title: Urokinase-type Plasminogen Activator (uPA) Binding to the uPA Receptor (uPAR) Promotes Axonal Regeneration in the Central Nervous System.
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 usedin vitroandin vivomodels 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.
authors.affiliation: From the Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.|the Division of Neurosciences, Yerkes National Primate Research Center, Atlanta, Georgia 30329, and.
authors.forename: Paola
authors.initials: P
authors.lastname: Merino
authors.affiliation: From the Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.|the Division of Neurosciences, Yerkes National Primate Research Center, Atlanta, Georgia 30329, and.
authors.forename: Ariel
authors.initials: A
authors.lastname: Diaz
authors.affiliation: From the Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.|the Division of Neurosciences, Yerkes National Primate Research Center, Atlanta, Georgia 30329, and.
authors.forename: Valerie
authors.initials: V
authors.lastname: Jeanneret
authors.affiliation: From the Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.|the Division of Neurosciences, Yerkes National Primate Research Center, Atlanta, Georgia 30329, and.
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.affiliation: From the Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.|the Division of Neurosciences, Yerkes National Primate Research Center, Atlanta, Georgia 30329, and.
authors.forename: Enrique
authors.initials: E
authors.lastname: Torre
authors.affiliation: From the Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.|the Division of Neurosciences, Yerkes National Primate Research Center, Atlanta, Georgia 30329, and.
authors.forename: Lihong
authors.initials: L
authors.lastname: Cheng
authors.affiliation: From the Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, myepes@emory.edu.|the Division of Neurosciences, Yerkes National Primate Research Center, Atlanta, Georgia 30329, and.|the Department of Neurology, Veterans Affairs Medical Center, Atlanta, Georgia 30033.
authors.forename: Manuel
authors.initials: M
authors.lastname: Yepes
mesh_terms: D001369:Axons / Q000502:physiology*; D002490:Central Nervous System / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D009416:Nerve Regeneration; D011485:Protein Binding; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D019012:Integrin beta1; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator
keywords: Rac; Ras-related C3 botulinum toxin substrate 1 (Rac1); integrin; plasmin; plasminogen; urokinase receptor