title: Tumor Suppressor HIPK2 Regulates Malignant Growth via Phosphorylation of Notch1.
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.
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Ann
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea. Institute for Cancer Genetics, Columbia University Medical Center, New York, New York.
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Jo
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyeok-Gu
authors.initials: HG
authors.lastname: Kang
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Chun
authors.affiliation: Department of Pathology, Chonnam National University Medical School and Research Institute of Medical Sciences, Gwangju, Republic of Korea.
authors.forename: Ji Shin
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: Cheol Yong
authors.initials: CY
authors.lastname: Choi
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, New York. Department of Pathology, Columbia University Medical Center, New York, New York. Department of Pediatrics, Columbia University Medical Center, New York, New York.
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Keesook
authors.initials: K
authors.lastname: Lee
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea. proteome@jnu.ac.kr.
authors.forename: Hee-Sae
authors.initials: HS
authors.lastname: Park
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000473:pathology; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases