Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
J Cell Sci. 2013 Jan 15;126(Pt 2):625-37. doi: 10.1242/jcs.116277. Epub 2012 Dec 10.
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.
表皮生长因子受体（EGFR）/ErbB1、HER2/ErbB2、ErbB3 和 ErbB4 是受体酪氨酸激酶 ErbB 家族的四个成员，在配体刺激下的质膜信号转导中发挥作用。神经调节蛋白-1（NRG-1）刺激 ErbB4 分裂并释放 ErbB4 细胞内结构域（4ICD），该结构域易位到细胞核以控制基因表达。然而，对于 4ICD 核信号通过酪氨酸磷酸化的调控知之甚少。我们在这里表明，EGF 诱导的 c-Src 激活通过 EGFR 拮抗 4ICD 核信号。NRG-1 产生的 4ICD 以依赖于 4ICD 核积累及其酪氨酸激酶活性的方式导致赖氨酸 9 上的三甲基组蛋白 H3（H3K9me3）水平增加。一旦 EGF 与 NRG-1 诱导的 ErbB4 激活同时激活 EGFR 下游的 c-Src，c-Src 就会与 4ICD 上的磷酸化 Tyr950 和磷酸化 Tyr1056 结合，从而减少 4ICD 的核积累并抑制 H3K9me3 水平的增加。此外，4ICD 诱导的人类端粒酶逆转录酶（hTERT）转录抑制被 EGF-EGFR-Src 信号转导抑制。因此，我们的研究结果揭示了 EGFR 激活时 c-Src 介导的 ErbB4 核信号的抑制调节。
