gamma -Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase.
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.
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Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Murphy
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Golde
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Carpenter
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D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D019556:COS Cells; D002219:Carbamates / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D020890:Neuregulin-1 / Q000494:pharmacology; D053764:Presenilin-1; D011480:Protease Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D066247:Receptor, ErbB-4; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D002219:Carbamates; D004151:Dipeptides; D005231:Fatty Acids, Unsaturated; C410009:L 685458; D008565:Membrane Proteins; D020890:Neuregulin-1; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011480:Protease Inhibitors; D011993:Recombinant Fusion Proteins; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D008666:Metalloendopeptidases; D013755:Tetradecanoylphorbol Acetate; C038753:leptomycin B