Publication Date:
2001-10-27
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ni, C Y -- Murphy, M P -- Golde, T E -- Carpenter, G -- CA24071/CA/NCI NIH HHS/ -- CA68485/CA/NCI NIH HHS/ -- DK20593/DK/NIDDK NIH HHS/ -- NS39072/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2001 Dec 7;294(5549):2179-81. Epub 2001 Oct 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11679632" target="_blank"〉PubMed〈/a〉
Keywords:
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
;
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, Epidermal Growth Factor/chemistry/*metabolism
;
Receptor, ErbB-4
;
Recombinant Fusion Proteins/metabolism
;
Signal Transduction
;
Tetradecanoylphorbol Acetate/pharmacology
;
Transcriptional Activation
;
Tumor Cells, Cultured
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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