title: Nuclear ErbB4 signaling through H3K9me3 is antagonized by EGFR-activated c-Src.
abstract: The ErbB family of receptor tyrosine kinases comprises four members: epidermal growth factor receptor (EGFR)/ErbB1, HER2/ErbB2, ErbB3 and ErbB4, and plays roles in signal transduction at the plasma membrane upon ligand stimulation. Stimulation with neuregulin-1 (NRG-1) cleaves ErbB4 and releases the ErbB4 intracellular domain (4ICD) that translocates into the nucleus to control gene expression. However, little is known about the regulation of 4ICD nuclear signaling through tyrosine phosphorylation. We show here that 4ICD nuclear signaling is antagonized by EGF-induced c-Src activation through EGFR. Generation of 4ICD by NRG-1 leads to increased levels of trimethylated histone H3 on lysine 9 (H3K9me3) in a manner dependent on the nuclear accumulation of 4ICD and its tyrosine kinase activity. Once EGF activates c-Src downstream of EGFR concomitantly with NRG-1-induced ErbB4 activation, c-Src associates with phospho-Tyr950 and phospho-Tyr1056 on 4ICD, thereby decreasing nuclear accumulation of 4ICD and inhibiting an increase of H3K9me3 levels. Moreover, 4ICD-induced transcriptional repression of the human telomerase reverse transcriptase (hTERT) is inhibited by EGF-EGFR-Src signaling. Thus, our findings reveal c-Src-mediated inhibitory regulation of ErbB4 nuclear signaling upon EGFR activation.
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishibashi
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Fukumoto
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Kohei
authors.initials: K
authors.lastname: Abe
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kubota
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Aoyama
authors.forename: Sho
authors.initials: S
authors.lastname: Kubota
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D020890:Neuregulin-1 / Q000494:pharmacology; D066247:Receptor, ErbB-4; D015398:Signal Transduction; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; D020890:Neuregulin-1; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; D019061:src-Family Kinases; D008239:Lysine