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

• Type of Material: Article
• Authors: Ariel Diaz, Emory University; Cynthia Martin-Jimenez, Emory University; Yang Xu, Emory University; Paola Merino, Emory University; Yena Woo, Emory University; Enrique Torre, Emory University; Manuel Yepes, Emory University
• Language: English
• Date: 2021-06-01
• Publisher: The Company of Biologists Ltd
• Publication Version: Final Published Version
• Copyright Statement: The Company of Biologists
• Final Published Version (URL): http://dx.doi.org/10.1242/jcs.255919
• Title of Journal or Parent Work: Journal of Cell Science
• Volume: 134
• Issue: 11
• Grant/Funding Information: This work was supported in part by National Institutes of Health grant NS-091201 (to M.Y.), Office of Patient Care Services, Department of Veterans Affairs MERIT award IO1BX003441 (to M.Y.), and American Heart Association post-doctoral fellowship grant 19POST34380009 (to A.D.). Deposited in PMC for release after 12 months.
• Keywords: Wound Healing; beta Catenin; Urokinase-type plasminogen activator; Urokinase-Type Plasminogen Activator; Wnt-β-catenin pathway; Cadherins; Receptors, Urokinase Plasminogen Activator; β-catenin; uPA; Plasmin; Low density lipoprotein receptor-related protein 6
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Urokinase-type plasminogen activator (uPA; encoded by Plau) is a serine proteinase that, in the central nervous system, induces astrocytic activation. β-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 β-catenin from cadherins, and β-catenin is then degraded by the proteasome following its phosphorylation by GSK3β. 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 β-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 β-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 GSK3β. Our work indicates that the ensuing cytoplasmic accumulation of β-catenin is followed by its nuclear translocation and β-catenin-triggered transcription of the receptor for uPA (Plaur), which in turn is required for uPA to induce astrocytic wound healing.