ELP3 Acetyltransferase is phosphorylated and regulated by the oncogenic anaplastic lymphoma kinase (ALK)
ELP3 Acetyltransferase is phosphorylated and regulated by the oncogenic anaplastic lymphoma kinase (ALK)
复制标题
ELP3 乙酰转移酶被磷酸化并受致癌间变性淋巴瘤激酶 (ALK) 调节
DOI：
10.1042/bcj20190106
复制
发表时间：
2019-08-15
影响因子：
4.1
通讯作者：
Yuan, Hai-Xin
中科院分区：
文献类型：
--
作者：
Li, Meng-Tian;Liang, Jun-Yun;Yuan, Hai-Xin
蛋白质赖氨酸乙酰化是哺乳动物组织中主要的翻译后修饰之一，目前已鉴定出数千种蛋白质发生乙酰化。机制研究揭示了乙酰化在蛋白质功能调节中的重要作用。关于乙酰转移酶本身是如何被调节的知之甚少。在目前的研究中，我们发现延长蛋白3（ELP 3）乙酰转移酶是由酪氨酸磷酸化修饰。我们证明间变性淋巴瘤激酶（ALK）是负责ELP 3酪氨酸磷酸化的主要酪氨酸激酶。ELP 3在表达致癌NPM-ALK融合蛋白的肿瘤细胞中被磷酸化。我们进一步确定Tyr 202是ELP 3中主要的ALK磷酸化位点。重要的是，将Y202磷酸化突变体ELP 3引入ALK阳性肿瘤细胞中会降低细胞生长并损害基因表达。总的来说，我们的研究揭示了ELP 3的一种新的调节机制，提供了一个乙酰转移酶本身可以被PTM调节的例子，并提出了ALK阳性癌症治疗的潜在靶点。
Protein lysine acetylation is one of the major posttranslational modifications (PTMs) with several thousands of proteins identified to be acetylated in mammalian tissues. Mechanistic studies have revealed important functions of acetylation in the regulation of protein function. Much less is known on how the acetyltransferases themselves are regulated. In the current study, we discover that the Elongator protein 3 (ELP3) acetyltransferase is modified by tyrosine phosphorylation. We demonstrate that the anaplastic lymphoma kinase (ALK) is the major tyrosine kinase responsible for ELP3 tyrosine phosphorylation. ELP3 is phosphorylated in tumor cells expressing oncogenic NPM-ALK fusion protein. We further identify Tyr202 as the major ALK phosphorylation site in ELP3. Importantly, the introduction of Y202 phosphorylation mutant ELP3 into ALK-positive tumor cells reduced cell growth and impaired gene expression. Collectively, our study reveals a novel regulatory mechanism for ELP3, provides an example that acetyltransferase itself can be regulated by PTM, and suggests a potential target for ALK-positive cancer therapies.