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Published online 28 May 2001. doi:10.1083/jcb.153.5.893
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© The Rockefeller University Press, 0021-9525/2001//893 $5.00
The Journal of Cell Biology, Volume 153, Number 5, , 2001 893-904

Original Article

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



Masahiro Kajitaa, Yoshifumi Itoha, Tadashige Chibaa, Hidetoshi Moria, Akiko Okadaa, Hiroaki Kinoha, and Motoharu Seikia

a Department of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
Department of Cancer Cell Research, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.81-3-5449-541481-3-5449-5255

mseiki{at}ims.u-tokyo.ac.jp

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.

Key Words: MT-MMP • metalloproteinase • motility • CD44 • invasion and metastasis

© 2001 The Rockefeller University Press

Abbreviations used in this paper: AEBSF, 4-(2-Aminoethyl)-benzenesulfonyl fluoride hydrochloride; E-64, N-[N-(L-3-Trans-carboxirane-2-carbonyl)-L-leucyl]-agmatine; ECM, extracellular matrix; FITC-HA, fluorescein-conjugated HA; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; HA, hyaluronic acid; MMP, matrix metalloproteinase; MT-MMP, membrane-type MMP; RT-PCR, reverse transcript PCR; sCD44, soluble CD44; TIMP, tissue inhibitor of metalloproteinases.


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