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Open AccessArticle

Regulation of MT1-MMP Activity through Its Association with ERMs

1
Molecular Biology Department, Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain
2
Severo Ochoa Molecular Biology Center (CBM-SO), Instituto de Investigación Sanitaria Princesa (IIS-IP), 28049 Madrid, Spain
3
Unit of Microscopy and Dynamic Imaging, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
4
Vascular Pathophysiology Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
5
Molecular Biomedicine Department, Centro e Investigacones Biologicas (CIB-CSIC), 28040 Madrid, Spain
*
Author to whom correspondence should be addressed.
Cells 2020, 9(2), 348; https://doi.org/10.3390/cells9020348
Received: 17 December 2019 / Revised: 31 January 2020 / Accepted: 1 February 2020 / Published: 3 February 2020
(This article belongs to the Special Issue Extracellular Matrix Remodeling 2019)
Membrane-bound proteases play a key role in biology by degrading matrix proteins or shedding adhesion receptors. MT1-MMP metalloproteinase is critical during cancer invasion, angiogenesis, and development. MT1-MMP activity is strictly regulated by internalization, recycling, autoprocessing but also through its incorporation into tetraspanin-enriched microdomains (TEMs), into invadopodia, or by its secretion on extracellular vesicles (EVs). We identified a juxtamembrane positively charged cluster responsible for the interaction of MT1-MMP with ERM (ezrin/radixin/moesin) cytoskeletal connectors in breast carcinoma cells. Linkage to ERMs regulates MT1-MMP subcellular distribution and internalization, but not its incorporation into extracellular vesicles. MT1-MMP association to ERMs and insertion into TEMs are independent phenomena, so that mutation of the ERM-binding motif in the cytoplasmic region of MT1-MMP does not preclude its association with the tetraspanin CD151, but impairs the accumulation and coalescence of CD151/MT1-MMP complexes at actin-rich structures. Conversely, gene deletion of CD151 does not impact on MT1-MMP colocalization with ERM molecules. At the plasma membrane MT1-MMP autoprocessing is severely dependent on ERM association and seems to be the dominant regulator of the enzyme collagenolytic activity. This newly characterized MT1-MMP/ERM association can thus be of relevance for tumor cell invasion.
Keywords: MT1-MMP; ERM; tetraspanin enriched-microdomains; extracellular vesicles MT1-MMP; ERM; tetraspanin enriched-microdomains; extracellular vesicles
MDPI and ACS Style

Suárez, H.; López-Martín, S.; Toribio, V.; Zamai, M.; Hernández-Riquer, M.V.; Genís, L.; Arroyo, A.G.; Yáñez-Mó, M. Regulation of MT1-MMP Activity through Its Association with ERMs. Cells 2020, 9, 348.

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