γ-Secretase Cleavage and Nuclear Localization of ErbB-4 Receptor Tyrosine Kinase

American Association for the Advancement of Science (AAAS) - Tập 294 Số 5549 - Trang 2179-2181 - 2001
Chang-Yuan Ni1, M. Paul Murphy2, Todd E. Golde2, Graham Carpenter3
1Department of Biochemistry
2Department of Neuroscience and Pharmacology, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.
3Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA

Tóm tắt

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 γ-secretase that releases the ErbB-4 intracellular domain from the membrane and facilitates its translocation to the nucleus. γ-Secretase cleavage was prevented by chemical inhibitors or a dominant negative presenilin. Inhibition of γ-secretase also prevented growth inhibition by HRG. γ-Secretase cleavage of ErbB-4 may represent another mechanism for receptor tyrosine kinase–mediated signaling.

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Tài liệu tham khảo

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Given that the nuclear export signal consensus sequence is XR 2–4 XR 2 XR 1 X (where X represents Leu Ile or Val and R represents any amino acid) there are three putative nuclear export signal sequences in the ErbB-4 cytoplasmic domain sequence: Leu 713 -Lys-Glu-Thr-Glu-Leu-Lys-Arg-Val-Lys-Val-Leu Leu 780 -Val-Arg-Leu-Leu-Gly-Val-Cys-Leu and Leu 939 -Pro-Gln-Pro-Pro-Ile-Cys-Thr-Ile-Asp-Val.

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For supplementary figures showing that the ErbB-4 COOH-terminal domain has activity in the GAL4 transactivation assay and is localized in the nucleus as a GFP fusion protein see Science Online (www.sciencemag.org/cgi/content/full/1065412/DC1).

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We thank H.-J. Liao X.-J. Wang and H.-P. Yuan for their help; A. Fauq and C. Ziani-Cherif for the synthesis of YIL and compound E; M. Yoshida for LMB; M. Kraus for ErbB-4 antibody; M. Vecchi for GAL4 constructs; and O. Tikhomirov for the GFP–ErbB-2 construct. Supported by NIH grants CA24071 (G.C.) and NS39072 (T.E.G.) and by an Ellison Medical Foundation New Scholars award (T.E.G.). Core facility support from grants CA68485 (Vanderbilt-Ingram Cancer Center) and DK20593 (Vanderbilt Diabetes Center) is acknowledged.

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American Association for the Advancement of Science (AAAS)

Tập 294 Số 5549

2179-2181

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