gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase

Science. 2001 Dec 7;294(5549):2179-81. doi: 10.1126/science.1065412. Epub 2001 Oct 25.

Abstract

ErbB-4 is a transmembrane receptor tyrosine kinase that regulates cell proliferation and differentiation. After binding of its ligand heregulin (HRG) or activation of protein kinase C (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA), the ErbB-4 ectodomain is cleaved by a metalloprotease. We now report a subsequent cleavage by gamma-secretase that releases the ErbB-4 intracellular domain from the membrane and facilitates its translocation to the nucleus. gamma-Secretase cleavage was prevented by chemical inhibitors or a dominant negative presenilin. Inhibition of gamma-secretase also prevented growth inhibition by HRG. gamma-Secretase cleavage of ErbB-4 may represent another mechanism for receptor tyrosine kinase-mediated signaling.

Publication types

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

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases
  • Animals
  • Aspartic Acid Endopeptidases
  • COS Cells
  • Carbamates / pharmacology
  • Cell Division / drug effects
  • Cell Line
  • Cell Membrane / metabolism
  • Cell Nucleus / metabolism*
  • Cytoplasm / metabolism
  • Dipeptides / pharmacology
  • Endopeptidases / metabolism*
  • ErbB Receptors / chemistry
  • ErbB Receptors / metabolism*
  • Fatty Acids, Unsaturated / pharmacology
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Metalloendopeptidases / metabolism
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Neuregulin-1 / pharmacology
  • Presenilin-1
  • Protease Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Receptor, ErbB-4
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcriptional Activation
  • Tumor Cells, Cultured

Substances

  • Carbamates
  • Dipeptides
  • Fatty Acids, Unsaturated
  • L 685458
  • Membrane Proteins
  • Neuregulin-1
  • PSEN1 protein, human
  • Presenilin-1
  • Protease Inhibitors
  • Recombinant Fusion Proteins
  • ERBB4 protein, human
  • ErbB Receptors
  • Erbb4 protein, mouse
  • Receptor, ErbB-4
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse
  • Metalloendopeptidases
  • Tetradecanoylphorbol Acetate
  • leptomycin B