Two-Chains Tissue Plasminogen Activator Unifies Met and NMDA Receptor Signalling to Control Neuronal Survival

Elodie Hedou, Sara Douceau, Arnaud Chevilley, Alexandre Varangot, Audrey M Thiebaut, Hortense Triniac, Isabelle Bardou, Carine Ali, Mike Maillasson, Tiziana Crepaldi, Paolo Comoglio, Eloïse Lemarchand, Véronique Agin, Benoit D Roussel, Denis Vivien

Research output: Contribution to journalArticlepeer-review


Tissue-type plasminogen activator (tPA) plays roles in the development and the plasticity of the nervous system. Here, we demonstrate in neurons, that by opposition to the single chain form (sc-tPA), the two-chains form of tPA (tc-tPA) activates the MET receptor, leading to the recruitment of N-Methyl-d-Aspartate receptors (NMDARs) and to the endocytosis and proteasome-dependent degradation of NMDARs containing the GluN2B subunit. Accordingly, tc-tPA down-regulated GluN2B-NMDAR-driven signalling, a process prevented by blockers of HGFR/MET and mimicked by its agonists, leading to a modulation of neuronal death. Thus, our present study unmasks a new mechanism of action of tPA, with its two-chains form mediating a crosstalk between MET and the GluN2B subunit of NMDARs to control neuronal survival.

Original languageEnglish
JournalInternational journal of molecular sciences
Issue number24
Publication statusPublished - Dec 15 2021


  • Animals
  • Cell Death/drug effects
  • Cell Survival/drug effects
  • Fetus
  • Mice
  • Neurons/metabolism
  • Primary Cell Culture
  • Protein Isoforms
  • Proto-Oncogene Proteins c-met/metabolism
  • Receptor Cross-Talk/physiology
  • Receptors, N-Methyl-D-Aspartate/metabolism
  • Signal Transduction
  • Tissue Plasminogen Activator/metabolism


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