AI Article Synopsis
- The study identifies HIPK2 as a key kinase that promotes the degradation of Notch1, a receptor linked to cancer progression, by phosphorylating it in a specific degradation motif.
- Notch1-IC levels are found to be higher in cancer cells compared to normal cells, and under stress conditions, HIPK2 helps keep these levels low through degradation processes.
- Mutations near the phosphorylation site T2512 on Notch1-IC can prevent its degradation, suggesting potential therapeutic approaches to inhibit Notch1-related cancer progression.
Article Abstract
The receptor Notch1 plays an important role in malignant progression of many cancers, but its regulation is not fully understood. In this study, we report that the kinase HIPK2 is responsible for facilitating the Fbw7-dependent proteasomal degradation of Notch1 by phosphorylating its intracellular domain (Notch1-IC) within the Cdc4 phosphodegron motif. Notch1-IC expression was higher in cancer cells than normal cells. Under genotoxic stress, Notch1-IC was phosphorylated constitutively by HIPK2 and was maintained at a low level through proteasomal degradation. HIPK2 phosphorylated the residue T2512 in Notch1-IC. Somatic mutations near this residue rendered Notch1-IC resistant to degradation, as induced either by HIPK2 overexpression or adriamycin treatment. In revealing an important mechanism of Notch1 stability, the results of this study could offer a therapeutic strategy to block Notch1-dependent progression in many types of cancer. Cancer Res; 76(16); 4728-40. ©2016 AACR.
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| http://dx.doi.org/10.1158/0008-5472.CAN-15-3310 | DOI Listing |
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