Membrane type-1 matrix metalloprotease-independent activation of pro-matrix metalloprotease-2 by proprotein convertases.

Full Abstract

Matrix metalloprotease-2 is implicated in many biological processes and degrades extracellular and non-extracellular matrix molecules. Matrix metalloprotease-2 maintains a latent state through a cysteine-zinc ion pairing which, when disrupted, results in full enzyme activation. This pairing can be disrupted by a conformational change or cleavage within the propeptide. The best known activation mechanism for pro-matrix metalloprotease-2 occurs via cleavage of the propeptide by membrane type-1 matrix metalloprotease. However, significant residual activation of pro-matrix metalloprotease-2 is seen in membrane type-1 matrix metalloprotease knockout mice and in fibroblasts treated with metalloprotease inhibitors. These findings indicate the presence of a membrane type-1 matrix metalloprotease-independent activation mechanism for pro-matrix metalloprotease-2 in vivo, which prompted us to explore an alternative activation mechanism for pro-matrix metalloprotese-2. In this study, we demonstrate membrane type-1 matrix metalloprotease-independent propeptide processing of matrix metalloprotease-2 in HEK293F and various tumor cell lines, and show that proprotein convertases can mediate the processing intracellularly as well as extracellularly. Furthermore, processed matrix metalloprotease-2 exhibits enzymatic activity that is enhanced by intermolecular autolytic cleavage. Thus, our experimental data, taken together with the broad expression of proprotein convertases, suggest that the proprotein convertase-mediated processing may be a general activation mechanism for pro-matrix metalloprotease-2 in vivo.

Author information

Author/s: Koo, Bon-Hun (BH); Kim, Hee-Hyun (HH); Park, Michael Y (MY); Jeon, Ok-Hee (OH); Kim, Doo-Sik (DS);

Affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 134 Sinchon-Dong Seodaemun-Gu, Seoul 120-749, South Korea. k4119(-atsign-)yonsei.ac.kr

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: The FEBS journal (FEBS J), published in England. (Language: eng)

Reference: 2009-Nov; vol 276 (issue 21) : pp 6271-84

Dates: Created 2009/10/14; Completed 2009/10/28;

PMID: 19780834, status: MEDLINE (last retrieval date: 10/28/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Humans
Matrix Metalloproteinase 14 - physiology
Molecular Sequence Data
Proprotein Convertase 5 - physiology
Proprotein Convertases - physiology
Serine Endopeptidases - physiology

Associated Chemicals: Enzyme Precursors (0) ; Proprotein Convertases (EC 3.4.-) ; PCSK6 protein, human (EC 3.4.21.-) ; Proprotein Convertase 5 (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-) ; Gelatinases (EC 3.4.24.-) ; progelatinase (EC 3.4.24.-) ; Matrix Metalloproteinase 14 (EC 3.4.24.80)

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