, in which oxidation activates the enzyme. Here we present a kinetic analysis of the effect of N-acetyl-l-cysteine (NAC) on c-Src, demonstrating that reduction reverts the oxidation-driven activation. In cancer cells, we show that NAC treatment produces an increase in specifically labeled reduced thiols of c-Src cysteines, thus confirming a redox transition. In addition to a decrease in Tyr419 phosphorylation, this leads to a massive shift of c-Src from plasma membranes-where its active form is located-to endolysosomal compartments. With the objective of deciphering the complex issue of c-Src regulation and of devising new strategies to revert its activation in cancers, redox regulation thus emerges as a promising area for study. (C) 2008 Elsevier Inc. All rights reserved.