ReviewMatrix metalloproteinase-2: Not (just) a “hero” of the past
Introduction
This minireview is not intended to present an extensive review on matrix metalloproteinase (MMP)-2. The purpose is to give an overview of key features of the two lives of MMP-2. Its first life (1980's – 1990's) was rich in biochemical characterization: structure, substrates, regulation, mechanisms of activation and inhibition … But most importantly, MMP-2 emerged as a key player in cancer invasion and metastasis, triggering a craze for strategies aiming at its in vivo inhibition. Unfortunately, adverse effects of broad spectrum MMP inhibitors (i.e. due to beneficial effects of MMPs) almost rang the bell for the whole field. However, MMP-2, like its close relative MMP-9, still continues to benefit from a sustained interest, as illustrated by the number of publications focusing on, or related with these two MMPs during the last five years (Fig. 1). This second life of MMP-2 (2000's and 2010's) is clearly focused on two major topics: a better knowledge of its precise functions in vivo and in pathologies, and the design of more specific inhibitors devoid of adverse effects.
In this minireview, we will summarize key features of MMP-2, in a rather historical (and nostalgic) approach, referring to seminal observations and/or outstanding reviews and we will also give a brief overview of the ongoing research.
Section snippets
Discovery
In the early 1970's, Harris and Krane identified in the rheumatoid synovial tissue culture medium an endopeptidase degrading the denatured form of type I collagen or gelatin, but not its native form [1]. By analogy with a previously described endopeptidase called collagenase because of its catalytic activity against native type I collagen [2], the gelatin-degrading enzyme was termed gelatinase. The gelatinase was then purified in a latent 72-kDa form from culture media of various tissues and
Biochemical and biological features
MMP-2 is a Zn2+-dependent enzyme encoded by a gene located on the long arm of chromosome 16 at position q12.2. The 27 kb-long MMP2 gene has 13 exons [8] and is classically transcribed in a 3.1 kb-mRNA [4]. The cDNA for MMP-2 codes for a 660 residues preproenzyme containing a 29 residues signal peptide responsible for translocation to the endoplasmic reticulum and followed by the 72-kDa-proenzyme (Fig. 2). ProMMP-2 is composed of a propeptide followed by a catalytic domain that is connected to a
Pathologies
From the first correlation established between metastatic potential and degradation of basement membrane type IV collagen by a 65-kDa endopeptidase [139] up to the discovery of MT1-MMP [140], MMP-2 overexpression was considered as a hallmark of cancer aggressiveness. Meta-analyses found that MMP-2 expression could be correlated (and often proposed to be used as prognostic marker) with pituitary adenomas [141], breast cancer [142], ovarian cancer [143], endometrial cancer [144], gastric cancer [
Perspectives and conclusion
As our knowledge progresses, the original “gelatinase”, described as being able to degrade denatured interstitial type I collagen, has grown considerably in importance. In this sense, it has followed the same route as other members of the MMP family: from basic proteinases degrading components of the extracellular matrix, they have become major actors with extra-, peri- and intra-cellular functions. As a predictable consequence, they have been implicated in many pathologies. In particular,
Funding sources
This work was supported by grants from the Fonds de la Recherche Scientifique (F.R.S.-FNRS, Belgium) to P.H. (Research Associate at F.R.S.-FNRS), and from the Université de Reims Champagne-Ardenne (URCA) and the Centre National de la Recherche Scientifique (CNRS, France) to H.E.
Conflict of interest
We have no conflict of interest to declare.
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2022, Bioorganic and Medicinal ChemistryCitation Excerpt :Matrix metalloproteinase (MMP) is an ensemble of 26 human zinc dependent metalloproteinases out of which 24 are available in humans1–4. These degrade the extra-cellular matrix that binds the tissues together.5–8 It has been proven that MMPs are important parameters in several pathways9–12.