Rho-ROCK-myosin signaling mediates membrane type 1 matrix metalloproteinase-induced cellular aggregation of keratinocytes.
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.
Dangi-Garimella
Surabhi
S
Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Redig
Amanda J
AJ
Shields
Mario A
MA
Siddiqui
Mohammed A
MA
Munshi
Hidayatullah G
HG
D000818:Animals; D055162:Biocatalysis; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D002449:Cell Aggregation; D045744:Cell Line, Tumor; D048429:Cell Size; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D024462:Myosin Type II / Q000378:metabolism; D009218:Myosins / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*
D054460:rho-Associated Kinases; D053511:Matrix Metalloproteinase 14; D024462:Myosin Type II; D009218:Myosins; D020741:rho GTP-Binding Proteins