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

• Published in: PloS one 2014-07, Vol.9 (7), p.e103839-e103839
• Main Authors: Thevenard, Jessica, Verzeaux, Laurie, Devy, Jerôme, Etique, Nicolas, Jeanne, Albin, Schneider, Christophe, Hachet, Cathy, Ferracci, Géraldine, David, Marion, Martiny, Laurent, Charpentier, Emmanuelle, Khrestchatisky, Michel, Rivera, Santiago, Dedieu, Stéphane, Emonard, Hervé
• Format: Article
• Language: English
• Subjects: Animals; Axonogenesis; Binding; Biology and Life Sciences; Cell adhesion & migration; Chains; CHO Cells; Cognitive science; Cricetinae; Cricetulus; Cytokines; Cytokines - metabolism; Endocytosis; Extracellular matrix; Growth cones; Growth Cones - metabolism; Inhibition; Inhibitors; Intracellular signalling; Kinases; Ligands; Low density lipoprotein receptors; Low density lipoproteins; Matrix metalloproteinases; Mice; Molecular modelling; Neurites - metabolism; Neuroplasticity; Neuroscience; Plasticity (neural); Protein Binding; Protein Interaction Domains and Motifs; Protein Transport; Proteins; Proteolysis; Receptor density; Receptors, LDL - physiology; Surface plasmon resonance; Tissue inhibitor of metalloproteinase 1; Tissue inhibitor of metalloproteinase 2; Tissue inhibitor of metalloproteinase 3; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Tumor Suppressor Proteins - physiology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0103839

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.