An ID2-dependent mechanism for VHL inactivation in cancer

Nature. 2016 Jan 14;529(7585):172-7. doi: 10.1038/nature16475. Epub 2016 Jan 6.

Abstract

Mechanisms that maintain cancer stem cells are crucial to tumour progression. The ID2 protein supports cancer hallmarks including the cancer stem cell state. HIFα transcription factors, most notably HIF2α (also known as EPAS1), are expressed in and required for maintenance of cancer stem cells (CSCs). However, the pathways that are engaged by ID2 or drive HIF2α accumulation in CSCs have remained unclear. Here we report that DYRK1A and DYRK1B kinases phosphorylate ID2 on threonine 27 (Thr27). Hypoxia downregulates this phosphorylation via inactivation of DYRK1A and DYRK1B. The activity of these kinases is stimulated in normoxia by the oxygen-sensing prolyl hydroxylase PHD1 (also known as EGLN2). ID2 binds to the VHL ubiquitin ligase complex, displaces VHL-associated Cullin 2, and impairs HIF2α ubiquitylation and degradation. Phosphorylation of Thr27 of ID2 by DYRK1 blocks ID2-VHL interaction and preserves HIF2α ubiquitylation. In glioblastoma, ID2 positively modulates HIF2α activity. Conversely, elevated expression of DYRK1 phosphorylates Thr27 of ID2, leading to HIF2α destabilization, loss of glioma stemness, inhibition of tumour growth, and a more favourable outcome for patients with glioblastoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cullin Proteins / metabolism
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology*
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism
  • Inhibitor of Differentiation Protein 2 / metabolism*
  • Male
  • Mice
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Oxygen / metabolism
  • Phosphorylation
  • Phosphothreonine / metabolism
  • Protein Binding
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Ubiquitination
  • Von Hippel-Lindau Tumor Suppressor Protein / antagonists & inhibitors*
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • CUL2 protein, human
  • Cullin Proteins
  • ID2 protein, human
  • Inhibitor of Differentiation Protein 2
  • Phosphothreonine
  • endothelial PAS domain-containing protein 1
  • EGLN2 protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Oxygen