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

Wei Hsuan Yu, Frederick Woessner, John D. McNeish, Ivan Stamenkovic

Research output: Contribution to journalArticlepeer-review

389 Scopus citations

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.

Original languageEnglish
Pages (from-to)307-323
Number of pages17
JournalGenes and Development
Volume16
Issue number3
DOIs
StatePublished - 1 Feb 2002
Externally publishedYes

Keywords

  • CD44
  • Complex
  • ErbB4
  • HB-EGF
  • MMP-7
  • Remodeling

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