Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes |
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| Authors: | Surabhi Dangi-Garimella Amanda J. Redig Mario A. Shields Mohammed A. Siddiqui Hidayatullah G. Munshi |
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| Affiliation: | From the ‡Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University.;§The Jesse Brown Veterans Affairs Medical Center, and ;¶The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611 |
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| Abstract: | Membrane type 1-matrix metalloproteinase (MT1-MMP, MMP14), which is associated with extracellular matrix (ECM) breakdown in squamous cell carcinoma (SCC), promotes tumor formation and epithelial-mesenchymal transition. However, in this report we demonstrate that MT1-MMP, by cleaving the underlying ECM, causes cellular aggregation of keratinocytes and SCC cells. Treatment with an MMP inhibitor abrogated MT1-MMP-induced phenotypic changes, but decreasing E-cadherin expression did not affect MT1-MMP-induced cellular aggregation. As ROCK1/2 can regulate cell-cell and cell-ECM interaction, we examined its role in mediating MT1-MMP-induced phenotypic changes. Blocking ROCK1/2 expression or activity abrogated the cellular aggregation resulting from MT1-MMP expression. Additionally, blocking Rho and non-muscle myosin attenuated MT1-MMP-induced phenotypic changes. Moreover, SCC cells expressing only the catalytically active MT1-MMP protein demonstrated increased cellular aggregation and increased myosin II activity in vivo when injected subcutaneously into nude mice. Together, these results demonstrate that expression of MT1-MMP may be anti-tumorigenic in keratinocytes by promoting cellular aggregation. |
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| Keywords: | Cell Adhesion Cell-Cell Interaction Collagen Extracellular Matrix Proteins Matrix Metalloproteinase Rho Skin MT1-MMP Keratinocyte |
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