Membrane-Type 1 Matrix Metalloproteinase Cleaves Cd44 and Promotes Cell Migration

By M. Kajita, Y. Itoh, Tadashige Chiba, H. Mori, A. Okada, H. Kinoh, M. Seiki. Journal of Cell Biology, 2001

780 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Immunology and Allergy, Oncology

View Paper: https://www.semanticscholar.org/paper/9300286936991f755b4376b634fe7e4a698ffc69

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Citations in the corpus

Metalloproteinases and Wound Healing (2015, background): “In addition to controlling proliferation, MT1-MMP also accelerates epithelial cell migration in vitro through the cleavage of syndecan-1, CD44, and laminin-332.(14,52,53)”
Hyaluronan: from extracellular glue to pericellular cue (2004, background): “, which results in increased CD44 shedding and cancer-cell migratio”
Cellular and molecular mechanisms in kidney fibrosis. (2014, positive): “TIMPs, on the other hand, have critical roles in regulating cell activity and survival (86–89).”
Matrix metalloproteinases and the regulation of tissue remodelling (2007, background): “Cleavage of other membrane proteins, such as E-cadherin and CD44, results in the release of specific, biologically active fragments of their extracellular domains, and in increased invasive behaviou”
New functions for the matrix metalloproteinases in cancer progression (2002, background): “cgi?l=999">E-cadherin and CD44 results in the release of fragments of the extracellular domains and in increased invasive behaviou”
Extracellular matrix remodelling: the role of matrix metalloproteinases (2003, background): “E-cadherin is cleaved by MMP-3 and -7 [56] whereas the extracellular domain of the hyaluronan (HA) receptor CD44 is cleaved by MMP-14 [57].”
Matrix MetalloProteinases (MMPs) andTissue Inhibitors of MetalloProteinases (TIMPs): positive and negative regulators intumor cell adhesion (2010, neutral): “Finally, the hyaluronan receptor CD44 is also cleaved by MT1-MMP releasing extracellular fragments that increase invasion of pancreatic and breast cancer cells [78].”