Page 156 - ebook

[B. Cell Biology/Stem Cell] B-13

HIPK2 phosphorylates Notch1-IC T2512 via Fbw7 in breast

cancer

Hyung-Ju Lee¹, Mi-Yeon Kim¹, Eun-Hye Jo¹, So-I Noh¹, Hee-Sae Park¹*

¹School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Korea

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 lowlevel through proteasomal
degradation. HIPK2 phosphorylated the residue T2512 in Notch1-IC. Somatic mutations near this residue

renderedNotch1-ICresistant 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.