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

doi:10.3390/ijms222413483

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

Istituto Oncologico Candiolo

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	International journal of molecular sciences
Volume	22
Issue number	24
DOIs	https://doi.org/10.3390/ijms222413483
Publication status	Published - Dec 15 2021

Keywords

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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Hedou, E., Douceau, S., Chevilley, A., Varangot, A., Thiebaut, A. M., Triniac, H., Bardou, I., Ali, C., Maillasson, M., Crepaldi, T., Comoglio, P., Lemarchand, E., Agin, V., Roussel, B. D., & Vivien, D. (2021). Two-Chains Tissue Plasminogen Activator Unifies Met and NMDA Receptor Signalling to Control Neuronal Survival. International journal of molecular sciences, 22(24). https://doi.org/10.3390/ijms222413483

Hedou, E, Douceau, S, Chevilley, A, Varangot, A, Thiebaut, AM, Triniac, H, Bardou, I, Ali, C, Maillasson, M, Crepaldi, T, Comoglio, P, Lemarchand, E, Agin, V, Roussel, BD & Vivien, D 2021, 'Two-Chains Tissue Plasminogen Activator Unifies Met and NMDA Receptor Signalling to Control Neuronal Survival', International journal of molecular sciences, vol. 22, no. 24. https://doi.org/10.3390/ijms222413483

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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.",

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AU - Hedou, Elodie

AU - Douceau, Sara

AU - Chevilley, Arnaud

AU - Varangot, Alexandre

AU - Thiebaut, Audrey M

AU - Triniac, Hortense

AU - Bardou, Isabelle

AU - Ali, Carine

AU - Maillasson, Mike

AU - Crepaldi, Tiziana

AU - Comoglio, Paolo

AU - Lemarchand, Eloïse

AU - Agin, Véronique

AU - Roussel, Benoit D

AU - Vivien, Denis

PY - 2021/12/15

Y1 - 2021/12/15

N2 - 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.

AB - 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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KW - Cell Death/drug effects

KW - Cell Survival/drug effects

KW - Fetus

KW - Mice

KW - Neurons/metabolism

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KW - Protein Isoforms

KW - Proto-Oncogene Proteins c-met/metabolism

KW - Receptor Cross-Talk/physiology

KW - Receptors, N-Methyl-D-Aspartate/metabolism

KW - Signal Transduction

KW - Tissue Plasminogen Activator/metabolism

U2 - 10.3390/ijms222413483

DO - 10.3390/ijms222413483

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JO - International journal of molecular sciences

JF - International journal of molecular sciences

IS - 24

ER -

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

Abstract

Keywords

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