Urokinase-type Plasminogen Activator (uPA) Binding to the uPA Receptor (uPAR) Promotes Axonal Regeneration in the Central Nervous System

• Type of Material: Article
• Authors: Paola Merino, Emory University; Ariel Diaz, Emory University; Valerie Jeanneret, Emory University; Fang Wu, Emory University; Enrique Torre, Emory University; Lihong Cheng, Emory University; Manuel Yepes, Emory University
• Language: English
• Date: 2017-02-17
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M116.761650
• Title of Journal or Parent Work: Journal of Biological Chemistry
• Volume: 292
• Issue: 7
• Start Page: 2741
• End Page: 2753
• Grant/Funding Information: This work was supported in part by National Institutes of Health Grants NS-079331 (to M. Y.) and NS-091201 (to M. Y.).
• Keywords: Rac; Integrin; plasmin; plasminogen; urokinase recepter; Ras-related C3 botulinum toxin substrate 1 (Rac1)
• Research Categories: Biology, Neuroscience

Abstract

Axonal injury is a common cause of neurological dysfunction. Unfortunately, in contrast to axons from the peripheral nervous system, the limited capacity of regeneration of central nervous system (CNS) axons is a major obstacle for functional recovery in patients suffering neurological diseases that involve the subcortical white matter. 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. uPAR expression increases after an injury, and signaling through uPAR promotes tissue remodeling. However, it is yet unknown whether uPA binding to uPAR has an effect on axonal recovery in the CNS. Here, we used in vitro and in vivo models of CNS axonal injury to test the hypothesis that uPA binding to uPAR promotes axonal regeneration in the CNS. We found that newly formed growth cones from axons re-emerging from an axonal injury express uPAR and that binding of uPA to this uPAR promotes axonal recovery by a mechanism that does not require the generation of plasmin. Our data indicate that the binding of recombinant uPA or endogenous uPA to uPAR induces membrane recruitment and activation of β1 integrin via the low density lipoprotein receptor-related protein-1 (LRP1), which leads to activation of the Rho family small GTPase Rac1 and Rac1-induced axonal regeneration. Our results show that the uPA/uPAR/LRP1 system is a potential target for the development of therapeutic strategies to promote axonal recovery following a CNS injury.