R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis

R-spondins (RSPOs) are secreted signaling molecules that potentiate the Wnt/β-catenin pathway by cooperating with Wnt ligands. 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 recombinant RSPO1 protein induced an enhanced interaction between Axin1 and CK1ε. Either knockout of CK1ε gene or treatment with the CK1δ/CK1ε inhibitor SR3029 caused an increase in Axin1 protein level, and attenuated RSPO1-induced degradation of Axin1 protein. Moreover, we observed the increased association 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 protein expression of Axin1 and enhanced the transcriptional activity of the SuperTOPFlash reporter. Taken together, this study uncovers a novel mechanism by which RSPOs activate Wnt/β-catenin signaling through a LRP6/CK1ε-mediated degradation of Axin.