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

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

Edité par CCSD ; MDPI -

International audience. 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.

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