The cytoplasmic domain of MT1-MMP is dispensable for migration augmentation but necessary to mediate viability of MCF-7 breast cancer cells |
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Authors: | Mario A. Cepeda Jacob JH. Pelling Caitlin L. Evered Hon S. Leong Sashko Damjanovski |
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Affiliation: | 1. Department of Biology, Faculty of Science, University of Western Ontario, London, ON, Canada;2. Department of Surgery, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada;3. Translational Prostate Cancer Research Laboratory, Lawson Health Research Institute, London, ON, Canada;4. Associate Scientist, Lawson Health Research Institute, London, ON, Canada |
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Abstract: | Membrane-type-1 Matrix Metalloproteinase (MT1-MMP) is a multifunctional protease that regulates ECM degradation, proMMP-2 activation, and varied cellular processes including migration and viability. MT1-MMP is believed to be a central mediator of tumourigenesis whose role is dictated by its functionally distinct protein domains. Both the localization and signal transduction capabilities of MT1-MMP are dependent on its cytoplasmic domain, exemplifying diverse regulatory functions. To further our understanding of the multifunctional contributions of MT1-MMP to cellular processes, we overexpressed cytoplasmic domain altered constructs in MCF-7 breast cancer cells and analyzed migration and viability in 2D culture conditions, morphology in 3D Matrigel culture, and tumorigenic ability in vivo. We found that the cytoplasmic domain was not needed for MT1-MMP mediated migration promotion, but was necessary to maintain viability during serum depravation in 2D culture. Similarly, during 3D Matrigel culture the cytoplasmic domain of MT1-MMP was not needed to initiate a protrusive phenotype, but was necessary to prevent colony blebbing when cells were serum deprived. We also tested in vivo tumorigenic potential to show that cells expressing cytoplasmic domain altered constructs demonstrated a reduced ability to vascularize tumours. These results suggest that the cytoplasmic domain regulates MT1-MMP function in a manner required for cell survival, but is dispensable for cell migration. |
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Keywords: | BM Basement Membrane CAM ChorioAllantoic Membrane CD Cytoplasmic Domain CD-44 Cluster of Differentiation 44 CM Conditioned Media ECM Extracellular Matrix ERK Extracellular Regulated Kinase F-actin Filamentous Actin FIH Factor Inhibiting HIF FL Full-Length HIF Hypoxia Inducible Factor MAPK Mitogen Activated Protein Kinase MMPs Matrix Metalloproteinases MMPi MMP inhibitor MT1/2-MMP Membrane Type 1/2 Matrix Metalloproteinase PH3 Phospho-Histone 3 TIMP-2 Tissue Inhibitor of Metalloproteinases 2 Zs ZsGreen MT1-MMP MMP-14 Cell migration Cell survival MCF-7 3D culture |
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