Tumor Suppressor HIPK2 Regulates Malignant Growth via Phosphorylation of Notch1
Tumor Suppressor HIPK2 Regulates Malignant Growth via Phosphorylation of Notch1
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DOI：
10.1158/0008-5472.can-15-3310
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发表时间：
2016-08-15
期刊：
影响因子：
11.2
通讯作者：
Park, Hee-Sae
中科院分区：
文献类型：
--
作者：
Ann, Eun-Jung;Kim, Mi-Yeon;Park, Hee-Sae
受体Notch1在许多癌症的恶性进展中起重要作用，但其调控尚不完全清楚。在这项研究中，我们报道了HIPK2激酶通过磷酸化Cdc4磷酸化子基序内的Notch1的胞内结构域（Notch1- ic），促进fbw7依赖性的Notch1的蛋白酶体降解。Notch1-IC在癌细胞中的表达高于正常细胞。在基因毒性胁迫下，Notch1-IC被HIPK2组成性磷酸化，并通过蛋白酶体降解维持在低水平。HIPK2磷酸化Notch1-IC中的残基T2512。该残基附近的体细胞突变使Notch1-IC耐降解，可由HIPK2过表达或阿霉素处理诱导。通过揭示Notch1稳定性的重要机制，本研究结果可以提供一种治疗策略来阻断许多类型癌症的Notch1依赖性进展。(c) 2016年aacr。
The receptor Notch1 plays an important role in malignant progression of many cancers, but its regulation is not fully understood. In this study, we report that the kinase HIPK2 is responsible for facilitating the Fbw7-dependent proteasomal degradation of Notch1 by phosphorylating its intracellular domain (Notch1-IC) within the Cdc4 phosphodegron motif. Notch1-IC expression was higher in cancer cells than normal cells. Under genotoxic stress, Notch1-IC was phosphorylated constitutively by HIPK2 and was maintained at a low level through proteasomal degradation. HIPK2 phosphorylated the residue T2512 in Notch1-IC. Somatic mutations near this residue rendered Notch1-IC resistant to degradation, as induced either by HIPK2 overexpression or adriamycin treatment. In revealing an important mechanism of Notch1 stability, the results of this study could offer a therapeutic strategy to block Notch1-dependent progression in many types of cancer. (C) 2016 AACR.