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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Active Transport, Cell Nucleus
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Amino Acid Sequence
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Amyloid Precursor Protein Secretases
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Animals
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Aspartic Acid Endopeptidases
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COS Cells
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Carbamates / pharmacology
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Cell Division / drug effects
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Cell Line
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Cell Membrane / metabolism
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Cell Nucleus / metabolism*
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Cytoplasm / metabolism
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Dipeptides / pharmacology
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Endopeptidases / metabolism*
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ErbB Receptors / chemistry
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ErbB Receptors / metabolism*
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Fatty Acids, Unsaturated / pharmacology
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Humans
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Metalloendopeptidases / metabolism
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Mice
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Molecular Sequence Data
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Mutation
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Neuregulin-1 / pharmacology
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Presenilin-1
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Protease Inhibitors / pharmacology
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Protein Structure, Tertiary
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Receptor, ErbB-4
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Recombinant Fusion Proteins / metabolism
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Signal Transduction
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Tetradecanoylphorbol Acetate / pharmacology
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Transcriptional Activation
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Tumor Cells, Cultured
Substances
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Carbamates
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Dipeptides
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Fatty Acids, Unsaturated
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L 685458
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Membrane Proteins
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Neuregulin-1
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PSEN1 protein, human
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Presenilin-1
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Protease Inhibitors
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Recombinant Fusion Proteins
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ERBB4 protein, human
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ErbB Receptors
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Erbb4 protein, mouse
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Receptor, ErbB-4
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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Bace1 protein, mouse
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Metalloendopeptidases
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Tetradecanoylphorbol Acetate
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leptomycin B