Molecular mechanisms of MT1-MMP regulation during cellular invasion
A. ECM-dependent regulation
MT1-MMP gene and its function can be upregulated by cell attachment to a collagen matrix in different cell types including fibroblasts, epithelial cells, and cancer cells. It deems natural for invading cells to upregulate MT1-MMP upon recognising its substrate, collagen, however, the mechanism is not understood. Since MT1-MMP cannot be induced by cytokines and growth factors easily, ECM-induced gene regulation may be a key mechanism of MT1-MMP regulation in vivo.
b. Localisation to the leading edge of invading cells
A key regulatory event during cell migration is to localise MT1-MMP at the leading edge of the cells. MT1-MMP localises at different forms of motility associated membrane structures including lamellipodia, filopodia and invadopodia. Understanding these mechanisms would identify potential therapeutic target for the diseases.
Movie 1. MT1-RFP-expressing HeLa cells migrating in 3D collagen gel. Control HeLa cells were unable to migrate in 3D collagen gel for 14h despite extension of pseudopods. On the other hand, cells expressing RFP-tagged MT1-MMP are able to migrate actively. Note that red signals (MT1-MMP) accumulate at extending membrane structures at leading edge of cells, where it is likely that degradation of collagen matrix takes place.
c. Cell surface molecular arrangement
We found that MT1-MMP forms homodimer through its hemopexin (Hpx) domain, and this is a crucial step to degrade fibrillar collagen on the cell surface. By analysing crystal structure of the Hpx domain, we identified the dimer interface (Fig 1), and dissociating the dimer significantly inhibited cell surface collagenolytic activity and cell invasion. MT1-MMP also form complexes with different membrane proteins including CD44, ADAM12, integrins and so on. Understanding how these complex formations affect MT1-MMP functions and cellular invasion may lead into discovery of novel mechanisms of cellular invasion.
Image: Model of MT1-MMP dimer on the cell surface MT1-MMP forms homodimer through Hpx and transmembrane domains to become a functional enzyme.