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PLoS One. 2014 Jul 30;9(7):e103839. doi: 10.1371/journal.pone.0103839. eCollection 2014.

Low-density lipoprotein receptor-related protein-1 mediates endocytic clearance of tissue inhibitor of metalloproteinases-1 and promotes its cytokine-like activities.

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Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 7369 Matrice Extracellulaire et Dynamique Cellulaire, Université de Reims-Champagne-Ardenne, Unité de Formation et de Recherche (UFR) Sciences Exactes et Naturelles, Reims, France.
Aix-Marseille Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille (CRN2M), UMR 7286, Plate-Forme de Recherche en Neurosciences (PFRN), Marseille, France.
VECT-HORUS SAS, Faculté de Médecine Secteur Nord, Marseille, France.
Neurobiologie des Interactions Cellulaires et Neurophysiopathologie (NICN), UMR 7259, Aix-Marseille Université, Marseille, France; NICN, CNRS UMR 7259, Marseille, France.


Tissue inhibitor of metalloproteinases-1 (TIMP-1) regulates the extracellular matrix turnover by inhibiting the proteolytic activity of matrix metalloproteinases (MMPs). TIMP-1 also displays MMP-independent activities that influence the behavior of various cell types including neuronal plasticity, but the underlying molecular mechanisms remain mostly unknown. The trans-membrane receptor low-density lipoprotein receptor-related protein-1 (LRP-1) consists of a large extracellular chain with distinct ligand-binding domains that interact with numerous ligands including TIMP-2 and TIMP-3 and a short transmembrane chain with intracellular motifs that allow endocytosis and confer signaling properties to LRP-1. We addressed TIMP-1 interaction with recombinant ligand-binding domains of LRP-1 expressed by CHO cells for endocytosis study, or linked onto sensor chips for surface plasmon resonance analysis. Primary cortical neurons bound and internalized endogenous TIMP-1 through a mechanism mediated by LRP-1. This resulted in inhibition of neurite outgrowth and increased growth cone volume. Using a mutated inactive TIMP-1 variant we showed that TIMP-1 effect on neurone morphology was independent of its MMP inhibitory activity. We conclude that TIMP-1 is a new ligand of LRP-1 and we highlight a new example of its MMP-independent, cytokine-like functions.

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