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Cited by 178Cytokine Signaling Pathways and InteractionsProtein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase Signaling

Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression

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SCHAPER, Fred, GENDO, Cornelia, ECK, Monika, SCHMITZ, Jochen, GRIMM, Carsten, ANHUF, Dirk, KERR, Ian M., HEINRICH, Peter C.·1998·Biochemical Journal
DOI 10.1042/bj3350557PMC PMC1219816
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Abstract

Stimulation of the interleukin-6 (IL-6) signalling pathway occurs via the IL-6 receptor–glycoprotein 130 (IL-6R–gp130) receptor complex and results in the regulation of acute-phase protein genes in liver cells. Ligand binding to the receptor complex leads to tyrosine phosphorylation and activation of Janus kinases (Jak), phosphorylation of the signal transducing subunit gp130, followed by recruitment and phosphorylation of the signal transducer and activator of transcription factors STAT3 and STAT1 and the src homology domain (SH2)-containing protein tyrosine phosphatase (SHP2). The tyrosine phosphorylated STAT factors dissociate from the receptor, dimerize and translocate to the nucleus where they bind to enhancer sequences of IL-6 target genes. Phosphorylated SHP2 is able to bind growth factor receptor bound protein (grb2) and thus might link the Jak/STAT pathway to the ras/raf/mitogen-activated protein kinase pathway. Here we present data on the dose-dependence, kinetics and kinase requirements for SHP2 phosphorylation after the activation of the signal transducer, gp130, of the IL-6-type family receptor complex. When human fibrosarcoma cell lines deficient in Jak1, Jak2 or tyrosine kinase 2 (Tyk2) were stimulated with IL-6–soluble IL-6R complexes it was found that only in Jak1-, but not in Jak 2- or Tyk2-deficient cells, SHP2 activation was greatly impaired. It is concluded that Jak1 is required for the tyrosine phosphorylation of SHP2. This phosphorylation depends on Tyr-759 in the cytoplasmatic domain of gp130, since a Tyr-759 → Phe exchange abrogates SHP2 activation and in turn leads to elevated and prolonged STAT3 and STAT1 activation as well as enhanced acute-phase protein gene induction. Therefore, SHP2 plays an important role in acute-phase gene regulation.

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  • SHP2 is rapidly recruited to gp130 and phosphorylated by JAKs, which hints to a function as early feedback inhibitor.

    “In response to IL-6 SHP2 is rapidly recruited to gp130 [8] and phosphorylated by JAKs [11], which hints to a function as early feedback inhibitor.”

    From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [11]

    The Introduction reports transient SHP2 phosphorylation alongside gp130 activation and SHP2–gp130 complex formation, and describes SHP2 as inhibitory. In “SHP2 phosphorylation requires specific Jaks,” the paper finds that Jak1 is required but says it cannot determine whether Jak1 phosphorylates SHP2 directly or another kinase does so. Thus it supports JAK-dependent phosphorylation, but not an unqualified claim that JAKs themselves phosphorylate SHP2. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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  • The lack of influence of SHP2 on robustness of late IL-6-induced STAT3 activation might be explained by the fact that SHP2 itself is phosphorylated rapidly in response to IL-6, which causes dissociation from gp130.

    “The lack of influence of SHP2 on robustness of late IL-6-induced STAT3 activation (Fig. 4) might be explained by the fact that SHP2 itself is phosphorylated rapidly in response to IL-6 (Fig. 1b) which causes dissociation from gp130 [9–11].”

    From The tyrosine phosphatase SHP2 increases robustness and information transfer within IL-6-induced JAK/STAT signalling (2021) · cites this paper as [11]

    In “The time-course of SHP2 phosphorylation corresponds to that of gp130” (page unavailable), SHP2 phosphorylation is detected five minutes after IL-6 stimulation, and SHP2–gp130 complex formation follows the phosphorylation time courses. The paper does not establish that phosphorylation of SHP2 causes it to dissociate from gp130; gp130 phosphorylation also declines over that period. (LLM, conf=0.85)

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Research works printed but not linked: 3

  1. Nicola, N. A. (1994) in Guidebook to Cytokines and their Receptors (Nicola, N. A., ed.), pp. 1-7, Oxford University Press, Oxford
  2. Murakami, M., Narazaki, M., Hibi, M., Yawata, H., Yasukawa, K., Hamaguchi, M., Taga, T. and Kishimoto, T. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 11349-11353
  3. Heinrich, P. C., Behrmann, I., Graeve, L., Gro$ tzinger, J., Haan, S., Horn, F., Horsten, U., Kerr, I. M., May, P., Mu$ ller-Newen, Schaper, F., Terstegen, L. and Thiel, S. (1998) in Signalling in the Liver (Ha$ ussinger, D. and Heinrich, P. C., eds.), pp. 55-71, Kluwer Academic Publishers, Dordrecht/Boston/London

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Authors
SCHAPER, F., GENDO, C., ECK, M., SCHMITZ, J., GRIMM, C., ANHUF, D., KERR, I. M., & HEINRICH, P. C.
Affiliations
  • RWTH Aachen University (DE)
  • Imperial Cancer Research Fund, 44 Lincoln's Inns Field, London WC2A 3PX, U.K.
Corresponding author
  • SCHAPER, Fred
  • GENDO, Cornelia
  • ECK, Monika
  • SCHMITZ, Jochen
  • GRIMM, Carsten
  • ANHUF, Dirk
ORCID
SCHAPER, Fred
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
1998-11-01
Volume
335
Issue
3
Pages
557-565
ISSN
  • 0264-6021 (ISSN-L)
  • 1470-8728
DOI
10.1042/bj3350557
PMC
PMC1219816
OpenAlex
W1939561089
Cited by
178
References
43
Citations by year
2026: 1 · 2024: 5 · 2023: 1 · 2022: 2 · 2021: 5 · 2020: 7 · 2019: 7 · 2018: 4 · 2017: 6 · 2016: 5 · 2015: 4 · 2014: 8 · 2013: 5 · 2012: 6
FWCI
4.68
Type
journal article
Language
en
Open access
Locations
  • Biochemical Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Deutscher Akademischer Austauschdienst
  • Deutsche Forschungsgemeinschaft
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
SHP2, protein tyrosine phosphatase, gp130, IL-6 signaling, JAK1, JAK2, TYK2, STAT3, STAT1, acute phase proteins, tyrosine phosphorylation, Grb2, RAS/RAF/MEK pathway, hepatic gene expression, fibrosarcoma cells
MeSH terms
DNA-Binding Proteins, Enzyme Activation, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Membrane Glycoproteins, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Tumor Cells, Cultured, Signal Transduction, Trans-Activators, Antigens, CD, Interleukin-6, Mutagenesis, Site-Directed, Protein Tyrosine Phosphatases, src Homology Domains, Receptors, Interleukin-6, Intracellular Signaling Peptides and Proteins, STAT3 Transcription Factor, Cytokine Receptor gp130, Janus Kinase 1, Janus Kinase 2, TYK2 Kinase, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatase, Non-Receptor Type 11, SH2 Domain-Containing Protein Tyrosine Phosphatases

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