CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling

  1. Wei-Hsuan Yu,
  2. J. Frederick Woessner, Jr.1,
  3. John D. McNeish2, and
  4. Ivan Stamenkovic3
  1. Molecular Pathology Unit, Massachusetts General Hospital, and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02129, USA; 1Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, Florida 33101, USA; 2Pfizer Central Research, Groton, Connecticut 06340, USA

Abstract

CD44 is a facultative proteoglycan implicated in cell adhesion and trafficking, as well as in tumor survival and progression. We demonstrate here that CD44 heparan sulfate proteoglycan (CD44HSPG) recruits proteolytically active matrix metalloproteinase 7 (matrilysin, MMP-7) and heparin-binding epidermal growth factor precursor (pro-HB-EGF) to form a complex on the surface of tumor cell lines, postpartum uterine and lactating mammary gland epithelium, and uterine smooth muscle. The HB-EGF precursor within this complex is processed by MMP-7, and the resulting mature HB-EGF engages and activates its receptor, ErbB4, leading to, among other events, cell survival. In CD44−/− mice, postpartum uterine involution is accelerated and maintenance of lactation is impaired. In both uterine and mammary epithelia of these mice, MMP-7 localization is altered and pro-HB-EGF processing as well as ErbB4 activation are decreased. Our observations provide a mechanism for the assembly and function of a cell surface complex composed of CD44HSPG, MMP 7, HB-EGF, and ErbB4 that may play an important role in the regulation of physiological tissue remodeling.

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Footnotes

  • 3 Corresponding author.

  • E-MAIL stamenko{at}helix.mgh.harvard.edu; FAX (617)726-5684.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.925702.

    • Received July 3, 2001.
    • Accepted December 10, 2001.
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