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Review
. 2022 Aug 23;23(17):9513.
doi: 10.3390/ijms23179513.

Novel Roles of MT1-MMP and MMP-2: Beyond the Extracellular Milieu

Deanna V Maybee  1 , Nicole L Ink  1 , Mohammad A M Ali  1
Affiliations
Review

Novel Roles of MT1-MMP and MMP-2: Beyond the Extracellular Milieu

Deanna V Maybee et al. Int J Mol Sci. .

Abstract

Matrix metalloproteinases (MMPs) are critical enzymes involved in a variety of cellular processes. MMPs are well known for their ability to degrade the extracellular matrix (ECM) and their extracellular role in cell migration. Recently, more research has been conducted on investigating novel subcellular localizations of MMPs and their intracellular roles at their respective locations. In this review article, we focus on the subcellular localization and novel intracellular roles of two closely related MMPs: membrane-type-1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2). Although MT1-MMP is commonly known to localize on the cell surface, the protease also localizes to the cytoplasm, caveolae, Golgi, cytoskeleton, centrosome, and nucleus. At these subcellular locations, MT1-MMP functions in cell migration, macrophage metabolism, invadopodia development, spindle formation and gene expression, respectively. Similar to MT1-MMP, MMP-2 localizes to the caveolae, mitochondria, cytoskeleton, nucleus and nucleolus and functions in calcium regulation, contractile dysfunction, gene expression and ribosomal RNA transcription. Our particular interest lies in the roles MMP-2 and MT1-MMP serve within the nucleus, as they may provide critical insights into cancer epigenetics and tumor migration and invasion. We suggest that targeting nuclear MT1-MMP or MMP-2 to reduce or halt cell proliferation and migration may lead to the development of new therapies for cancer and other diseases.

Keywords: MMP-2; MT1-MMP; intracellular roles; matrix metalloproteinases (MMPs); subcellular localization.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of MMP domains of a membrane-type (MT1-MMP) and a gelatinase (MMP-2) member of MMPs. MT1-MMP has transmembrane and cytoplasmic domains that are absent in MMP-2. MMP-2 has fibronectin (FN) type-II inserts within its catalytic domain.
Figure 2
Figure 2
MT1-MMP, a membrane-bound protease, is also found in various intracellular locales, and it functions in various cellular processes inside the cell. The red arrow indicates the canonical trafficking of MT1-MMP to the cell membrane. Black arrows indicate novel intracellular locales of MT1-MMP to caveola, Golgi, cytoskeleton, centrosome, and nucleus. In red, potential substrates or partners of MT1-MMP are listed in these locations.
Figure 3
Figure 3
MMP-2 was first described as a secreted protease; however, MMP-2 is localized to prominent subcellular locales and functions at these locations. The red arrow indicates the canonical trafficking of MMP-2 outside the cell. Black arrows indicate new intracellular locales of MMP-2 to caveola, sarcomere, cytoskeleton, mitochondria, nucleolus, and nucleus. In red, potential substrates or partners of MMP-2 are listed in these locations.
See this image and copyright information in PMC

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