title: An ID2-dependent mechanism for VHL inactivation in cancer.
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.
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York 10032, USA.
authors.forename: Sang Bae
authors.initials: SB
authors.lastname: Lee
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York 10032, USA.
authors.forename: Veronique
authors.initials: V
authors.lastname: Frattini
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York 10032, USA.|Center for Computational Biology and Bioinformatics, Columbia University Medical Center, New York 10032, USA.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Bansal
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York 10032, USA.
authors.forename: Angelica M
authors.initials: AM
authors.lastname: Castano
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York 10014, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Sherman
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York 10014, USA.
authors.forename: Keino
authors.initials: K
authors.lastname: Hutchinson
authors.affiliation: Department of Neurosurgery, Columbia University Medical Center, New York 10032, USA.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York 10032, USA.|Center for Computational Biology and Bioinformatics, Columbia University Medical Center, New York 10032, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York 10032, USA.
authors.forename: Guangchao
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York 10014, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Cardozo
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York 10032, USA.|Department of Neurology, Columbia University Medical Center, New York 10032, USA.|Department of Pathology, Columbia University Medical Center, New York 10032, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Iavarone
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York 10032, USA.|Department of Pathology, Columbia University Medical Center, New York 10032, USA.|Department of Pediatrics, Columbia University Medical Center, New York 10032, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Lasorella
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism*; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D054875:Ubiquitination; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000097603:Dyrk Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D044842:Cullin Proteins; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051797:Inhibitor of Differentiation Protein 2; D010100:Oxygen; D010769:Phosphothreonine; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000097603:Dyrk Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C105153:CUL2 protein, human; C497450:ID2 protein, human; C447780:EGLN2 protein, human