Urokinase-type plasminogen activator (uPA) promotes ezrin-mediated reorganization of the synaptic cytoskeleton in the ischemic brain

• Type of Material: Article
• Authors: Paola Merino, Emory University; Ariel Diaz, Emory University; Luis Guillermo Manrique, Emory University; Lihong Cheng, Emory University; Manuel Yepes, Emory University
• Language: English
• Date: 2018-06-15
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Michalski and Williams Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.RA118.002534
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 293
• Issue: 24
• Start Page: 9234
• End Page: 9247
• Grant/Funding Information: This work was supported in part by National Institutes of Health Grants NS-091201 (to M. Y.) and NS-079331 (to M. Y.) and Veterans Affairs Merit Award IO1BX003441 (to M. Y.).
• Keywords: Animals; Male; Integrin beta3; Urokinase-Type Plasminogen Activator; stroke; plasmin; synapse; Brain; ezrin; Cytoskeleton; urokinase receptor; Nerve Tissue Proteins; Receptors, Urokinase Plasminogen Activator; Cytoskeletal Proteins; cytoskeleton; Synapses; Mice, Inbred C57BL; Cells, Cultured; Brain Ischemia; Membrane Glycoproteins
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience

Abstract

Synaptic repair in the ischemic brain is a complex process that requires reorganization of the actin cytoskeleton. Ezrin, radixin, and moesin (ERM) are a group of evolutionarily conserved proteins that link the plasma membrane to the actin cytoskeleton and act as scaffolds for signaling transduction. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to the urokinase-type plasminogen activator receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface and activates intracellular signaling pathways. Early studies indicate that uPA and uPAR expression increase during the recovery phase from an ischemic stroke and that uPA binding to uPAR promotes neurorepair in the ischemic brain. The in vitro and in vivo studies presented here show that either the release of neuronal uPA or treatment with recombinant uPA induces the local synthesis of ezrin in the synapse andthe recruitment of 3-integrintothe postsynaptic density (PSD) of cerebral cortical neurons by a plasminogen-independent mechanism. We found that 3-integrin has a double effect on ezrin, inducing its recruitment to the PSD via the intercellular adhesion molecule-5 (ICAM-5) and its subsequent activation by phosphorylation at Thr-567. Finally, our data indicate that by triggering the reorganization of the actin cytoskeleton in the postsynaptic terminal, active ezrin induces the recovery of dendritic spines and synapses that have been damaged by an acute ischemic stroke. In summary, our data show that uPA? uPAR binding promotes synaptic repair in the ischemic brain via ezrin-mediated reorganization of the actin cytoskeleton in the postsynaptic terminal.