An ID2-dependent mechanism for VHL inactivation in cancer

Sang Bae Lee; Veronique Frattini; Mukesh Bansal; Angelica M. Castano; Dan Sherman; Keino Hutchinson; Jeffrey N. Bruce; Andrea Califano; Guangchao Liu; Timothy Cardozo; Antonio Iavarone; Anna Lasorella

doi:10.1038/nature16475

An ID2-dependent mechanism for VHL inactivation in cancer

Sang Bae Lee
, Veronique Frattini
, Mukesh Bansal
, Angelica M. Castano
, Dan Sherman
, Keino Hutchinson
, Jeffrey N. Bruce
, Andrea Califano
, Guangchao Liu
, Timothy Cardozo
, Antonio Iavarone
, Anna Lasorella

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

104 Scopus citations

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.

Original language	English
Pages (from-to)	172-177
Number of pages	6
Journal	Nature
Volume	529
Issue number	7585
DOIs	https://doi.org/10.1038/nature16475
State	Published - 14 Jan 2016
Externally published	Yes

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@article{69fd3b8d1dcb46b69f054f2c2538a710,

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.",

author = "Lee, \{Sang Bae\} and Veronique Frattini and Mukesh Bansal and Castano, \{Angelica M.\} and Dan Sherman and Keino Hutchinson and Bruce, \{Jeffrey N.\} and Andrea Califano and Guangchao Liu and Timothy Cardozo and Antonio Iavarone and Anna Lasorella",

note = "Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited.",

year = "2016",

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doi = "10.1038/nature16475",

language = "English",

volume = "529",

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T1 - An ID2-dependent mechanism for VHL inactivation in cancer

AU - Lee, Sang Bae

AU - Frattini, Veronique

AU - Bansal, Mukesh

AU - Castano, Angelica M.

AU - Sherman, Dan

AU - Hutchinson, Keino

AU - Bruce, Jeffrey N.

AU - Califano, Andrea

AU - Liu, Guangchao

AU - Cardozo, Timothy

AU - Iavarone, Antonio

AU - Lasorella, Anna

PY - 2016/1/14

Y1 - 2016/1/14

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84954235083

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DO - 10.1038/nature16475

M3 - Article

C2 - 26735018

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SN - 0028-0836

VL - 529

SP - 172

EP - 177

JO - Nature

JF - Nature

IS - 7585

ER -

An ID2-dependent mechanism for VHL inactivation in cancer

Abstract

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