PDF(Pubmed)
Abstract：
R-spondins (RSPOs) are secreted signaling molecules that potentiate the Wnt/β-catenin pathway by cooperating with Wnt ligands. RSPO1 is crucial in tissue development and tissue homeostasis. However, the molecular mechanism by which RSPOs activate Wnt/β-catenin signaling remains elusive. In this study, we found that RSPOs could mediate the degradation of Axin through the ubiquitin-proteasome pathway. The results of Co-IP showed that the recombinant RSPO1 protein promoted the interaction between Axin1 and CK1ε. Either knockout of the CK1ε gene or treatment with the CK1δ/CK1ε inhibitor SR3029 caused an increase in Axin1 protein levels and attenuated RSPO1-induced degradation of the Axin1 protein. Moreover, we observed an increase in the number of associations of LRP6 with CK1ε and Axin1 following RSPO1 stimulation. Overexpression of LRP6 further potentiated Axin1 degradation mediated by RSPO1 or CK1ε. In addition, recombinant RSPO1 and Wnt3A proteins synergistically downregulated the protein expression of Axin1 and enhanced the transcriptional activity of the SuperTOPFlash reporter. Taken together, these results uncover the novel mechanism by which RSPOs activate Wnt/β-catenin signaling through LRP6/CK1ε-mediated degradation of Axin.
摘要：
R-spondins（RSPO）是分泌的信号分子，通过与Wnt配体合作来增强Wnt/β-catenin途径。RSPO1在组织发育和组织稳态中至关重要。然而,RSPO激活Wnt/β-catenin信号的分子机制仍然难以捉摸。在这项研究中,我们发现RSPO可以通过泛素-蛋白酶体途径介导Axin的降解。Co-IP结果表明，重组RSPO1蛋白促进了Axin1与CK1ε的相互作用。敲除CK1ε基因或用CK1δ/CK1ε抑制剂SR3029处理均导致Axin1蛋白水平增加，并减弱了RSPO1诱导的Axin1蛋白降解。此外，我们观察到RSPO1刺激后LRP6与CK1ε和Axin1的关联数量增加。LRP6的过表达进一步增强了由RSPO1或CK1ε介导的Axin1降解。此外,重组RSPO1和Wnt3A蛋白协同下调Axin1的蛋白表达并增强SuperTOPFlash报道分子的转录活性。一起来看,这些结果揭示了RSPO通过LRP6/CK1ε介导的Axin降解激活Wnt/β-catenin信号的新机制。
