Regulation of MT1-MMP Activity through Its Association with ERMs

• Published in: Cells (Basel, Switzerland) Switzerland), 2020-02, Vol.9 (2), p.348
• Main Authors: Suárez, Henar, López-Martín, Soraya, Toribio, Victor, Zamai, Moreno, Hernández-Riquer, María Victoria, Genís, Laura, Arroyo, Alicia García, Yáñez-Mó, María
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Binding Sites; Cytoskeletal Proteins - metabolism; erm; extracellular vesicles; Humans; Matrix Metalloproteinase 14 - chemistry; Matrix Metalloproteinase 14 - genetics; Matrix Metalloproteinase 14 - metabolism; MCF-7 Cells; Membrane Microdomains - metabolism; Membrane Proteins - metabolism; Microfilament Proteins - metabolism; mt1-mmp; Mutation - genetics; Protein Binding; Protein Domains; Subcellular Fractions - metabolism; Tetraspanin 24 - metabolism; tetraspanin enriched-microdomains
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells9020348

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.