Tumor necrosis factor-alpha converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability

J Biol Chem. 2002 Apr 12;277(15):12838-45. doi: 10.1074/jbc.M112050200. Epub 2002 Jan 31.

Abstract

We previously implicated tumor necrosis factor-alpha converting enzyme (TACE/ADAM17) in the processing of the integral membrane precursor to soluble transforming growth factor-alpha (TGF-alpha), pro-TGF-alpha. Here we examined TGF-alpha processing in a physiologically relevant cell model, primary keratinocytes, showing that cells lacking TACE activity shed dramatically less TGF-alpha as compared with wild-type cultures and that TGF-alpha cleavage was partially restored by infection of TACE-deficient cells with TACE-encoding adenovirus. Moreover, cotransfection of TACE-deficient fibroblasts with pro-TGF-alpha and TACE cDNAs increased shedding of mature TGF-alpha with concomitant conversion of cell-associated pro-TGF-alpha to a processed form. Purified TACE accurately cleaved pro-TGF-alpha in vitro at the N-terminal site and also cleaved a soluble form of pro-TGF-alpha containing only the ectodomain at the C-terminal site. In vitro, TACE accurately cleaved peptides corresponding to cleavage sites of several epidermal growth factor (EGF) family members, and transfection of TACE into TACE-deficient cells increased the shedding of amphiregulin and heparin-binding EGF (HB-EGF) proteins. Consistent with the hypothesis that TACE regulates EGF receptor (EGFR) ligand availability in vivo, mice heterozygous for Tace and homozygous for an impaired EGFR allele (wa-2) were born with open eyes significantly more often than Tace(+/+)Egfr(wa-2)(/)(wa-2) counterparts. Collectively, these data support a broad role for TACE in the regulated shedding of EGFR ligands.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ADAM Proteins
  • ADAM17 Protein
  • Alleles
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • DNA Primers
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Ligands
  • Metalloendopeptidases / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Phenotype
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Transforming Growth Factor alpha / physiology

Substances

  • DNA Primers
  • Ligands
  • Transforming Growth Factor alpha
  • ErbB Receptors
  • ADAM Proteins
  • Metalloendopeptidases
  • ADAM17 Protein
  • Adam17 protein, mouse