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Cited by 170Protein Tyrosine PhosphatasesCytokine Signaling Pathways and InteractionsProtein Kinase Regulation and GTPase Signaling

Dual Signaling Role of the Protein Tyrosine Phosphatase SHP-2 in Regulating Expression of Acute-Phase Plasma Proteins by Interleukin-6 Cytokine Receptors in Hepatic Cells

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Kim, Hongkyun, Baumann, Heinz·1999·Molecular and Cellular Biology
DOI 10.1128/mcb.19.8.5326PMC PMC84376
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Abstract

One of the major actions of interleukin-6 (IL-6) is the transcriptional activation of acute-phase plasma proteins (APP) genes in liver cells. Signaling by the IL-6 receptor is mediated through the signal transducing subunit gp130 and involves the activation of Janus-associated kinases (JAKs), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein (MAP) kinase. Functional analysis of gp130 in rat hepatoma cells by using transduced chimeric G-CSFR-gp130 receptor constructs demonstrates that SHP-2, the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase, acts as a negative regulator of the JAK/STAT signaling in part by downregulating JAK activity, thereby indirectly moderating the induction of STAT3-dependent APP genes. This study shows that in hepatoma cells, the recruitment and tyrosine phosphorylation of SHP-2, but not SHC, is the primary signaling event associated with the activation of MAP kinases (ERK1/2) by gp130. Overexpression of truncated SHP-2 that lacks Grb2-interacting sites, but not the full-length catalytically inactive SHP-2, reduces ERK activation by IL-6, confirming the signal-mediating role of SHP-2. Activation of ERK1/2 is correlated with induction of the immediate-early response genes. Stimulation of the c-fos, c-jun, and egr-1 genes is essentially absent in cells expressing gp130 with a Y759F mutation, which is unable to recruit SHP-2. Interestingly, both JAK/STAT and SHP-2 pathways regulate the induction of the junB gene. Moreover, disengagement of SHP-2 from gp130 signaling not only enhances APP gene induction but also further reduces cell proliferation, in part correlated with the attenuated expression of immediate-early response genes. These results suggest that IL-6 regulation of APP genes is affected by SHP-2 in two ways: SHP-2 acts as a phosphatase on the JAK/STAT pathway and serves as linker to the MAP kinase pathway, which in turn moderates APP production.

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  • SHP2 has a dual function in IL-6-induced signalling: it reduces JAK/STAT signalling and is indispensable for IL-6-induced MAPK pathway activation.

    “SHP2 has a dual function in IL-6-induced signalling. While it reduces JAK/STAT signalling it is indispensable for IL-6-induced MAPK pathway activation [32, 33].”

    From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [33]

    The Abstract states that SHP-2 negatively regulates JAK/STAT signaling and helps mediate gp130-dependent ERK activation in hepatoma cells. But it reports that interfering with SHP-2 reduces ERK activation, not that SHP-2 is indispensable for all IL-6-induced MAPK activation; the claim also omits the hepatic-cell setting. (LLM, conf=0.86)

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Authors
Kim, H., & Baumann, H.
Affiliations
Roswell Park Comprehensive Cancer Center (US)
ORCID
Kim, Hongkyun
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
1999-08-01
Volume
19
Issue
8
Pages
5326-5338
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.19.8.5326
PMC
PMC84376
OpenAlex
W2119074033
Cited by
170
References
85
Citations by year
2026: 2 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 2 · 2019: 3 · 2017: 2 · 2016: 4 · 2015: 7 · 2014: 1 · 2013: 6 · 2012: 9
FWCI
5.06
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01ca026122-19)
  • National Cancer Institute (CA-26122, CA 16056., P30CA016056)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
SHP2, protein tyrosine phosphatase, interleukin-6, gp130, JAK/STAT signaling, MAPK signaling, ERK1/2, STAT3, hepatoma cells, liver, immediate early genes, c-fos, c-Jun, EGR1, JunB, cell proliferation, cytokine receptor signaling
MeSH terms
Acute-Phase Proteins, Acute-Phase Reaction, Animals, DNA-Binding Proteins, Enzyme Activation, Gene Expression Regulation, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Liver Neoplasms, Experimental, Membrane Glycoproteins, Neoplasm Proteins, Phosphorylation, Protein Processing, Post-Translational, Protein-Tyrosine Kinases, Proteins, Recombinant Fusion Proteins, Transcription, Genetic, Transfection, Signal Transduction, Transcriptional Activation, Trans-Activators, Antigens, CD, Interleukin-6, Gene Expression Regulation, Neoplastic, Protein Tyrosine Phosphatases, Calcium-Calmodulin-Dependent Protein Kinases, Receptors, Interleukin-6, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinases, Intracellular Signaling Peptides and Proteins, Mitogen-Activated Protein Kinase 3, Adaptor Proteins, Signal Transducing, STAT3 Transcription Factor, Cytokine Receptor gp130, GRB2 Adaptor Protein, Rats, Janus Kinase 1, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatase, Non-Receptor Type 11, SH2 Domain-Containing Protein Tyrosine Phosphatases

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