Trends in Biochemical Sciences
Research FocusMT1-MMP: an enzyme with multidimensional regulation
Section snippets
Activation and inhibition of MT1-MMP proteolytic activity
MT1-MMP consists of a signal peptide, a propeptide, a catalytic domain, linker-1 (hinge), a hemopexin-like (Hpx) domain, linker-2 (stalk), a transmembrane domain and a short cytoplasmic tail of 20 amino acids. During the secretory process, its signal peptide is removed by a signal peptidase and the propeptide by proprotein convertases so that the enzyme is expressed on the cell surface in active form.
The active enzyme is inhibited by tissue inhibitors of metalloproteinases TIMP-2, TIMP-3 and
Modulation of MT1-MMP activities by glycosylation
Recently, Wu et al. [15] have shown that MT1-MMP is O-glycosylated in its linker-1 region, and that this post-translational modification is essential for proMMP-2 activation. Glycosylation-defective mutants fail to activate proMMP-2, but retain the ability to degrade collagen I and undergo autocatalytic degradation. Thus, glycosylation appears to selectively modify only a subset of the activities of MT1-MMP. It was shown that carbohydrate-free MT1-MMP cannot bind to TIMP-2 on the cell surface
Localization, internalization and recycling of MT1-MMP
In migrating cells, MT1-MMP localizes predominantly to the lamellipodium through an interaction with CD44; this interaction, and shedding of CD44 by MT1-MMP, stimulates cell motility [21]. In addition, turnover of the enzyme on the cell surface by internalization appears to be essential for promotion of cell migration by MT1-MMP [22]. Initially, it was thought that internalization was mediated only by a clathrin-dependent pathway 22, 23. However, recent studies have demonstrated that there are
Concluding remarks
The multidimensional mechanisms of MT1-MMP regulation have begun to be unveiled, and it is amazing how precisely, and well, the enzyme is adapted to work effectively on the cell surface. Therefore, it is interesting to know how these mechanisms are integrated into the actual action of MT1-MMP and whether there is cross-talk between the mechanisms. It is plausible that such a complex regulatory system has evolved in response to the crucial roles that MT1-MMP has in various situations. Because of
Acknowledgements
We thank Hideaki Nagase for useful discussion.
References (29)
- et al.
Concanavalin A produces a matrix-degradative phenotype in human fibroblasts. Induction and endogenous activation of collagenase, 72-kDa gelatinase, and Pump-1 is accompanied by the suppression of the tissue inhibitor of matrix metalloproteinases
J. Biol. Chem.
(1990) Membrane type-matrix metalloproteinases (MT-MMP)
Curr. Top. Dev. Biol.
(2003)MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover
Cell
(1999)Membrane-type 1 matrix metalloproteinase: a key enzyme for tumor invasion
Cancer Lett.
(2003)Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins
Cell
(1998)Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix
Cell
(2003)The low density lipoprotein receptor-related protein LRP is regulated by membrane type-1 matrix metalloproteinase (MT1-MMP) proteolysis in malignant cells
J. Biol. Chem.
(2004)Oligomerization through hemopexin and cytoplasmic domains regulates the activity and turnover of membrane-type 1 matrix metalloproteinase
J. Biol. Chem.
(2002)Glycosylation broadens the substrate profile of membrane type 1 matrix metalloproteinase
J. Biol. Chem.
(2004)The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis
Cell
(2001)
TIMP-2 promotes activation of progelatinase A by membrane-type 1 matrix metalloproteinase immobilized on agarose beads
J. Biol. Chem.
Co-recycling of MT1-MMP and MT3-MMP through the trans-golgi network: identification of DKV582 as a recycling signal
J. Biol. Chem.
Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of β-catenin, and enhanced tumor cell invasion
Cancer Cell
Independent expression and cellular processing of Mr 72,000 type IV collagenase and interstitial collagenase in human tumorigenic cell lines
Cancer Res.
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