Abstract
Membrane type-1 matrix metalloproteinase (MT1-MMP) degrades the extracellular matrix, initiates the activation pathway of soluble MMPs and regulates the functionality of cell adhesion signaling receptors, thus playing an important role in many cell functions. Intracellular transport mechanisms, currently incompletely understood, regulate the presentation of MT1-MMP at the cell surface. We have focused our efforts on identifying these mechanisms. To understand the transport of MT1-MMP across the cell, we used substitution and deletion mutants, the trafficking of which was examined using antibody uptake and Chariot delivery experiments. Our experiments have demonstrated that the microtubulin cytoskeleton and the centrosomes (the microtubulin cytoskeleton-organizing centers) are essential for the trafficking and the internalization of MT1-MMP. We determined that after reaching the plasma membrane, MT1-MMP is internalized in the Rab-4-positive recycling endosomes and the Rab-11-positive pericentrosomal recycling endosomes. The microtubular trafficking causes the protease to accumulate in the pericentrosomal region of the cell. We believe that the presence of the transmembrane domain is required for the microtubular vesicular trafficking of MT1-MMP because the soluble mutants are not presented at the cell surface and they are not delivered to the centrosomes. The observed transport mechanisms provide a vehicle for the intracellular targets and, accordingly, for an intracellular cleavage function of MT1-MMP in malignant cells, which routinely overexpress this protease.
Highlights
Membrane type-1 matrix metalloproteinase (MT1-MMP) is a prototypic member of a membrane-anchored MMP subfamily (Egeblad and Werb, 2002; Holmbeck et al, 2004)
MT1-MMP degrades a broad spectrum of the extracellular matrix (ECM) substrata including fibronectin, vitronectin, proteoglycan, collagen and laminin (d’Ortho et al, 1997; Ohuchi et al, 1997; Osenkowski et al, 2004), initiates the activation cascade of soluble MMPs (Cowell et al, 1998; Knauper et al, 1996; Sato et al, 1994; Toth et al, 2003), and is directly involved in the cleavage of cell surface receptors including tissue transglutaminase (Belkin et al, 2001), CD44 (Mori et al, 2002), pro-␣v integrin (Deryugina et al, 2002a), syndecan-1 (Endo et al, 2003), low-density lipoprotein receptor-related protein (Rozanov et al, 2004b) and -glycan (Velasco-Loyden et al, 2004)
We have demonstrated that MT1-MMP either naturally expressed by the cells or the overexpressed recombinant constructs were trafficked to the pericentrosomal compartment and, as a result, accumulated in the centrosomes (Golubkov et al, 2005)
Summary
MT1-MMP is a prototypic member of a membrane-anchored MMP subfamily (Egeblad and Werb, 2002; Holmbeck et al, 2004) This subfamily consists of the six individual enzymes that share a significant peptide sequence homology. MT1-MMP degrades a broad spectrum of the extracellular matrix (ECM) substrata including fibronectin, vitronectin, proteoglycan, collagen and laminin (d’Ortho et al, 1997; Ohuchi et al, 1997; Osenkowski et al, 2004), initiates the activation cascade of soluble MMPs (Cowell et al, 1998; Knauper et al, 1996; Sato et al, 1994; Toth et al, 2003), and is directly involved in the cleavage of cell surface receptors including tissue transglutaminase (Belkin et al, 2001), CD44
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