Sulfated Glycosaminoglycans Control the Extracellular Trafficking and the Activity of the Metalloprotease Inhibitor TIMP-3

By L. Troeberg, Christopher Lazenbatt, Md. Ferdous Anower-E-Khuda, C. Freeman, O. Federov, H. Habuchi, O. Habuchi, K. Kimata, Hideaki Nagase. 2014

77 citations recorded by the source corpus.

Summary Tissue inhibitor of metalloproteinase 3 (TIMP-3) is an important regulator of extracellular matrix (ECM) turnover. TIMP-3 binds to sulfated ECM glycosaminoglycans or is endocytosed by cells via low-density lipoprotein receptor-related protein 1 (LRP-1). Here, we report that heparan sulfate (HS) and chondroitin sulfate E (CSE) selectively regulate postsecretory trafficking of TIMP-3 by inhibiting its binding to LRP-1. HS and CSE also increased TIMP-3 affinity for glycan-binding metalloproteinases, such as adamalysin-like metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), by reducing the dissociation rate constants. The sulfation pattern was crucial for these activities because monosulfated or truncated heparin had a reduced ability to bind to TIMP-3 and increase its affinity for ADAMTS-5. Therefore, sulfation of ECM glycans regulates the levels and inhibitory activity of TIMP-3 and modulates ECM turnover, and small mimicries of sulfated glycans may protect the tissue from the excess destruction seen in diseases such as osteoarthritis, cancer, and atherosclerosis.

Subfields: Cancer Research, Cell Biology, Immunology and Allergy

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In Cancer Research

1. R. Khalil
2. S. Zhong
3. D. Edwards

In Immunology and Allergy

1. S. Zhong
2. R. Khalil

Citations in the corpus

• A Disintegrin and Metalloproteinase (ADAM) and ADAM with Thrombospondin Motifs (ADAMTS) Family in Vascular Biology and Disease (2019, background): “Also, heparan sulfate glycosaminoglycans (GAGs) enhance TIMP-3 activity and therefore modulate its inhibitory effect on ADAMTS [59].”
• The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family (2015, background): “As LRP-1 also binds and internalizes TIMP-3, and as this interaction is blocked by heparan sulfate GAGs, which also potentiates TIMP-3 activity, there is potential for modulating the tissue activities of ADAMTS using sulfated glycan mimics [45].”