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  • The EMBO Journal (2002) 21, 3949 - 3959
  • doi:10.1093/emboj/cdf411

CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain

Hidetoshi Mori1, Taizo Tomari1, Naohiko Koshikawa1, Masahiro Kajita1, Yoshifumi Itoh2, Hiroshi Sato3, Hideaki Tojo4, Ikuo Yana1 and Motoharu Seiki1

  1. Department of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
  2. Department of Matrix Biology, Kennedy Institute of Rheumatology, Imperial College, Faculty of Medicine, Hammersmith, London, UK
  3. Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
  4. Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan

Correspondence to:

Motoharu Seiki, E-mail: mseiki@ims.u-tokyo.ac.jp

Received 20 February 2002; Accepted 13 June 2002; Revised 13 June 2002

Membrane-type 1 matrix metalloproteinase (MT1- MMP) localizes at the front of migrating cells and degrades the extracellular matrix barrier during cancer invasion. However, it is poorly understood how the polarized distribution of MT1-MMP at the migration front is regulated. Here, we demonstrate that MT1-MMP forms a complex with CD44H via the hemopexin-like (PEX) domain. A mutant MT1-MMP lacking the PEX domain failed to bind CD44H and did not localize at the lamellipodia. The cytoplasmic tail of CD44H, which comprises interfaces that associate with the actin cytoskeleton, was important for its localization at lamellipodia. Overexpression of a CD44H mutant lacking the cytoplasmic tail also prevented MT1-MMP from localizing at the lamellipodia. Modulation of F-actin with cytochalasin D revealed that both CD44H and MT1-MMP co-localize closely with the actin cytoskeleton, dependent on the cytoplasmic tail of CD44H. Thus, CD44H appears to act as a linker that connects MT1-MMP to the actin cytoskeleton and to play a role in directing MT1-MMP to the migration front. The PEX domain of MT1-MMP was indispensable in promoting cell migration and CD44H shedding.

  • Keywords:

    • actin,
    • CD44,
    • invasion,
    • lamellipodium,
    • MT1-MMP