Abstract
Cleavage of membrane-anchored heparin-binding EGF-like growth factor (proHB-EGF) via metalloprotease activation yields amino- and carboxy-terminal regions (HB-EGF and HB-EGF-C, respectively), with HB-EGF widely recognized as a key element of epidermal growth factor receptor transactivation in G protein-coupled receptor signaling. Here, we show a biological role of HB-EGF-C in cells. Subsequent to proteolytic cleavage of proHB-EGF, HB-EGF-C translocated from the plasma membrane into the nucleus. This translocation triggered nuclear export of the transcriptional repressor, promyelocytic leukemia zinc finger (PLZF), which we identify as an HB-EGF-C binding protein. Suppression of cyclin A and delayed entry of S-phase in cells expressing PLZF were reversed by the production of HB-EGF-C. These results indicate that released HB-EGF-C functions as an intracellular signal and coordinates cell cycle progression with HB-EGF.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / genetics*
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Animals
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Cell Line
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Cell Membrane / genetics
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Cell Membrane / metabolism*
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Cell Nucleus / genetics
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Cell Nucleus / metabolism*
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Cyclin A / genetics
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Cyclin A / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Epidermal Growth Factor / genetics
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Epidermal Growth Factor / metabolism*
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Female
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Genes, Regulator / genetics
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Heparin-binding EGF-like Growth Factor
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Humans
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Hyperplasia / genetics
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Hyperplasia / metabolism
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Hyperplasia / physiopathology
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Intercellular Signaling Peptides and Proteins
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Keratinocytes / cytology
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Keratinocytes / metabolism
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Kruppel-Like Transcription Factors
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Mice
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Mice, Inbred C57BL
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Peptide Hydrolases / genetics
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Peptide Hydrolases / metabolism
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Promyelocytic Leukemia Zinc Finger Protein
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Protein Precursors / metabolism
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Protein Structure, Tertiary / genetics
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Repressor Proteins / genetics
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S Phase / genetics
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Signal Transduction / genetics
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Skin / metabolism
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Skin / pathology
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Skin / physiopathology
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Cyclin A
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DNA-Binding Proteins
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HBEGF protein, human
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Hbegf protein, mouse
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins
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Kruppel-Like Transcription Factors
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Promyelocytic Leukemia Zinc Finger Protein
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Protein Precursors
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Repressor Proteins
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Transcription Factors
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Zbtb16 protein, mouse
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ZBTB16 protein, human
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Epidermal Growth Factor
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Peptide Hydrolases