Urokinase-type plasminogen activator (uPA) regulates the expression and function of growth-associated protein 43 (GAP-43) in the synapse

• Type of Material: Article
• Authors: Paola Merino, Yerkes National Primate Research Center; Ariel Diaz, Yerkes National Primate Research Center; Enrique Torre, Emory University; Manuel Yepes, Emory University
• Language: English
• Date: 2020-01-10
• Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
• Publication Version: Final Published Version
• Copyright Statement: 2019
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.RA119.010644
• Title of Journal or Parent Work: JOURNAL OF BIOLOGICAL CHEMISTRY
• Volume: 295
• Issue: 2
• Start Page: 619
• End Page: 630
• Grant/Funding Information: This work was supported in part by NINDS, National Institutes of Health Grant NS-NS091201 (to M. Y.), VA MERIT Award IO1BX003441 (to M. Y.), and American Heart Association Postdoctoral Fellowship Grant 19POST34380009 (to A. D.).
• Keywords: MESSENGER-RNA; PROMOTES; IN-SITU HYBRIDIZATION; plasmin; LOCALIZATION; HIPPOCAMPAL; Biochemistry & Molecular Biology; PHOSPHORYLATION; GAP-43; NMDA RECEPTOR; protease; synapse; Science & Technology; plasminogen; HUD BINDS; Life Sciences & Biomedicine; KINASE-C SUBSTRATE; urokinase receptor; NEURONAL MIGRATION
• Research Categories: Biology, Molecular; Biology, Animal Physiology; Chemistry, Biochemistry

Abstract

Growth-associated protein 43 (GAP-43) plays a central role in the formation of presynaptic terminals, synaptic plasticity, and axonal growth and regeneration. During development, GAP-43 is found in axonal extensions of most neurons. In contrast, in the mature brain, its expression is restricted to a few presynaptic terminals and scattered axonal growth cones. Urokinase-type plasminogen activator (uPA) is a serine proteinase that, upon binding to its receptor (uPAR), catalyzes the conversion of plasminogen into plasmin and activates signaling pathways that promote cell migration, proliferation, and survival. In the developing brain, uPA induces neuritogenesis and neuronal migration. In contrast, the expression and function of uPA in the mature brain are poorly understood. However, recent evidence reveals that different forms of injury induce release of uPA and expression of uPAR in neurons and that uPA/uPAR binding triggers axonal growth and synapse formation. Here we show that binding of uPA to uPAR induces not only the mobilization of GAP-43 from the axonal shaft to the presynaptic terminal but also its activation in the axonal bouton by PKC-induced calcium-dependent phosphorylation at Ser-41 (pGAP-43). We found that this effect requires open presynaptic N-methyl-Daspartate receptors but not plasmin generation. Furthermore, our work reveals that, following its activation by uPA/uPAR binding, pGAP-43 colocalizes with presynaptic vesicles and triggers their mobilization to the synaptic release site. Together, these data reveal a novel role of uPA as an activator of the synaptic vesicle cycle in cerebral cortical neurons via its ability to induce presynaptic recruitment and activation of GAP-43.