Urokinase-type plasminogen activator-mediated crosstalk between N-cadherin and β-catenin promotes wound healing

Urokinase-type plasminogen activator (uPA; encoded by Plau) is a serine proteinase that, in the central nervous system, induces astrocytic activation. beta-Catenin is a protein that links the cytoplasmic tail of cadherins to the actin cytoskeleton, thus securing the formation of cadherin-mediated cell adhesion complexes. Disruption of cell-cell contacts leads to the detachment of beta-catenin from cadherins, and beta-catenin is then degraded by the proteasome following its phosphorylation by GSK3 beta. Here, we show that astrocytes release uPA following a scratch injury, and that this uPA promotes wound healing via a plasminogen-independent mechanism. We found that uPA induces the detachment of beta-catenin from the cytoplasmic tail of N-cadherin (NCAD; also known as CDH2) by triggering its phosphorylation at Tyr654. Surprisingly, this is not followed by degradation of beta-catenin because uPA also induces the phosphorylation of the low density lipoprotein receptor-related protein 6 (LRP6) at Ser1490, which then blocks the kinase activity of GSK3 beta. Our work indicates that the ensuing cytoplasmic accumulation of beta-catenin is followed by its nuclear translocation and beta-catenin-triggered transcription of the receptor for uPA (Plaur), which in turn is required for uPA to induce astrocytic wound healing.

Automated summary

The study shows that urokinase-type plasminogen activator (uPA) released by astrocytes following injury promotes wound healing independent of plasminogen. uPA induces detachment of beta-catenin from N-cadherin through phosphorylation, but prevents its degradation by blocking GSK3 beta activity via phosphorylation of LRP6. This leads to nuclear translocation of beta-catenin and transcription of the receptor for uPA, necessary for uPA-induced astrocytic wound healing.