Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) Ubiquitination at Lys581 Increases Cellular Invasion through Type I Collagen

Abstract

Background: MT1-MMP is a membrane-anchored matrix metalloproteinase involved in pericellular proteolysis and invasion. Results: MT1-MMP is monoubiquitinated intracellularly at Lys 581 , modulating intracellular trafficking and cellular invasion. Conclusion: Regulation of the activity of MT1-MMP by monoubiquitination emphasizes the importance of its intracellular domain during MT1-MMP-driven cellular invasion. Significance: Given the key role MT1-MMP plays in pathological conditions, a better understanding of the regulation of MT1-MMP is essential for therapeutic intervention.

p63 drives invasion in keratinocytes expressing HPV16 E6/E7 genes through regulation of Src-FAK signalling

“…Recent studies in gastric carcinoma, breast cancer and chondrosarcoma cells exemplify the Src-FAK-mediated regulation of MMPs like MMP9 and MMP13 via activation of AP-1 transcription factors like c-Jun and c-Fos [36, 37]. In addition, active Src is known to directly phosphorylate MMP14 at Tyr 573 and promote its mono-ubiquitination at Lys 581 , which enhances its cytoplasmic trafficking and increases cellular migration and invasion through collagen-I matrix [38, 39]. In breast cancers, activated Src-FAK signalling enriches the cell surface with active MMP14 to promote metastasis, thus indicating posttranslational modification and membrane localisation are essential in MMP14-mediated invasion [40, 41].…”

Epigallocatechin Gallate Targeting of Membrane Type 1 Matrix Metalloproteinase-mediated Src and Janus Kinase/Signal Transducers and Activators of Transcription 3 Signaling Inhibits Transcription of Colony-stimulating Factors 2 and 3 in Mesenchymal Stromal Cells

“…Interestingly, MT1-MMP-mediated phosphorylation of Src is also believed to trigger a positive feedback loop resulting in increased MT1-MMP phosphorylation which may also regulate MT1-MMP ubiquitination at Lys 581 and lead to increased cell migration (39). Src-mediated phosphorylation was, in fact, shown to occur within the Tyr 573 of the intracellular domain of MT1-MMP where it was suggested to affect endothelial cell migration (40).…”

MMP-14 in skeletal muscle repair

“…Caveolin-1 (residing in lipid rafts) is activated by Src kinase, mediates phosphorylation of Tyr 573 and facilitates endocytosis of MMP-14 into early endosomes (Cavallo-Medved et al 2009;Galvez et al 2004). The DKV 582 (Asp-Lys-Val 582 ) sequence at the end of the cytoplasmic tail (including Lys 581 that has been tagged with a single ubiquitin) serves as a recognition motif that allows extraction of MMP-14 from the early endosomes and its return to the plasma membrane for continued catalytic activity (Eisenach et al 2012) (Fig. 1b).…”