Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, 751 23 Uppsala, Sweden.
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, 751 23 Uppsala, Sweden.
Cell Rep. 2018 Jul 31;24(5):1278-1289. doi: 10.1016/j.celrep.2018.06.064.
MIG6 is an important tumor suppressor that binds to and negatively regulates epidermal growth factor receptor (EGFR). Here, we report an EGFR-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 βTrCP-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.
MIG6 是一种重要的肿瘤抑制因子，它可以结合并负调控表皮生长因子受体（EGFR）。在这里，我们报告了 MIG6 的一个 EGFR 非依赖性功能，即作为细胞周期机制的一个组成部分。我们发现，MIG6 的耗竭会导致有丝分裂的提前进入和延迟退出。这是由于 CDK1 的过早和延长激活，CDK1 是 G2/M 期以及中期和后期过渡的有丝分裂进程的关键调节剂。此外，MIG6 对于 DNA 损伤后抑制 CDK1 以及随后的 G2/M 细胞周期阻滞是必需的。在机制上，我们发现 MIG6 的耗竭会导致 CDK1 在抑制性 WEE1 靶向的酪氨酸-15 残基上的磷酸化减少。MIG6 与 WEE1 相互作用，并通过干扰 βTrCP-SCF E3 泛素连接酶的募集和随后 WEE1 的蛋白酶体降解来促进其稳定性。我们的发现揭示了 MIG6 在细胞周期进展中的关键作用，这可能有助于其强大的肿瘤抑制特性。
