title: 3-D collagen-dependent cell surface expression of MT1-MMP and MMP-2 activation regardless of integrin β1 function and matrix stiffness.
abstract: Matrix metalloproteinases (MMPs) play roles in spatially dynamic processes, including morphogenesis, wound healing, and tumor invasion. Three-dimensional (3-D) type I collagen stimulates cellular activation of MMP-2, however, the mechanisms underlying this are controversial. The present study investigated mechanisms for 3-D collagen-induced MMP-2 activation in highly invasive human malignant mesothelioma cells. MMP-2 was effectively activated by cells cultured in 3-D collagen but not in 2-D collagen, whereas MMP-2 activation was not regulated by the flexibility of collagen. The 3-D collagen did not largely increase the gene expression of MMP-2 and MT1-MMP. However, MT1-MMP exposed to the cell surface was much increased by 3-D collagen, and loss of MT1-MMP abolished MMP-2 activation in response to 3-D collagen. MT1-MMP and integrin β1 translocated to pericellular regions interacting with collagen-coated microbeads, however their localization was different. Importantly, inhibition of integrin β1 function and expression did not affect 3-D collagen-induced cell surface localization of MT1-MMP and MMP-2 activation. Our results strongly suggest that 3-D collagen scaffolding may provide opportunity for direct and multivalent interaction with MT1-MMP, by which MMP-2 activation occur in abundant cell surface MT1-MMP-dependent manner, rather than a manner regulated by matrix stiffness and integrin β1 function.
authors.affiliation: Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Sakai
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Takafumi
authors.initials: T
authors.lastname: Imizu
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
mesh_terms: D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology*; D024042:Collagen Type I / Q000737:chemistry*; D004548:Elasticity; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000201:enzymology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D011487:Protein Conformation; D054457:Tissue Scaffolds
chemical_list: D024042:Collagen Type I; D019012:Integrin beta1; D020778:Matrix Metalloproteinase 2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14