CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity

Youzhou Sang, Yanxin Li, Yingwen Zhang, Angel A Alvarez, Bo Yu, Weiwei Zhang, Bo Hu, Shi-Yuan Cheng, Haizhong Feng*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Despite the development of adjuvant therapies, glioblastoma (GBM) patients remain incurable, thus justifying the urgent need of new therapies. CDK5 plays a critical role in GBM and is a potential target for GBM. However, the mechanism by which CDK5 promotes GBM tumorigenicity remains largely unknown. Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis–trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation. Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. These findings are confirmed by inhibition of CDK5-activated TRIM59 activity that results in suppression of intracranial tumor growth. Correlative expressions of the components of this pathway are clinically prognostic. Our findings suggest targeting CDK5/TRIM59 signaling axis as a putative strategy for treating GBM.

Original languageEnglish (US)
Article number4013
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

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phosphorylation
Phosphorylation
Ubiquitination
Glioblastoma
Tumors
therapy
tumors
Karyopherins
Ligases
Isomerization
Ubiquitin
Histones
Serine
isomerization
Chemical activation
retarding
activation
degradation
Degradation
Substrates

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

@article{c072401a599d44ce97606ed04aff22e0,
title = "CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity",
abstract = "Despite the development of adjuvant therapies, glioblastoma (GBM) patients remain incurable, thus justifying the urgent need of new therapies. CDK5 plays a critical role in GBM and is a potential target for GBM. However, the mechanism by which CDK5 promotes GBM tumorigenicity remains largely unknown. Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis–trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation. Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. These findings are confirmed by inhibition of CDK5-activated TRIM59 activity that results in suppression of intracranial tumor growth. Correlative expressions of the components of this pathway are clinically prognostic. Our findings suggest targeting CDK5/TRIM59 signaling axis as a putative strategy for treating GBM.",
author = "Youzhou Sang and Yanxin Li and Yingwen Zhang and Alvarez, {Angel A} and Bo Yu and Weiwei Zhang and Bo Hu and Shi-Yuan Cheng and Haizhong Feng",
year = "2019",
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language = "English (US)",
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publisher = "Nature Publishing Group",
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CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity. / Sang, Youzhou; Li, Yanxin; Zhang, Yingwen; Alvarez, Angel A; Yu, Bo; Zhang, Weiwei; Hu, Bo; Cheng, Shi-Yuan; Feng, Haizhong.

In: Nature communications, Vol. 10, No. 1, 4013, 01.12.2019.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Sang, Youzhou

AU - Li, Yanxin

AU - Zhang, Yingwen

AU - Alvarez, Angel A

AU - Yu, Bo

AU - Zhang, Weiwei

AU - Hu, Bo

AU - Cheng, Shi-Yuan

AU - Feng, Haizhong

PY - 2019/12/1

Y1 - 2019/12/1

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AB - Despite the development of adjuvant therapies, glioblastoma (GBM) patients remain incurable, thus justifying the urgent need of new therapies. CDK5 plays a critical role in GBM and is a potential target for GBM. However, the mechanism by which CDK5 promotes GBM tumorigenicity remains largely unknown. Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis–trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation. Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. These findings are confirmed by inhibition of CDK5-activated TRIM59 activity that results in suppression of intracranial tumor growth. Correlative expressions of the components of this pathway are clinically prognostic. Our findings suggest targeting CDK5/TRIM59 signaling axis as a putative strategy for treating GBM.

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