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Cited by 74Cytokine Signaling Pathways and InteractionsNF-κB Signaling PathwaysTGF-β signaling in diseases

Nucleus, mitochondrion, or reticulum? STAT3 à La Carte

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Avalle, Lidia, Poli, Valeria·2018·International Journal of Molecular Sciences
DOI 10.3390/ijms19092820PMC PMC6164042
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Abstract

The transcription factor signal transducer and activator of transcription (STAT)3 mediates the functions of cytokines, growth factors, and oncogenes under both physiological and pathological conditions. Uncontrolled/constitutive STAT3 activity is often detected in tumors of different types, where its role is mostly that of an oncogene, contributing in multiple ways to tumor transformation, growth, and progression. For this reason, many laboratories and pharmaceutical companies are making efforts to develop specific inhibitors. However, STAT3 has also been shown to act as a tumor suppressor in a number of cases, suggesting that its activity is strongly context-specific. Here, we discuss the bases that can explain the multiple roles of this factor in both physiological and pathological contexts. In particular, we focus on the following four features: (i) the distinct properties of the STAT3α and β isoforms; (ii) the multiple post-translational modifications (phosphorylation on tyrosine or serine, acetylation and methylation on different residues, and oxidation and glutathionylation) that can affect its activities downstream of multiple different signals; (iii) the non-canonical functions in the mitochondria, contributing to the maintenance of energy homeostasis under stress conditions; and (iv) the recently discovered functions in the endoplasmic reticulum, where STAT3 contributes to the regulation of calcium homeostasis, energy production, and apoptosis.

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  • The effect of S727 phosphorylation on STAT3 gene transcription is varied and depends on the phosphorylating kinase and cell type.

    “The effect of S727 phosphorylation (pS) on STAT3 gene transcription is varied and depends on the phosphorylating kinase, as well as the cell type, which likely dictates the availability of other transcription factors and proteins that help STAT3 bind to kinase (Avalle and Poli, 2018).”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Avalle and Poli, 2018

    Section 3.3 says S727 phosphorylation can be carried out by several kinases and can affect transcriptional induction or STAT3 activation dynamics. Section 3 also says STAT3 activates different genes across cell types, partly through differences in binding-site accessibility and interactions with transcription factors and cofactors. The paper does not establish that the transcriptional effect of S727 phosphorylation depends on which kinase phosphorylates it, or that those proteins help STAT3 bind to a kinase. (LLM, conf=0.83)

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Authors
Avalle, L., & Poli, V.
Affiliations
University of Turin (IT)
Corresponding author
  • Avalle, Lidia
  • Poli, Valeria
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2018-09-18
Volume
19
Issue
9
Pages
2820
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms19092820
PMC
PMC6164042
OpenAlex
W2890064317
Cited by
74
References
131
Citations by year
2026: 6 · 2025: 4 · 2024: 8 · 2023: 11 · 2022: 7 · 2021: 15 · 2020: 13 · 2019: 10
FWCI
0.99
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
Funders
Italian Cancer Research Association AIRC IG16930 (AIRC IG16930)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
STAT3, post-translational modification, tyrosine phosphorylation, serine phosphorylation, acetylation, methylation, glutathionylation, mitochondrial STAT3, calcium homeostasis, energy homeostasis, apoptosis, oncogenes, tumor suppressor, STAT3 inhibitor, cytokine signaling
MeSH terms
Animals, Cell Nucleus, Endoplasmic Reticulum, Energy Metabolism, Humans, Mitochondria, Neoplasms, Oncogenes, Protein Processing, Post-Translational, Apoptosis, STAT3 Transcription Factor

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