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A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor.

The ectodomains of many proteins located at the cell surface are shed upon cell stimulation. One such protein is the heparin-binding EGF-like growth factor (HB-EGF) that exists in a membrane-anchored form which is converted to a soluble form upon cell stimulation with TPA, an activator of protein kinase C (PKC). We show that PKCdelta binds in vivo and in vitro to the cytoplasmic domain of MDC9/meltrin-gamma/ADAM9, a member of the metalloprotease-disintegrin family. Furthermore, the presence of constitutively active PKCdelta or MDC9 results in the shedding of the ectodomain of proHB-EGF, whereas MDC9 mutants lacking the metalloprotease domain, as well as kinase-negative PKCdelta, suppress the TPA-induced shedding of the ectodomain. These results suggest that MDC9 and PKCdelta are involved in the stimulus-coupled shedding of the proHB-EGF ectodomain.

Pubmed ID: 9857183


  • Izumi Y
  • Hirata M
  • Hasuwa H
  • Iwamoto R
  • Umata T
  • Miyado K
  • Tamai Y
  • Kurisaki T
  • Sehara-Fujisawa A
  • Ohno S
  • Mekada E


The EMBO journal

Publication Data

December 15, 1998

Associated Grants


Mesh Terms

  • ADAM Proteins
  • Catalytic Domain
  • Disintegrins
  • Epidermal Growth Factor
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Isoenzymes
  • Membrane Proteins
  • Metalloendopeptidases
  • Muscle Proteins
  • Mutation
  • Protein Binding
  • Protein Kinase C
  • Protein Kinase C-delta
  • Protein Precursors
  • Protein Processing, Post-Translational
  • Recombinant Proteins
  • Solubility
  • Tetradecanoylphorbol Acetate