Two‐chains tissue plasminogen activator unifies met and nmda receptor signalling to control neuronal survival

Abstract

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.