期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 296, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.jbc.2021.100593
关键词
-
资金
- Academy of Finland [309373, 287040]
- Jane and Aatos Erkko Foundation
- Drug Research Doctoral Programme
- Turku Doctoral Programme of Molecular Medicine
- Swedish Cultural Foundation of Finland
- Emil Aaltonen Foundation
- Maud Kuistila Memorial Foundation
- K. Albin Johansson Foundation
- European Community Mobility Programme EMA2
- Turku University Foundation
- Instrumentarium Science Foundation
- Sigrid Juselius Foundation
- Tor, Joe, and Pentti Borg's Foundation
- Swedish Cancer Society
- National Institutes of Health [CA178974]
- Finnish-Norwegian Medical Foundation
- Ida Montin Foundation
- Academy of Finland (AKA) [287040, 309373, 309373, 287040] Funding Source: Academy of Finland (AKA)
Research shows that PIM kinases modulate the signaling output of different Notch paralogs through distinct mechanisms, promoting breast cancer tumorigenesis. Despite losing interaction with CSL after phosphorylation, Notch3 still maintains tumorigenic potential under estrogenic conditions.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据