Phosphorylation of α-CateninS641 Suppresses the NF-κB Pathway in Fibroblasts to Activate Skin Wound Repair

Skin wound healing is a complex process involving intricate molecular mechanisms that remain unknown. Restoration of homeostasis after wounding requires the remodeling function of fibroblasts. Here, we demonstrate that phosphorylation of α-cateninS641 was upregulated in fibroblasts upon wounding, which accelerated their proliferation and migration to restore the skin barrier. At the wound edge, phospho-α-cateninS641 stabilized IκBα and thereby impaired expression of NF-κB target genes to promote proliferation and migration of fibroblasts. Mechanically, phospho-α-cateninS641 blocked K48-linked polyubiquitination and proteasomal degradation of IκBα. Moreover, we also demonstrated that EGF/EGFR/CK2α was function as a key upstream signaling of α-catenin by phosphorylating α-catenin at S641. Wound repair was significantly disrupted in skin of mice in which α-catenin phosphorylation and CK2α kinase activity were perturbed in fibroblasts. These findings provide insights into the molecular control of fibroblast proliferation and migration in response to wounding and identify potential targets for the treatment of defective wound repair.