Tumor suppressor HIPK2 regulates malignant growth via phosphorylation of NOTCH

Eun Jung Ann; Mi Yeon Kim; Ji Hye Yoon; Ji Seon Ahn; Eun Hye Jo; Hye Jin Lee; Hyun Woo Lee; Hyeok Gu Kang; Dong Wook Choi; Kyung Hee Chun; Ji Shin Lee; Cheol Yong Choi; Adolfo A. Ferrando; Keesook Lee; Hee Sae Park

doi:10.1158/0008-5472.CAN-15-3310

Tumor suppressor HIPK2 regulates malignant growth via phosphorylation of NOTCH

Eun Jung Ann, Mi Yeon Kim, Ji Hye Yoon, Ji Seon Ahn, Eun Hye Jo, Hye Jin Lee, Hyun Woo Lee, Hyeok Gu Kang, Dong Wook Choi, Kyung Hee Chun, Ji Shin Lee, Cheol Yong Choi, Adolfo A. Ferrando, Keesook Lee, Hee Sae Park

Department of Biological Sciences

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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 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. Cancer Res; 76(16); 4728-40.

Original language	English
Pages (from-to)	4728-4740
Number of pages	13
Journal	Cancer Research
Volume	76
Issue number	16
DOIs	https://doi.org/10.1158/0008-5472.CAN-15-3310
State	Published - 15 Aug 2016

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@article{dd85572684c94365833002d137c28bad,

title = "Tumor suppressor HIPK2 regulates malignant growth via phosphorylation of NOTCH",

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 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. Cancer Res; 76(16); 4728-40.",

author = "Ann, \{Eun Jung\} and Kim, \{Mi Yeon\} and Yoon, \{Ji Hye\} and Ahn, \{Ji Seon\} and Jo, \{Eun Hye\} and Lee, \{Hye Jin\} and Lee, \{Hyun Woo\} and Kang, \{Hyeok Gu\} and Choi, \{Dong Wook\} and Chun, \{Kyung Hee\} and Lee, \{Ji Shin\} and Choi, \{Cheol Yong\} and Ferrando, \{Adolfo A.\} and Keesook Lee and Park, \{Hee Sae\}",

note = "Publisher Copyright: {\textcopyright} 2016 American Association for Cancer Research.",

year = "2016",

month = aug,

day = "15",

doi = "10.1158/0008-5472.CAN-15-3310",

language = "English",

volume = "76",

pages = "4728--4740",

journal = "Cancer Research",

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publisher = "American Association for Cancer Research Inc.",

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T1 - Tumor suppressor HIPK2 regulates malignant growth via phosphorylation of NOTCH

AU - Ann, Eun Jung

AU - Kim, Mi Yeon

AU - Yoon, Ji Hye

AU - Ahn, Ji Seon

AU - Jo, Eun Hye

AU - Lee, Hye Jin

AU - Lee, Hyun Woo

AU - Kang, Hyeok Gu

AU - Choi, Dong Wook

AU - Chun, Kyung Hee

AU - Lee, Ji Shin

AU - Choi, Cheol Yong

AU - Ferrando, Adolfo A.

AU - Lee, Keesook

AU - Park, Hee Sae

PY - 2016/8/15

Y1 - 2016/8/15

N2 - 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. Cancer Res; 76(16); 4728-40.

AB - 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. Cancer Res; 76(16); 4728-40.

UR - https://www.scopus.com/pages/publications/84982168624

U2 - 10.1158/0008-5472.CAN-15-3310

DO - 10.1158/0008-5472.CAN-15-3310

M3 - Article

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AN - SCOPUS:84982168624

SN - 0008-5472

VL - 76

SP - 4728

EP - 4740

JO - Cancer Research

JF - Cancer Research

IS - 16

ER -

Tumor suppressor HIPK2 regulates malignant growth via phosphorylation of NOTCH

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