Role for tyrosine phosphorylation of SUV39H1 histone methyltransferase in enhanced trimethylation of histone H3K9 via neuregulin-1/ErbB4 nuclear signaling.
Role for tyrosine phosphorylation of SUV39H1 histone methyltransferase in enhanced trimethylation of histone H3K9 via neuregulin-1/ErbB4 nuclear signaling.
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DOI：
10.1016/j.bbrc.2019.02.130
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发表时间：
2019-04
影响因子：
3.1
通讯作者：
Haruna Nakajo;K. Ishibashi;Kazumasa Aoyama;Sho Kubota;H. Hasegawa;N. Yamaguchi;N. Yamaguchi
中科院分区：
文献类型：
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作者：
Haruna Nakajo;K. Ishibashi;Kazumasa Aoyama;Sho Kubota;H. Hasegawa;N. Yamaguchi;N. Yamaguchi
蛋白酪氨酸激酶通过在不同的细胞事件中磷酸化其底物来传递信号。受体型酪氨酸激酶 ErbB4 是表皮生长因子受体亚家族的成员，在配体刺激下被激活并蛋白水解裂解，裂解的 ErbB4 胞内结构域 (4ICD) 被释放到细胞质和细胞核中。我们之前表明，神经调节蛋白-1 (NRG-1) 刺激产生的核 4ICD 增强了组蛋白 H3 在赖氨酸 9 (H3K9me3) 处的三甲基化水平。然而，目前尚不清楚核 4ICD 如何增强 H3K9me3 水平。在这里，我们表明组蛋白 H3K9 甲基转移酶 SUV39H1 与 NRG-1/ErbB4 介导的 H3K9me3 相关。 SUV39H1 的敲低可阻止 NRG-1 介导的 H3K9me3 水平增强。核 4ICD 主要在人类、小鼠和果蝇中保守的 Tyr-297、-303 和 -308 处磷酸化 SUV39H1。此外，敲低拯救实验表明，不可磷酸化的SUV39H1突变体（3YF）在NRG-1刺激后无法增强H3K9me3的水平。这些结果表明，核 ErbB4 通过 NRG-1/ErbB4 信号介导的染色质重塑中 SUV39H1 的酪氨酸磷酸化来增强 H3K9me3 水平。
Protein-tyrosine kinases transmit signals by phosphorylating their substrates in diverse cellular events. The receptor-type tyrosine kinase ErbB4, a member of the epidermal growth factor receptor subfamily, is activated and proteolytically cleaved upon ligand stimulation, and the cleaved ErbB4 intracellular domain (4ICD) is released into the cytoplasm and the nucleus. We previously showed that generation of nuclear 4ICD by neuregulin-1 (NRG-1) stimulation enhances the levels of trimethylation of histone H3 at lysine 9 (H3K9me3). However, it remains unclear how nuclear 4ICD enhances H3K9me3 levels. Here we show that the histone H3K9 methyltransferase SUV39H1 associates with NRG-1/ErbB4-mediated H3K9me3. Knockdown of SUV39H1 blocked NRG-1-mediated enhancement of the levels of H3K9me3. Nuclear 4ICD was found to phosphorylate SUV39H1 primarily at Tyr-297, -303, and −308 that are conserved among humans, mice, and flies. Furthermore, knockdown-rescue experiments showed that the unphosphorylatable SUV39H1 mutant (3 YF) was incapable of enhancing the levels of H3K9me3 upon NRG-1 stimulation. These results suggest that nuclear ErbB4 enhances H3K9me3 levels through tyrosine phosphorylation of SUV39H1 in NRG-1/ErbB4 signal-mediated chromatin remodeling.