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  • The EMBO Journal (2001) 20, 3342 - 3350
  • doi:10.1093/emboj/20.13.3342

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

Eiichiro Nishi1, Annik Prat2, Véronique Hospital2, Klaus Elenius1,3 and Michael Klagsbrun1,4

  1. Department of Surgical Research, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA
  2. Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec, H2W 1R7, Canada
  3. Present address: Medicity Research Laboratories and the Department of Medical Biochemistry and Molecular Biology, University of Turku, FIN-20520 Turku, Finland
  4. Department of Pathology, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA

Correspondence to:

Michael Klagsbrun, E-mail: michael.klagsbrun@tch.harvard.edu

Received 28 September 2000; Accepted 15 May 2001; Revised 12 April 2001

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.

  • Keywords:

    • cell motility,
    • EGF family,
    • EGF receptors,
    • metalloendopeptidases