Guangdong Provincial Key Laboratory of Regional Immunity and Disease, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China.
Department of Research, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, China.
Cell Commun Signal. 2024 Jan 5;22(1):14. doi: 10.1186/s12964-023-01456-y.
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.
RSPO（R-spondin）是一类分泌型信号分子，通过与 Wnt 配体合作增强 Wnt/β-catenin 信号通路。RSPO1 在组织发育和组织稳态中起着至关重要的作用。然而，RSPO 激活 Wnt/β-catenin 信号的分子机制仍不清楚。在本研究中，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 的结果表明，重组 RSPO1 蛋白促进了 Axin1 和 CK1ε 的相互作用。CK1ε 基因敲除或 CK1δ/CK1ε 抑制剂 SR3029 的处理均导致 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 的结合数量增加。LRP6 的过表达进一步增强了 RSPO1 或 CK1ε 介导的 Axin1 降解。此外，重组 RSPO1 和 Wnt3A 蛋白协同地下调 Axin1 的蛋白表达，并增强 SuperTOPFlash 报告基因的转录活性。总之，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。
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