Low-density-lipoprotein-receptor-related protein 1 mediates Notch pathway activation
Low-density-lipoprotein-receptor-related protein 1 mediates Notch pathway activation
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DOI：
10.1016/j.devcel.2021.09.015
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发表时间：
2021-10-25
影响因子：
11.8
通讯作者：
Li, Xu
中科院分区：
文献类型：
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作者：
Bian, Weixiang;Tang, Mengfan;Li, Xu
Notch信号通路控制细胞生长，分化和命运决定，其失调与各种人类遗传疾病和癌症有关。为了全面了解Notch通路的全球组织并确定Notch相关疾病的潜在药物靶点，我们建立了人类Notch通路的蛋白质相互作用景观。通过将遗传和表型数据与生物信息学分析相结合，我们极大地扩展了这一途径，并确定了许多关键调控因子，包括低密度脂蛋白受体相关蛋白1（LRP 1）。我们证明LRP 1介导Delta配体的泛素化链连接转换，这进一步影响配体再循环、膜定位和稳定性。在白血病模型中，LRP 1抑制导致Notch信号传导抑制和肿瘤发生减少。我们的研究提供了对Notch通路相互作用网络的一瞥，并揭示了LRP 1作为Notch通路的一个关键调节因子，以及Notch相关癌症的可能治疗靶点。
The Notch signaling pathway controls cell growth, differentiation, and fate decisions, and its dysregulation has been linked to various human genetic disorders and cancers. To comprehensively understand the global organization of the Notch pathway and identify potential drug targets for Notch-related diseases, we established a protein interaction landscape for the human Notch pathway. By combining and analyzing genetic and phenotypic data with bioinformatics analysis, we greatly expanded this pathway and identified many key regulators, including low-density-lipoprotein-receptor-related protein 1 (LRP1). We demonstrated that LRP1 mediates the ubiquitination chain linkage switching of Delta ligands, which further affects ligand recycling, membrane localization, and stability. LRP1 inhibition led to Notch signaling inhibition and decreased tumorigenesis in leukemia models. Our study provides a glimpse into the Notch pathway interaction network and uncovers LRP1 as one critical regulator of the Notch pathway, as well as a possible therapeutic target for Notch-related cancers.