The Tumor Suppressor MIG6 Controls Mitotic Progression and the G2/M DNA Damage Checkpoint by Stabilizing the WEE1 Kinase
The Tumor Suppressor MIG6 Controls Mitotic Progression and the G2/M DNA Damage Checkpoint by Stabilizing the WEE1 Kinase
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DOI：
10.1016/j.celrep.2018.06.064
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发表时间：
2018-07-31
期刊：
影响因子：
8.8
通讯作者：
Ferby, Ingvar
中科院分区：
文献类型：
--
作者：
Sasaki, Mari;Terabayashi, Takeshi;Ferby, Ingvar
MIG 6是一种重要的肿瘤抑制因子，可与表皮生长因子受体（EGFR）结合并负性调节。在这里，我们报告了一个EGFR独立的功能，作为一个不可分割的组成部分，细胞周期机制的MIG 6。我们发现MIG 6的缺失导致加速进入和延迟退出有丝分裂。这是由于CDK 1的过早和长期激活，CDK 1是G2/M和Meta和后期转换时有丝分裂进程的关键调节因子。此外，在DNA损伤和随后的G2/M细胞周期停滞时，需要MIG 6来抑制CDK 1。从机制上讲，我们发现MIG 6消耗导致抑制性WEE 1靶向酪氨酸-15残基上的CDK 1磷酸化减少。MIG 6与WEE 1相互作用，并通过干扰β TrCP-SCF E3泛素连接酶的募集和随后的WEE 1蛋白酶体降解来促进其稳定性。我们的研究结果揭示了MIG 6在细胞周期进程中的关键作用，这可能有助于其有效的肿瘤抑制特性。
MIG6 is an important tumor suppressor that binds to and negatively regulates epidermal growth factor receptor (EGFR). Here, we report anEGFR-independent function for MIG6 as an integral component of the cell cycle machinery. We found that depletion of MIG6 causes accelerated entry into and delayed exit from mitosis. This is due to premature and prolonged activation of CDK1, a key regulator of mitotic progression at the G2/M and meta- and anaphase transitions. Furthermore, MIG6 is required for inhibition of CDK1 upon DNA damage and subsequent G2/M cell cycle arrest. Mechanistically, we found that MIG6 depletion results in reduced phosphorylation of CDK1 on the inhibitory WEE1-targeted tyrosine-15 residue. MIG6 interacts with WEE1 and promotes its stability by interfering with the recruitment of the beta TrCP-SCF E3 ubiquitin ligase and consequent proteasomal degradation of WEE1. Our findings uncover a critical role of MIG6 in cell cycle progression that is likely to contribute to its potent tumor-suppressive properties.