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PMID: 11679632 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Science (New York, N.Y.) ·Vol. 294 ·No. 5549 ·2001-12-07 ·Pages 2179-81

Ni CY, Murphy MP, Golde TE, Carpenter G

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.

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,metabolism Fatty Acids, Unsaturated/pharmacology Humans Membrane Proteins/genetics,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
Chemicals
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
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Ni C Y
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Murphy M P
Golde T E
Carpenter G
Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
0036-8075
DOI
10.1126/science.1065412
Published
2001-12-07
Epub
2001-00-25
Pages
2179-81
Language
English
Region
United States
NLM ID
0404511
Subset
IM
Grants
NCI NIH HHS · CA24071 · United States
NCI NIH HHS · CA68485 · United States
NIDDK NIH HHS · DK20593 · United States
NINDS NIH HHS · NS39072 · United States
External Links
PubMed source DOI: 10.1126/science.1065412 View journal details
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