Projects per year
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 is phosphorylated within the RAM 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 Notch3 ICD sterically hinders its interaction with CSL, and thereby inhibits its CSL-dependent transcriptional activity. Surprisingly however, phosphorylated Notch3 ICD 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 independent mechanisms.
|Journal||Journal of Biological Chemistry|
|Publication status||Published - 2021|
|MoE publication type||A1 Journal article-refereed|
- PIM kinase
- Notch proteins
- Protein–protein interaction
- Transcription regulation
- Tumor cell biology
- Breast cancer
FingerprintDive into the research topics of 'PIM-induced phosphorylation of Notch3 promotes breast cancer tumorigenicity in a CSL-independent fashion'. Together they form a unique fingerprint.
CellMech: Center of Excellence in Cellular Mechanostasis
Sahlgren, C., Sistonen, L., Eriksson, J., Toivola, D., Meinander, A., Cheng, F. & Jacquemet, G.
01/03/19 → 29/02/24
AKT-mediated post-translational regulation of NOTCH3 – decoding the Notch phosphorylation switchboard for targeted therapies in cancer
01/09/19 → 30/09/22
PESCADoR: Phenotypic Screening for Cancer Drug Discovery
Nees, M., Rosenholm, J. & Sahlgren, C.
01/09/17 → 31/08/21
Project: Academy of Finland/Other Research Councils