GSK3β regulates a novel β-Catenin degradation pathway via the GID complex in Wnt signaling.

The canonical Wnt signaling pathway plays a pivotal role in regulating cell proliferation, differentiation, and tissue homeostasis. These functions are largely regulated through the degradation of β-Catenin. Under Wnt-off conditions, β-Catenin is phosphorylated by the destruction complex, including GSK3β, and subsequently ubiquitinated by the E3 ligase βTrCP, leading to proteasomal degradation. In this study, we identified a regulatory mechanism in which suppression of GSK3β promotes β-Catenin degradation via the GID complex, a conserved multi-subunit E3 ubiquitin ligase. GSK3β knockdown increased β-Catenin ubiquitination and decreased its protein levels in both the cytoplasm and nucleus, independent of βTrCP. This degradation was rescued by knockdown of GID components MAEA and RMND5A, but not by suppression of βTrCP. Furthermore, Wnt stimulation promoted the interaction between GSK3β and the GID E3 ligases, disrupting the association between MAEA and β-Catenin and thereby stabilizing β-Catenin. Together, these findings reveal a GSK3β-dependent mechanism of β-Catenin regulation mediated by the GID complex.