Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response
Site-specific methylation of Notch1 controls the amplitude and duration of the Notch1 response
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DOI：
10.1126/scisignal.2005892
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发表时间：
2015-03-24
影响因子：
7.3
通讯作者：
Borggrefe, Tilman
中科院分区：
文献类型：
--
作者：
Hein, Kerstin;Mittler, Gerhard;Borggrefe, Tilman
生理上，Notch信号转导在分化过程中起关键作用；病理上，Notch信号在肿瘤的发生发展中起重要作用。Notch靶基因的转录激活涉及配体结合反应中Notch受体的切割、Notch胞内域(NICD)的产生、NICD向细胞核内的迁移和共激活复合体的组装。NICD的翻译后修饰对于其转录活性和蛋白质周转是重要的。Notch信号的解除调控和稳定Notch1的突变与白血病的发生有关。我们发现，甲基转移酶CARM1(辅活化子相关精氨酸甲基转移酶1；也被称为PRMT4)在C末端反式激活结构域的五个保守的精氨酸残基上甲基化NICD。CARM1在物理和功能上与NICD-辅活化子复合体相互作用，并以Notch依赖的方式在基因增强子上被发现。虽然甲基化缺陷的NICD突变体在生化上更稳定，但通过在非洲爪哇和Danio rerio的胚胎中进行Notch试验，该突变体的生物学活性较低。数学模型表明，完整但短暂和瞬时的Notch信号需要NICD的甲基化。
Physiologically, Notch signal transduction plays a pivotal role in differentiation; pathologically, Notch signaling contributes to the development of cancer. Transcriptional activation of Notch target genes involves cleavage of the Notch receptor in response to ligand binding, production of the Notch intracellular domain (NICD), and NICD migration into the nucleus and assembly of a coactivator complex. Posttranslational modifications of the NICD are important for its transcriptional activity and protein turnover. Deregulation of Notch signaling and stabilizing mutations of Notch1 have been linked to leukemia development. We found that the methyltransferase CARM1 (coactivator-associated arginine methyltransferase 1; also known as PRMT4) methylated NICD at five conserved arginine residues within the C-terminal trans-activation domain. CARM1 physically and functionally interacted with the NICD-coactivator complex and was found at gene enhancers in a Notch-dependent manner. Although a methylation-defective NICD mutant was biochemically more stable, this mutant was biologically less active as measured with Notch assays in embryos of Xenopus laevis and Danio rerio. Mathematical modeling indicated that full but short and transient Notch signaling required methylation of NICD.