Journal
CELLS
Volume 9, Issue 2, Pages -Publisher
MDPI
DOI: 10.3390/cells9020348
Keywords
MT1-MMP; ERM; tetraspanin enriched-microdomains; extracellular vesicles
Categories
Funding
- Ministerio Espanol de Economia y Competitividad (MINECO) [BFU2014-55478-R, REDIEX. SAF2015-71231-REDT, BIO2017-86500-R]
- Fundacion Ramon Areces Ayudas a la Investigacion en Ciencias de la Vida y de la Materia, 2014
- FPI-UAM fellowship
- Ministry of Ciencia, Innovacion y Universidades
- Pro CNIC Foundation
- European Regional Development Fund (FEDER) Una manera de hacer Europa
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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.
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