Membrane type I-matrix metalloproteinase (MT1-MMP) is internalised by two different pathways and is recycled to the cell surface

Abstract

Membrane type 1-matrix metalloproteinase (MT1-MMP) is an integral type I transmembrane multidomain zinc-dependent endopeptidase involved in extracellular matrix remodelling in physiological as well as pathological processes. MT1-MMP participates in the regulated turnover of various extracellular matrix components as well as the activation of secreted metalloproteinases and the cleavage of various cell membrane components. MT1-MMP expression has been reported to correlate with the malignancy of various tumour types and is thought to be an important mediator of cell migration and invasion. Recently, it has been proposed that internalisation of the enzyme from the cell surface is a major short-term level of MT1-MMP regulation controlling the net amount of active enzyme present at the plasma membrane. In this paper we show that, in HT1080 fibrosarcoma cells, MT1-MMP is internalised from the cell surface and colocalises with various markers of the endocytic compartment. Interestingly, we observed that in these cells, internalisation occurs by a combination of both clathrin-mediated and -independent pathways, most probably involving caveolae. In addition, internalised MT1-MMP is recycled to the cell surface, which could, in addition to downregulation of the enzymatic activity, represent a rapid response mechanism used by the cell for relocalising active MT1-MMP at the leading edge during migration.

Hic-5 mediates endothelial sprout initiation by regulating a key surface metalloproteinase

“…Once activated, MT1-MMP translocates to the surface where it can cleave ECM proteins (Remacle et al, 2006). In addition, active MT1-MMP undergoes endocytosis and can be recycled from the cell surface to early and late endosomes (Remacle et al, 2003). The activity assays performed were conducted on total cell lysates and cannot distinguish between surface-associated and internalized MT1-MMP, explaining why no gross differences were observed in MT1-MMP activity.…”

Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation

“…Exposure to concavalin A, a potent activator of MMP-2, can induce translocation of MT1-MMP from trans-Golgi network/endosomes to the plasma membrane (Zucker et al, 2002). Furthermore, the dynamic turnover of MT1-MMP by internalization in clathrin-coated vesicles, endosome targeting and degradation processes have all been shown to be key for proper regulation of enzyme function at the cell membrane during cell migration and invasion (Jiang et al, 2001;Remacle et al, 2003;Takino et al, 2003;Wang et al, 2004). Interestingly, Deschamps et al (2005) showed in a model of ischemia/reperfusion that MT1-MMP was translocated to the cell membrane during the reoxygenation period, indicating that anoxia and/or reactive oxygen stress contributes to MT1-MMP trafficking.…”

“…MT1-MMP activation pathways have been demonstrated by concavalin A stimulation, cytokine treatments and chemokine exposure (Yu et al, 1997;Sameshima et al, 2000;Bartolome et al, 2004). Proper localization and trafficking of MT1-MMP to the plasma membrane are also very important mechanisms of functional regulation (Mori et al, 2002;Remacle et al, 2003;Rozanov et al, 2004;Wang et al, 2004). Since it is possible that numerous factors control MT1-MMP expression and function, we examined whether hypoxia, a critical tumor microenvironmental stress, could influence the ability of breast cancer cells to activate MMP-dependent invasive mechanisms.…”

Furin regulates the intracellular activation and the uptake rate of cell surface-associated MT1-MMP

“…Membrane type-1 matrix metalloproteinase is regulated at the transcriptional and post-translational levels by the coordinated mechanisms of exocytosis, endocytosis and recycling, activation of the latent MT1-MMP proenzyme by furin-like proprotein convertase (PCs), autolytic degradation, and by inhibition by tissue inhibitors of MMPs (TIMPs) (Remacle et al, 2003;Deryugina et al, 2004;Osenkowski et al, 2004;Rozanov et al, 2004;Wang et al, 2004a, b). To exercise its functional activity, MT1-MMP requires removal of the N-terminal prodomain sequence.…”