title: Conformations of tissue plasminogen activator (tPA) orchestrate neuronal survival by a crosstalk between EGFR and NMDAR.
abstract: Tissue-type plasminogen activator (tPA) is a pleiotropic serine protease of the central nervous system (CNS) with reported neurotrophic and neurotoxic functions. Produced and released under its single chain form (sc), the sc-tPA can be cleaved by plasmin or kallikrein in a two chain form, tc-tPA. Although both sc-tPA and tc-tPA display a similar fibrinolytic activity, we postulated here that these two conformations of tPA (sc-tPA and tc-tPA) could differentially control the effects of tPA on neuronal survival. Using primary cultures of mouse cortical neurons, our present study reveals that sc-tPA is the only one capable to promote N-methyl-D-aspartate receptor (NMDAR)-induced calcium influx and subsequent excitotoxicity. In contrast, both sc-tPA and tc-tPA are capable to activate epidermal growth factor receptors (EGFRs), a mechanism mediating the antiapoptotic effects of tPA. Interestingly, we revealed a tPA dependent crosstalk between EGFR and NMDAR in which a tPA-dependent activation of EGFRs leads to downregulation of NMDAR signaling and to subsequent neurotrophic effects.
authors.affiliation: Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
authors.forename: T
authors.initials: T
authors.lastname: Bertrand
authors.affiliation: Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
authors.forename: F
authors.initials: F
authors.lastname: Lesept
authors.affiliation: Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
authors.forename: A
authors.initials: A
authors.lastname: Chevilley
authors.affiliation: Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
authors.forename: S
authors.initials: S
authors.lastname: Lenoir
authors.affiliation: Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
authors.forename: M
authors.initials: M
authors.lastname: Aimable
authors.affiliation: Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
authors.forename: A
authors.initials: A
authors.lastname: Briens
authors.affiliation: Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Hommet
authors.affiliation: Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
authors.forename: I
authors.initials: I
authors.lastname: Bardou
authors.affiliation: Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
authors.forename: J
authors.initials: J
authors.lastname: Parcq
authors.affiliation: Inserm, Inserm U919, Serine Proteases and Pathophysiology of the Neurovascular Unit, University Caen Basse-Normandie, GIP Cyceron, Caen, France.
authors.forename: D
authors.initials: D
authors.lastname: Vivien
mesh_terms: D017209:Apoptosis; D020013:Calcium Signaling; D002470:Cell Survival; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D011487:Protein Conformation; D020239:Receptor Cross-Talk; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000737:chemistry / Q000502:physiology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; C512478:EGFR protein, human; D066246:ErbB Receptors; C067262:PLAT protein, human; D010959:Tissue Plasminogen Activator