Neuronal conversion of single-chain tissue-type plasminogen activator into its two-chain form: implications in neurodevelopment, learning, and memory

Tissue-type plasminogen activator (tPA) is a serine protease expressed in the central nervous system (CNS) that exhibits various effects, from neurodevelopment to learning and memory processes. tPA is secreted in its single-chain form (sc-tPA) and can be cleaved into a two-chain form (tc-tPA), with...

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Bibliographic Details
Published in:Cell death & disease Vol. 16; no. 1; pp. 811 - 11
Main Authors: Triniac, Hortense, Lebatard, Simon, Roussel, Valerie, Lechevallier, Charlotte, Lebouvier, Laurent, Vivien, Denis, Roussel, Benoit D.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 07.11.2025
Springer Nature B.V
Nature Publishing Group
Subjects:
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Amino acids
Animals
Antibodies
Biochemistry
Biochemistry, Molecular Biology
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell surface
Cellular Biology
Central nervous system
Enzymes
Experiments
Fibrinolysin - metabolism
Fibroblasts
Growth factors
Humans
Immunology
Isoforms
Learning
Learning - physiology
Life Sciences
Memory - physiology
Mice
Molecular biology
Neurodevelopment
Neurons
Neurons - metabolism
Neurons and Cognition
Plasmin
Plasminogen - metabolism
Protein Isoforms - metabolism
Proteins
Rats
Serine proteinase
t-Plasminogen activator
Tissue Plasminogen Activator - chemistry
Tissue Plasminogen Activator - genetics
Tissue Plasminogen Activator - metabolism
United States > US
ISSN:2041-4889, 2041-4889
Online Access:Get full text
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Summary:Tissue-type plasminogen activator (tPA) is a serine protease expressed in the central nervous system (CNS) that exhibits various effects, from neurodevelopment to learning and memory processes. tPA is secreted in its single-chain form (sc-tPA) and can be cleaved into a two-chain form (tc-tPA), with the two isoforms displaying sometimes opposite effects within the CNS. Using Alexa Fluor-conjugated recombinant tPA and complementary pharmacological approaches, we evaluated the ability of brain cells to process sc- into tc-tPA and the mechanisms involved. Our data revealed that neurons are the main brain cells capable to cleave sc-tPA into tc-tPA. This process occurs in three steps: 1) plasminogen binds to the cell surface of cortical neurons; 2) sc-tPA activates plasminogen into plasmin; 3) the generated plasmin cleaves sc-tPA into tc-tPA. The cleavage of tPA requires its Kringle 2 domain and is independent of plasminogen LBS. This cleavage mechanism represents a new modulation of tPA’s functions within the CNS.
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PMCID: PMC12594754
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-025-08132-8