Tumor Suppressor HIPK2 Regulates Malignant Growth via Phosphorylation of Notch1

Cancer Res. 2016 Aug 15;76(16):4728-40. doi: 10.1158/0008-5472.CAN-15-3310. Epub 2016 Jun 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Carrier Proteins / metabolism*
  • Cell Proliferation / physiology
  • Cell Survival / physiology
  • Female
  • Fluorescent Antibody Technique
  • Heterografts
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Mice
  • Mutation
  • Neoplasm Invasiveness / pathology
  • Phosphorylation
  • Polymerase Chain Reaction
  • Protein Stability
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*

Substances

  • Carrier Proteins
  • NOTCH1 protein, human
  • Receptor, Notch1
  • HIPK2 protein, human
  • Protein-Serine-Threonine Kinases