The Soluble Heparin-Binding EGF-Like Growth Factor Stimulates EGF Receptor Trafficking to the Nucleus

Most ligands of epidermal growth factor receptor (EGFR) have the ability to induce EGFR translocation into the nucleus, where EGFR acts as an important transcriptional regulator. Soluble form of heparin-binding EGF-like growth factor (sHB-EGF) is one of the ligands for EGFR in many cell types; howev...

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Bibliographic Details
Published in:PloS one 2015-05, Vol.10 (5), p.e0127887-e0127887
Main Authors: Korotkevych, Nataliia V, Labyntsev, Andrii Ju, Kolybo, Denis V, Komisarenko, Serhiy V
Format: Article
Language:English
Subjects:
Anticoagulants
Binding
Biochemistry
Cancer
Cell Line
Cell Nucleus - drug effects
Cell Nucleus - metabolism
Chemical properties
Chromatin
Cloning
Confocal microscopy
Coordination compounds
Cyclin D1
Cyclin D1 - metabolism
Data processing
Deoxyribonucleic acid
DNA
Enzyme inhibitors
Epidermal growth factor
Epidermal growth factor receptors
Epidermal growth factors
Genes
Heparin
Heparin-binding EGF-like Growth Factor - metabolism
Humans
Immunology
Immunoprecipitation
Importation
Kinases
Ligands
Localization
Microscopy
Nuclear transport
Nuclei (cytology)
Phosphorylation
Plasmids
Promoter Regions, Genetic - drug effects
Protein Kinase Inhibitors - pharmacology
Protein transport
Protein Transport - drug effects
Proteins
Quinazolines - pharmacology
Receptor, Epidermal Growth Factor - metabolism
Transcription
Translocation
Tumors
Tyrosine
Tyrphostins - pharmacology
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Summary:Most ligands of epidermal growth factor receptor (EGFR) have the ability to induce EGFR translocation into the nucleus, where EGFR acts as an important transcriptional regulator. Soluble form of heparin-binding EGF-like growth factor (sHB-EGF) is one of the ligands for EGFR in many cell types; however, there is no evidence for the ability of sHB-EGF to induce EGFR nuclear importation. Here, we demonstrated that treatment of A431 cells with sHB-EGF resulted in nuclear localization of EGFR and such translocation occurs via retrograde pathway. It was shown by confocal microscopy and co-immunoprecipitation assay that the translocation complex consisted of both ligand and receptor. The chromatin immunoprecipitation assay showed the association of sHB-EGF-EGFR complex with promoter region of cyclin D1 in the cell nucleus and this association was prevented by application of EGFR kinase inhibitor AG-1478. The obtained data suggest that sHB-EGF acts similarly to other EGFR ligands and is capable to induce EGFR nuclear translocation as a part of ligand-receptor complex in a tyrosine phosphorylation-dependent manner.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0127887