Low-density-lipoprotein-receptor-related protein 1 mediates Notch pathway activation

• Published in: Developmental cell 2021-10, Vol.56 (20), p.2902-2919.e8
• Main Authors: Bian, Weixiang, Tang, Mengfan, Jiang, Hua, Xu, Wenyan, Hao, Wanyu, Sui, Yue, Hou, Yingnan, Nie, Litong, Zhang, Huimin, Wang, Chao, Li, Nan, Wang, Jiadong, Qin, Jun, Wu, Lianfeng, Ma, Xianjue, Chen, Junjie, Wang, Wenqi, Li, Xu
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation - physiology; Cell Proliferation - physiology; Cells, Cultured; DLL3; Endocytosis - physiology; Humans; interaction network; leukemia; Ligands; Lipoproteins - genetics; Lipoproteins - metabolism; Low Density Lipoprotein Receptor-Related Protein-1 - genetics; Low Density Lipoprotein Receptor-Related Protein-1 - metabolism; LRP1; Mice; Notch pathway; Signal Transduction - physiology
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2021.09.015

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. [Display omitted] •Proteomic analysis defines the human Notch pathway protein-protein interaction network•Genetic and genomic data identifies novel key components of the pathway•LRP1 mediates ubiquitination chain linkage switching and recycling of Delta ligands•LRP1 mediates Notch pathway activation in worm, fly, and human leukemia models Bian et al. establish a human Notch pathway interaction network based on proteomics and identify LRP1 as a critical regulator of Notch signaling via interaction with DLL3 ligand. Their findings provide a potential therapeutic strategy for treatment of Notch-related cancers.