Abstract
Migratory cells including invasive tumor cells frequently express CD44, a major receptor for hyaluronan and membrane-type 1 matrix metalloproteinase (MT1-MMP) that degrades extracellular matrix at the pericellular region. In this study, we demonstrate that MT1-MMP acts as a processing enzyme for CD44H, releasing it into the medium as a soluble 70-kD fragment. Furthermore, this processing event stimulates cell motility; however, expression of either CD44H or MT1-MMP alone did not stimulate cell motility. Coexpression of MT1-MMP and mutant CD44H lacking the MT1-MMP-processing site did not result in shedding and did not promote cell migration, suggesting that the processing of CD44H by MT1-MMP is critical in the migratory stimulation. Moreover, expression of the mutant CD44H inhibited the cell migration promoted by CD44H and MT1-MMP in a dominant-negative manner. The pancreatic tumor cell line, MIA PaCa-2, was found to shed the 70-kD CD44H fragment in a MT1-MMP-dependent manner. Expression of the mutant CD44H in the cells as well as MMP inhibitor treatment effectively inhibited the migration, suggesting that MIA PaCa-2 cells indeed use the CD44H and MT1-MMP as migratory devices. These findings revealed a novel interaction of the two molecules that have each been implicated in tumor cell migration and invasion.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Cell Movement* / drug effects
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Cell Size / drug effects
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Extracellular Matrix / drug effects
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Extracellular Matrix / enzymology
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Extracellular Matrix / metabolism
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Genes, Dominant / genetics
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Humans
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Hyaluronan Receptors / chemistry
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / metabolism*
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Leucine / analogs & derivatives*
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Leucine / pharmacology
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Ligands
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Matrix Metalloproteinase 14
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Matrix Metalloproteinases, Membrane-Associated
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Metalloendopeptidases / antagonists & inhibitors
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Metalloendopeptidases / genetics
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Metalloendopeptidases / metabolism*
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Mice
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Molecular Sequence Data
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Neoplasm Invasiveness
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Pancreatic Neoplasms / enzymology
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Phenylalanine / analogs & derivatives*
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Phenylalanine / pharmacology
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Plant Proteins / pharmacology
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Protein Processing, Post-Translational / drug effects
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Sequence Deletion / genetics
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Solubility
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Sulfones / pharmacology
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Thiophenes / pharmacology
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Tissue Inhibitor of Metalloproteinase-1 / pharmacology
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Tissue Inhibitor of Metalloproteinase-2 / pharmacology
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Trypsin Inhibitors
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Tumor Cells, Cultured
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alpha-Amylases / antagonists & inhibitors
Substances
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Hyaluronan Receptors
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Ligands
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Mmp14 protein, mouse
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Plant Proteins
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Sulfones
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Thiophenes
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Tissue Inhibitor of Metalloproteinase-1
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Trypsin Inhibitors
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Tissue Inhibitor of Metalloproteinase-2
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4-(2-aminoethyl)benzenesulfonylfluoride
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Phenylalanine
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batimastat
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alpha-Amylases
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Matrix Metalloproteinases, Membrane-Associated
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Metalloendopeptidases
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Matrix Metalloproteinase 14
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Leucine
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E 64