FIGURE 5. WNT and RSPO actions. Under steady state conditions (red dotted arrows), ZNRF3 provokes the ubiquitination and degradation of Frizzled, receptor of WNT family factors. GSK3 phosphorylates β-catenin, which is then degraded. R-spondin (RSPO) family members binding to their receptors LGR4/5/6 results in complex formation with ZNRF3. Consequently, more Frizzled molecules become available for WNT signaling. Under these conditions (blue full arrows), the complex formed by GSK3, Axin, CKIα and APC is recruited to the WNT–receptor complex and inactivated, allowing β‑catenin to translocate to the nucleus and regulate target genes.