ArticleThe Journal of biological chemistry
PIM-induced phosphorylation of Notch3 promotes breast cancer tumorigenicity in a CSL-independent fashion.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 16 citations in OpenAlex.
- Notch receptors in breast cancer: context-dependent roles and therapeutic targeting.Cell communication and signaling : CCS · 2026Review
- Disrupting Notch signalling by a small molecule inhibiting dihydroorotate dehydrogenase activity.Scientific reports · 2026Article
- Regulation of Notch signaling by multiple Ankyrin repeat containing protein Mask.Cell communication and signaling : CCS · 2025Article
- PIM1 kinase and its diverse substrate in solid tumors.Cell communication and signaling : CCS · 2024Review
- UM171 suppresses breast cancer progression by inducing KLF2.Breast cancer research and treatment · 2024Article
- Analysing potent biomarkers along phytochemicals for breast cancer therapy: an in silico approach.Breast cancer research and treatment · 2024Article
- Silencing Notch4 promotes tumorigenesis and inhibits metastasis of triple-negative breast cancer via Nanog and Cdc42.Cell death discovery · 2023Article
- The structure, binding and function of a Notch transcription complex involving RBPJ and the epigenetic reader protein L3MBTL3.Nucleic acids research · 2022Article
- Roles of Notch Signaling in the Tumor Microenvironment.International journal of molecular sciences · 2022Review
- Identification of senescence-related subtypes, establishment of a prognosis model, and characterization of a tumor microenvironment infiltration in breast cancer.Frontiers in immunology · 2022Article
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Authors and funding
14 authors at 4 institutions in 4 countries.
Funding
Abstract
Dysregulation of the developmentally important Notch signaling pathway is implicated in several types of cancer, including breast cancer. However, the specific roles and regulation of the four different Notch receptors have remained elusive. We have previously reported that the oncogenic PIM kinases phosphorylate Notch1 and Notch3. Phosphorylation of Notch1 within the second nuclear localization sequence of its intracellular domain (ICD) enhances its transcriptional activity and tumorigenicity. In this study, we analyzed Notch3 phosphorylation and its functional impact. Unexpectedly, we observed that the PIM target sites are not conserved between Notch1 and Notch3. Notch3 ICD (N3ICD) is phosphorylated within a domain, which is essential for formation of a transcriptionally active complex with the DNA-binding protein CSL. Through molecular modeling, X-ray crystallography, and isothermal titration calorimetry, we demonstrate that phosphorylation of N3ICD sterically hinders its interaction with CSL and thereby inhibits its CSL-dependent transcriptional activity. Surprisingly however, phosphorylated N3ICD still maintains tumorigenic potential in breast cancer cells under estrogenic conditions, which support PIM expression. Taken together, our data indicate that PIM kinases modulate the signaling output of different Notch paralogs by targeting distinct protein domains and thereby promote breast cancer tumorigenesis via both CSL-dependent and CSL-independent mechanisms.
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