N-arginine dibasic convertase is a specific receptor for heparin-binding EGF-like growth factor that mediates cell migration

Authors

  • Eiichiro Nishi,

    1. Department of Surgical Research, Children's Hospital and Harvard Medical School, Boston, MA, USA
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  • Annik Prat,

    1. Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
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  • Véronique Hospital,

    1. Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
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  • Klaus Elenius,

    1. Department of Surgical Research, Children's Hospital and Harvard Medical School, Boston, MA, USA
    2. Present address: Medicity Research Laboratories and the Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland
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  • Michael Klagsbrun

    Corresponding author
    1. Department of Surgical Research, Children's Hospital and Harvard Medical School, Boston, MA, USA
    2. Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA, USA
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Abstract

Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a mitogen and chemotactic factor, binds to two receptor tyrosine kinases, erbB1 and erbB4. Now we demonstrate that HB-EGF also binds to a novel 140 kDa receptor on MDA-MB 453 cells. Purification of this receptor showed it to be identical to N-arginine dibasic convertase (NRDc), a metalloendopeptidase of the M16 family. Binding to cell surface NRDc and NRDc in solution was highly specific for HB-EGF among EGF family members. When overexpressed in cells, NRDc enhanced their migration in response to HB-EGF but not to EGF. Conversely, inhibition of endogenous NRDc expression in cells by antisense morpholino oligonucleotides inhibited HB-EGF-induced cell migration. Anti-erbB1 neutralizing antibodies completely abrogated the ability of NRDc to enhance HB-EGF-dependent migration, demonstrating that this NRDc activity was dependent on erbB1 signaling. Although NRDc is a metalloproteinase, enzymatic activity was not required for HB-EGF binding or enhancement of cell migration; neither did NRDc cleave HB-EGF. Together, these results suggest that NRDc is a novel specific receptor for HB-EGF that modulates HB-EGF-induced cell migration via erbB1.

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