Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl St., Rehovot, Israel.
Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, 234 Herzl St., Rehovot, Israel.
Cereb Cortex. 2018 Sep 1;28(9):3115-3128. doi: 10.1093/cercor/bhx180.
The evolutionarily conserved Notch pathway plays an important role in regulation of stem cell renewal and cell fate determination in numerous organs, and as such is a key pathway in normal health and disease processes. Canonical Notch signaling is usually activated by cell contact where transmembrane ligands such as Delta-like and Jagged bind to Notch receptors. Notch activation results in the translocation of the cleaved Notch intracellular domain (NICD) into the nucleus and subsequent activation of transcription. Poly-ubiquitination leading to proteosome degradation of pathway components is one mean of regulating the Notch pathway. Here, we identified that Shootin1 exhibits the surprising propensity of activating the pathway either by interacting with LNX1/2 and promoting poly-ubiquitination of Numb or by complexing with Itch and impairing poly-ubiquitination of NICD. Within the developing brain Shootin1 modulates neuroblasts cell fate by executing 2 opposing activities on ubiquitin ligases, which control Notch signaling on 2 different levels.
进化保守的 Notch 通路在众多器官中干细胞更新和细胞命运决定的调控中发挥重要作用，因此是正常健康和疾病过程中的关键途径。经典的 Notch 信号通常通过细胞接触激活，其中跨膜配体如 Delta-like 和 Jagged 与 Notch 受体结合。Notch 激活导致切割的 Notch 细胞内结构域 (NICD) 易位到细胞核中，并随后激活转录。多泛素化导致途径成分的蛋白酶体降解是调节 Notch 途径的一种手段。在这里，我们发现 Shootin1 具有令人惊讶的倾向，可以通过与 LNX1/2 相互作用并促进 Numb 的多泛素化，或者通过与 Itch 复合物并损害 NICD 的多泛素化来激活途径。在发育中的大脑中，Shootin1 通过在两种不同水平上对控制 Notch 信号的泛素连接酶执行 2 种相反的活性，来调节神经母细胞的细胞命运。
