Journal
DEVELOPMENTAL CELL
Volume 56, Issue 20, Pages 2902-+Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2021.09.015
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Funding
- Westlake University Supercomputer Center
- Natural Science Foundation of China [91954103]
- Westlake Education Foundation
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The Notch signaling pathway plays a crucial role in cell growth, differentiation, and disease progression. Research has identified LRP1 as a critical regulator of the Notch pathway, with LRP1 inhibition showing potential for reducing cancer development.
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.
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