Acetylation within the N- and C-Terminal Domains of Src Regulates Distinct Roles of STAT3-Mediated Tumorigenesis
Acetylation within the N- and C-Terminal Domains of Src Regulates Distinct Roles of STAT3-Mediated Tumorigenesis
复制标题
Src N 端和 C 端结构域内的乙酰化调节 STAT3 介导的肿瘤发生的不同作用
DOI：
10.1158/0008-5472.can-17-2314
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发表时间：
2018-06-01
期刊：
影响因子：
11.2
通讯作者：
Chin, Y. Eugene
中科院分区：
文献类型：
--
作者：
Huang, Chao;Zhang, Zhe;Chin, Y. Eugene
哺乳动物c-Src的n端和c端结构域的翻译后修饰调节着不同的功能。G2的肉豆肉酰化控制其细胞膜结合，Y419/Y527的磷酸化分别控制其激活或失活。我们提供的证据表明，src -细胞膜结合-解离和催化活化-失活都受乙酰化调节。在egf处理的细胞中，CREB结合蛋白（CBP）使c-Src的n端赖氨酸簇（K5、K7和K9）乙酰化，以促进c-Src与细胞膜的分离。CBP还使c-Src的c端K401、K423和K427乙酰化，以激活STAT3募集和激活的内在激酶活性。c-Src磷酸化STAT3的n端结构域（Y14， Y45和Y68）可激活STAT3的转录活性二聚体。此外，乙酰基src易位到细胞核中，在细胞核中形成Src-STAT3增强体，用于基因调控和癌细胞增殖。因此，c-Src在n端和c端结构域的乙酰化在Src活性和调控中起着不同的作用。意义：cbp介导的c-Src的n端和c端赖氨酸簇的乙酰化提供了对STAT3转录活性的额外水平的控制。(c) 2018年aacr。
Posttranslational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions. Myristoylation of G2 controls its cell membrane association and phosphorylation of Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src-cell membrane association-dissociation and catalytic activation-inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylates an N-terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane. CBP also acetylates the C-terminal K401, K423, and K427 of c-Src to activate intrinsic kinase activity for STAT3 recruitment and activation. N-terminal domain phosphorylation (Y14, Y45, and Y68) of STAT3 by c-Src activates transcriptionally active dimers of STAT3. Moreover, acetyl-Src translocates into nuclei, where it forms the Src-STAT3 enhanceosome for gene regulation and cancer cell proliferation. Thus, c-Src acetylation in the N-terminal and C-terminal domains play distinct roles in Src activity and regulation.Significance: CBP-mediated acetylation of lysine clusters in both the N-terminal and C-terminal regions of c-Src provides additional levels of control over STAT3 transcriptional activity. (C) 2018 AACR.