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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Cytokines / metabolism
  • Endocytosis
  • Growth Cones / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Mice
  • Neurites / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Transport
  • Receptors, LDL / physiology*
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism*
  • Tumor Suppressor Proteins / physiology*


  • Cytokines
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse
  • Receptors, LDL
  • Timp1 protein, mouse
  • Tissue Inhibitor of Metalloproteinase-1
  • Tumor Suppressor Proteins

Grants and funding

This work was supported by The National Centre for Scientific Research (CNRS) and a grant from The French National Research Agency (ANR) grant number [ANR-08-MNPS-042-04 TIMPAD to S.R. and H.E.]. A.J. is recipient of a doctoral fellowship from the French Ministry of Research; L.V. and S.D. are recipients of grants from Région Champagne-Ardenne; M.K. acknowledges support from the ANR [ANR-09-BIOT-015-01 VECtoBrain and ANR-2011-MALZ-007-01 PREVENTAD]; and S.R. acknowledges support from the Ligue Européenne Contre la Maladie d'Alzheimer (LECMA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.