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CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix

Naoko Suenaga1, Hidetoshi Mori, Yoshifumi Itoh

  • 1Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.

Oncogene
|November 24, 2004
PubMed

Insights

Membrane-type 1 matrix metalloproteinase (MT1-MMP) binding to CD44H is essential for CD44H shedding, which promotes tumor cell migration. This interaction highlights CD44H’s role in assembling MT-MMPs on cell surfaces.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Cancer Research

Background:

  • Membrane-type 1 matrix metalloproteinase (MT1-MMP) regulates the tumor microenvironment and cell migration.
  • MT1-MMP interacts with CD44H, a hyaluronan receptor, at the cell migration front.
  • MT1-MMP mediates CD44H shedding, supporting cell migration.

Purpose of the Study:

  • To investigate if MT1-MMP binding to CD44H is a prerequisite for CD44H shedding.
  • To determine the role of the hemopexin-like (HPX) domain in MT1-MMP-mediated CD44H shedding.
  • To explore the substrate specificity of MT1-MMP and related enzymes for CD44H shedding.

Main Methods:

  • Deletion mutagenesis of the HPX domain of MT1-MMP.
  • Overexpression of HPX fragments to disrupt CD44H/MT1-MMP complexes.
  • Domain swapping experiments between different MT-MMP family members.

Main Results:

  • Deletion of the HPX domain abolished MT1-MMP shedding activity.
  • Disruption of the CD44H/MT1-MMP complex inhibited CD44H shedding, indicating CD44H is the substrate.
  • Conserved HPX domain binding to CD44H across MT-MMPs, but varied shedding activity based on catalytic domains.

Conclusions:

  • MT1-MMP binding to CD44H via its HPX domain is essential for CD44H shedding.
  • CD44H serves as a substrate for MT1-MMP proteolysis.
  • CD44H may function as a scaffold for assembling various MT-MMPs on the cell surface.

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