SUMOylation of Csk Negatively Modulates its Tumor Suppressor Function
SUMOylation of Csk Negatively Modulates its Tumor Suppressor Function
复制标题
Csk 的 SUMO 化负向调节其肿瘤抑制功能
DOI：
10.1016/j.neo.2019.04.010
复制
发表时间：
2019-07-01
期刊：
影响因子：
4.8
通讯作者：
Huang, Jian
中科院分区：
文献类型：
--
作者：
Cui, Nan;Liu, Tianqi;Huang, Jian
CSK是一种非受体酪氨酸激酶，是Src家族蛋白激酶(SFK)不可或缺的负性调节因子。然而，到目前为止，对CSK表达的调控知之甚少。苏莫化是一种可逆的翻译后修饰，已被证明调节许多生物学过程，特别是在肿瘤进展中。在此，我们报道了在体外和体内，CSK在53位赖氨酸(K53)上被SUMO1共价修饰。过氧化氢处理在一定程度上抑制了这种修饰，但被鉴定为CSK的主要特异性SUMO E3连接酶的PIAS3可以显著提高SUMO1-CSK水平。此外，CSK的活性部位Ser364的磷酸化对这种修饰没有影响。相扑缺陷突变体CSK(K53R)的异位表达比野生型CSK更有可能抑制肿瘤细胞的生长。与生物学表型一致，CSK的相扑修饰降低了其与CBP(CSK结合蛋白)的相互作用活性，导致Y527处c-Src磷酸化降低。我们的结果表明，主要位于赖氨酸53位的CSK的SUMO化通过减少其与CBP的结合而负向调节其肿瘤抑制功能，从而诱导c-Src的激活。
Csk, a non-receptor tyrosine kinase, serves as an indispensable negative regulator of the Src family kinases (SFKs). However, little is known about regulation of Csk expression so far. SUMOylation, a reversible post-translational modification, has been shown to regulate many biological processes especially in tumor progression. Here we report that Csk is covalently modified by SUMO1 at lysine 53 (K53) both in vitro and in vivo. Treatment with hydrogen peroxide inhibited this modification to a certain extent, but PIAS3, identified as the main specific SUMO E3 ligase for Csk, could significantly enhance SUMO1-Csk level. In addition, phosphorylation at Ser364, the active site in Csk, had no effect on this modification. Ectopic expression of SUMO-defective mutant, Csk (K53R), inhibited tumor cell growth more potentially than Csk wild-type. Consistent with the biological phenotype, the SUMO modification of Csk impaired its activity to interact with Cbp (Csk binding protein) leading to decreased c-Src phosphorylation at Y527. Our results suggest that SUMOylation of Csk mainly at lysine 53 negatively modulates its tumor suppressor function by reducing its binding with Cbp and consequently, inducing c-Src activation.