Role of plasminogen activation in neuronal organization and survival.
We characterized the interactions between plasminogen and neurons and investigated the associated effects on extracellular matrix proteolysis, cell morphology, adhesion, signaling and survival. Upon binding of plasminogen to neurons, the plasmin formed by constitutively expressed tissue plasminogen activator (tPA) degrades extracellular matrix proteins, leading to retraction of the neuron monolayer that detaches from the matrix. This sequence of events required both interaction of plasminogen with carboxy-terminal lysine residues and the proteolytic activity of plasmin. Surprisingly, 24h after plasminogen addition, plasmin-detached neurons survived and remained associated in clusters maintaining focal adhesion kinase phosphorylation contrasting with other adherent cell types fully dissociated by plasmin. However, long-term incubation (72 h) with plasminogen was associated with an increased rate of apoptosis, suggesting that prolonged exposure to plasmin may cause neurotoxicity. Regulation of neuronal organization and survival by plasminogen may be of pathophysiological relevance, as plasminogen is expressed in the brain and/or extravasate during vascular accidents or inflammatory processes.
Ho-Tin-Noé
Benoît
B
Inserm U698, Université Paris Diderot-Paris 7, 75018 Paris, France.
Enslen
Hervé
H
Doeuvre
Loïc
L
Corsi
Jean-Marc
JM
Lijnen
H Roger
HR
Anglés-Cano
Eduardo
E
D015119:Aminocaproic Acid / Q000378:metabolism; D000818:Animals; D000933:Antifibrinolytic Agents / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D010958:Plasminogen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000378:metabolism
D000933:Antifibrinolytic Agents; D016326:Extracellular Matrix Proteins; D010958:Plasminogen; D051418:Focal Adhesion Kinase 2; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D015119:Aminocaproic Acid