NOTCH4 信号转导的负调控
中文名称
通路描述
NOTCH4 信号转导可在 NOTCH4 细胞内片段（NICD4）的核转位水平上受到负调控。AKT 介导的 NICD4 磷酸化促进 NICD4 与 14-3-3-zeta（YWHAZ）的结合，导致 NICD4 滞留于细胞质中（Ramakrishnan et al. 2015）。E3 泛素连接酶 FBXW7，作为 SCF 泛素连接酶复合物的组分，结合并泛素化磷酸化的 NICD4，将其靶向至蛋白酶体介导的降解（Wu et al. 2001）。Fbxw7 敲除小鼠胚胎中 NICD4 的水平显著增加，这些胚胎在胚胎期死亡且血管系统发育受损（Tsunematsu et al. 2004）。NOTCH4 与 ELOC（elongin C）的结合涉及蛋白酶体介导的 NOTCH4 降解，但确切机制尚未阐明（Cummins et al. 2011）。MDM2，一种 TP53 诱导的泛素连接酶，据报道在 TP53 激活时泛素化 NICD4 并靶向其降解（Sun et al. 2011）。NOTCH4 信号转导被 NICD4 与转化酸性螺旋结构蛋白 3 的结合所抑制，但机制尚不清楚（Bargo et al. 2010）。
英文描述
Negative regulation of NOTCH4 signaling NOTCH4 signaling can be negatively regulated at the level of nuclear translocation of the NOTCH4 intracellular domain fragment (NICD4). AKT-mediated phosphorylation of NICD4 promotes binding of NICD4 with 14-3-3-zeta (YWHAZ), leading to retention of NICD4 in the cytosol (Ramakrishnan et al. 2015).
The E3 ubiquitin ligase FBXW7, a component of the SCF ubiquitin ligase complex, binds to and ubiquitinates phosphorylated NICD4, targeting it for proteasome-mediated degradation (Wu et al. 2001). The level of NICD4 is significantly increased in Fbxw7 knockout mouse embryos, which die in utero and have impaired development of the vascular system (Tsunematsu et al. 2004).
Binding of NOTCH4 to ELOC (elongin C) is involved in proteasome-mediated degradation of NOTCH4, but the exact mechanism has not been elucidated (Cummins et al. 2011). MDM2, a TP53-induced ubiquitin ligase, was reported to ubiquitinate NICD4 and target it for degradation in response to TP53 activation (Sun et al. 2011).
NOTCH4 signaling is inhibited by binding of NICD4 to the transforming acidic coiled-coil protein-3, but he mechanism is not known (Bargo et al. 2010).
The E3 ubiquitin ligase FBXW7, a component of the SCF ubiquitin ligase complex, binds to and ubiquitinates phosphorylated NICD4, targeting it for proteasome-mediated degradation (Wu et al. 2001). The level of NICD4 is significantly increased in Fbxw7 knockout mouse embryos, which die in utero and have impaired development of the vascular system (Tsunematsu et al. 2004).
Binding of NOTCH4 to ELOC (elongin C) is involved in proteasome-mediated degradation of NOTCH4, but the exact mechanism has not been elucidated (Cummins et al. 2011). MDM2, a TP53-induced ubiquitin ligase, was reported to ubiquitinate NICD4 and target it for degradation in response to TP53 activation (Sun et al. 2011).
NOTCH4 signaling is inhibited by binding of NICD4 to the transforming acidic coiled-coil protein-3, but he mechanism is not known (Bargo et al. 2010).
所含基因
43 个基因