Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration.
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.
Kajita
M
M
Department of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.
Itoh
Y
Y
Chiba
T
T
Mori
H
H
Okada
A
A
Kinoh
H
H
Seiki
M
M
D000595:Amino Acid Sequence; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008024:Ligands; D053511:Matrix Metalloproteinase 14; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010940:Plant Proteins / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017384:Sequence Deletion / Q000235:genetics; D012995:Solubility; D013450:Sulfones / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology; D014361:Trypsin Inhibitors; D014407:Tumor Cells, Cultured; D000516:alpha-Amylases / Q000037:antagonists & inhibitors
D018960:Hyaluronan Receptors; D008024:Ligands; C507096:Mmp14 protein, mouse; D010940:Plant Proteins; D013450:Sulfones; D013876:Thiophenes; D019715:Tissue Inhibitor of Metalloproteinase-1; D014361:Trypsin Inhibitors; D019716:Tissue Inhibitor of Metalloproteinase-2; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D010649:Phenylalanine; C080985:batimastat; D000516:alpha-Amylases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053511:Matrix Metalloproteinase 14; D007930:Leucine; C024974:E 64