Huang Yongsheng, Wang Peng, Chen Hua, Ding Yi, Chen Ye-Guang
*The State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Biochem J. 2015 Mar 15;466(3):499-509. doi: 10.1042/BJ20141143.
Wnt signalling regulates embryonic development and tissue homoeostasis by modulating cell proliferation, differentiation and migration. Dapper1 (Dpr1) has been shown to be an important key negative regulator of Wnt signalling by promoting Dishevelled (Dvl) degradation. In the present study, we found that Myc-interacting zinc-finger protein 1 (MIZ1) interacts with Dpr1 and this interaction attenuates the ability of Dpr1 to induce Dvl2 degradation, thus enhancing Wnt signalling. Mechanistically, MIZ1 is translocated from the nucleus to the cytoplasm upon Wnt3a stimulation or overexpression of Dpr1 and Dvl2, disrupting the interaction between Dpr1 and Dvl2. Furthermore, MIZ1 can promote the proliferation of breast cancer MDA-MB-231 and BT-549 cells through Wnt signalling and reverse the anti-proliferative effect of Dpr1 on colorectal cancer Caco-2. Together, our findings establish a novel layer of Wnt signalling regulation via the MIZ1-Dpr1-Dvl axis.
Wnt信号通路通过调节细胞增殖、分化和迁移来调控胚胎发育和组织稳态。Dapper1(Dpr1)已被证明是Wnt信号通路的一个重要关键负调控因子,它通过促进Dishevelled(Dvl)降解来发挥作用。在本研究中,我们发现Myc相互作用锌指蛋白1(MIZ1)与Dpr1相互作用,这种相互作用减弱了Dpr1诱导Dvl2降解的能力,从而增强了Wnt信号通路。从机制上讲,在Wnt3a刺激或Dpr1和Dvl2过表达时,MIZ1从细胞核转移到细胞质,破坏了Dpr1与Dvl2之间的相互作用。此外,MIZ1可通过Wnt信号通路促进乳腺癌MDA-MB-231和BT-549细胞的增殖,并逆转Dpr1对结直肠癌Caco-2细胞的抗增殖作用。总之,我们的研究结果通过MIZ1-Dpr1-Dvl轴建立了一层新的Wnt信号通路调控机制。