STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor

Wang, Yuxin; van Boxel-Dezaire, Anette H. H.; Cheon, HyeonJoo; Yang, Jinbo; Stark, George R.

doi:10.1073/pnas.1315862110

Cited by 329Cytokine Signaling Pathways and InteractionsNF-κB Signaling PathwaysPsoriasis: Treatment and Pathogenesis

STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor

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Wang, Yuxin, van Boxel-Dezaire, Anette H. H., Cheon, HyeonJoo, Yang, Jinbo, Stark, George R.·2013·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1315862110PMC PMC3801081

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Abstract

The activation of STAT3 by tyrosine phosphorylation, essential for normal development and for a normal inflammatory response to invading pathogens, is kept in check by negative regulators. Abnormal constitutive activation of STAT3, which contributes to the pathology of cancer and to chronic inflammatory diseases such as rheumatoid arthritis, occurs when negative regulation is not fully effective. SOCS3, the major negative regulator of STAT3, is induced by tyrosine-phosphorylated STAT3 and terminates STAT3 phosphorylation about 2 h after initial exposure of cells to members of the IL-6 family of cytokines by binding cooperatively to the common receptor subunit gp130 and JAKs 1 and 2. We show here that when the epidermal growth factor receptor (EGFR) is present and active, STAT3 is rephosphorylated about 4 h after exposure of cells to IL-6 or oncostatin M and remains active for many hours. Newly synthesized IL-6 drives association of the IL-6 receptor and gp130 with EGFR, leading to EGFR-dependent rephosphorylation of STAT3, which is not inhibited by the continued presence of SOCS3. This second wave of STAT3 activation supports sustained expression of a subset of IL-6-induced proteins, several of which play important roles in inflammation and cancer, in which both IL-6 secretion and EGFR levels are often elevated.

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STAT3 activation potentiates IL-6 signaling by increasing receptor and ligand levels.
“STAT3 activation potentiates IL-6 signaling by increasing receptor and ligand levels”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [37]
The Discussion (page not provided) describes IL-6-driven secretion of more IL-6 and a second wave of STAT3 activation, supporting a feedback effect on ligand availability. It describes association of IL-6R with EGFR, not an increase in receptor levels caused by STAT3 activation. (LLM, conf=0.84)
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IL-6 受体与 EGF 受体相互作用增强 IL-6 诱导的 STAT3 信号转导作用研究
王宇昕 (2013) · Lanzhou University Institutional Repository
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Authors: Wang, Y., van Boxel-Dezaire, A. H. H., Cheon, H., Yang, J., & Stark, G. R.
Affiliations: Cleveland Clinic (US)
Department of Molecular Genetics, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195
ORCID: Wang, Yuxin
Stark, George R.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2013-09-30
Volume: 110
Issue: 42
Pages: 16975-16980
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1315862110
PMC: PMC3801081
OpenAlex: W2054464764
Cited by: 327
References: 39
Citations by year: 2026: 21 · 2025: 37 · 2024: 31 · 2023: 21 · 2022: 34 · 2021: 30 · 2020: 32 · 2019: 31 · 2018: 22 · 2017: 21 · 2016: 18 · 2015: 14 · 2014: 12 · 2013: 1
FWCI: 8.04
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: other-oa
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion, other-oa)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Lanzhou University Institutional Repository (submittedVersion, cc-by-nc)
Funders: National Cancer Institute (P01CA062220)
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 › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords: STAT3 activation, interleukin-6, epidermal growth factor receptor, IL-6 receptor, SOCS3, gp130, constitutive STAT3 activation, oncostatin M, IL-6 family cytokines, receptor heterodimerization, inflammation, cancer
MeSH terms: Suppressor of Cytokine Signaling 3 Protein, Antineoplastic Agents, Gene Expression Regulation, Humans, Inflammation, Neoplasms, Phosphorylation, Protein Binding, Interleukin-6, STAT3 Transcription Factor, Cytokine Receptor gp130, Suppressor of Cytokine Signaling Proteins, Janus Kinase 1, Janus Kinase 2, Oncostatin M, Hep G2 Cells, ErbB Receptors

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STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor

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