CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci

Martínez-Fábregas, Jonathan; Wang, Luopin; Pöhler, Elizabeth; Cozzani, Adeline; Wilmes, Stephan; Kazemian, Majid; Mitra, Suman; Moraga, Ignacio

doi:10.1016/j.celrep.2020.108545

Cited by 28 publications

(25 citation statements)

References 87 publications

(123 reference statements)

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“…Surprisingly, this inhibitor does not have any effect on mitochondrial transcription. It is known from literature that other kinases, such as CDK8 ( Martinez-Fabregas et al, 2020 ), TBK-1 ( Balic et al, 2020 ) and FAK cells ( Visavadiya et al, 2016 ) are able to target S727. Therefore, it is likely that PD98059 is indeed targeting S727 through MEKs other than MEK1,2 or that, at least in zebrafish, its specificity is broader than expected.…”

Section: Discussionmentioning

confidence: 99%

Y705 and S727 are required for the mitochondrial import and transcriptional activities of STAT3, and for regulation of stem cell proliferation

et al. 2021

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The STAT3 transcription factor, acting both in the nucleus and mitochondria, maintains embryonic stem cell pluripotency and promotes their proliferation. In this work, using zebrafish, we determined in vivo that mitochondrial STAT3 regulates mtDNA transcription in embryonic and larval stem cell niches and that this activity affects their proliferation rates. As a result, we demonstrated that STAT3 import inside mitochondria requires Y705 phosphorylation by Jak, while its mitochondrial transcriptional activity, as well as its effect on proliferation, depends on the MAPK target S727. These data were confirmed using mouse embryonic stem cells: while the Y705 mutated STAT3 cannot enter mitochondria, the S727 mutation does not affect the import in the organelle and is responsible for STAT3-dependent mitochondrial transcription. Surprisingly, STAT3-dependent increase of mitochondrial transcription seems independent from STAT3 binding to STAT3 responsive elements. Finally, loss of function experiments, with chemical inhibition of the JAK/STAT3 pathway or genetic ablation of stat3 gene, demonstrated that STAT3 is also required for cell proliferation in the intestine of zebrafish.

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Section: Discussionmentioning

confidence: 99%

Y705 and S727 are required for the mitochondrial import and transcriptional activities of STAT3, and for regulation of stem cell proliferation

et al. 2021

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“…As an example, kinetics of STAT activation might not only determine nuclear shuttling rates but as a direct consequence could alter on-off rates on STAT-responsive promoters and therefore regulate expression of STAT-responsive genes in a specific manner. A recent report has demonstrated that fine-tuning of STAT3 resident time at STAT-responsive genes indeed alters gene expression ( Martinez-Fabregas et al, 2020 ). The design of cytokine variants that favor particular compartment-specific receptor signaling would be an elegant way for the design of future therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Endosomes as Signaling Platforms for IL-6 Family Cytokine Receptors

Schmidt-Arras

Rose–John

2021

Front. Cell Dev. Biol.

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Interleukin-6 (IL-6) is the name-giving cytokine of a family of eleven members, including IL-6, CNTF, LIF, and IL-27. IL-6 was first recognized as a B-cell stimulating factor but we now know that the cytokine plays a pivotal role in the orchestration of inflammatory processes as well as in inflammation associated cancer. Moreover, IL-6 is involved in metabolic regulation and it has been shown to be involved in major neural activities such as neuroprotection, which can help to repair and to reduce brain damage. Receptor complexes of all members formed at the plasma membrane contain one or two molecules of the signaling receptor subunit GP130 and the mechanisms of signal transduction are well understood. IL-6 type cytokines can also signal from endomembranes, in particular the endosome, and situations have been reported in which endocytosis of receptor complexes are a prerequisite of intracellular signaling. Moreover, pathogenic GP130 variants were shown to interfere with spatial activation of downstream signals. We here summarize the molecular mechanisms underlying spatial regulation of IL-6 family cytokine signaling and discuss its relevance for pathogenic processes.

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“…In particular, the mouse ESC dataset ( Yang et al , 2019 ) (PRIDE: PXD010621), the human glioblastoma dataset ( Recasens et al , 2021 ) (PRIDE: PXD020441) and the mouse adipocyte dataset ( Su et al , 2019 ) (PRIDE: PXD011525) are used for evaluating the stability of selected SPSs. The human ESC dataset ( Billing et al , 2019 ) (PRIDE: PXD004652), the HCT116 dataset ( Hahn et al , 2021 ) (PRIDE: PXD023703), the T-cell dataset ( Martinez-Fabregas et al , 2020 ) (PRIDE: PXD020964) and the AGS cell dataset ( Yin et al , 2020 ) (PRIDE: PXD005093) are included for independent validation of the reproducibility of the proposed framework. All other human phosphoproteomic datasets were curated from the qPhos database ( Yu et al , 2019 , http://qphos.cancerbio.info ) and its updated version ( http://qptm.omicsbio.info ).…”

Section: Methodsmentioning

confidence: 99%

Functional analysis of the stable phosphoproteome reveals cancer vulnerabilities

Xiao¹,

Kim

Pang

et al. 2022

Bioinformatics

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Motivation The advance of mass spectrometry-based technologies enabled the profiling of the phosphoproteomes of a multitude of cell and tissue types. However, current research primarily focused on investigating the phosphorylation dynamics in specific cell types and experimental conditions, whereas the phosphorylation events that are common across cell/tissue types and stable regardless of experimental conditions are, so far, mostly ignored. Results Here, we developed a statistical framework to identify the stable phosphoproteome across 53 human phosphoproteomics datasets, covering 40 cell/tissue types and 194 conditions/treatments. We demonstrate that the stably phosphorylated sites (SPSs) identified from our statistical framework are evolutionarily conserved, functionally important, and enriched in a range of core signalling and gene pathways. Particularly, we show that SPSs are highly enriched in the RNA splicing pathway, an essential cellular process in mammalian cells, and frequently disrupted by cancer mutations, suggesting a link between the dysregulation of RNA splicing and cancer development through mutations on SPSs. Availability The source code for data analysis in this study is available from Github repository https://github.com/PYangLab/SPSs under the open-source license of GPL-3. The data used in this study are publicly available (see section ‘Data availability’). Supplementary information Supplementary data are available at Bioinformatics online.

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CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci

Abstract: Highlights d CDK8 regulates IL-6-mediated STAT3 S727 phosphorylation in primary human T cells d CDK8 controls STAT3 activity by limiting its resident time at gene loci d CDK8 inhibition increases IL-6-mediated Th17 differentiation

Cited by 28 publications

References 87 publications

Y705 and S727 are required for the mitochondrial import and transcriptional activities of STAT3, and for regulation of stem cell proliferation

Y705 and S727 are required for the mitochondrial import and transcriptional activities of STAT3, and for regulation of stem cell proliferation

Endosomes as Signaling Platforms for IL-6 Family Cytokine Receptors

Functional analysis of the stable phosphoproteome reveals cancer vulnerabilities

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