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

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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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Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway
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Stat3: a STAT Family Member Activated by Tyrosine Phosphorylation in Response to Epidermal Growth Factor and Interleukin-6
Zhong, Z., Wen, Z., & Darnell, J. E. (1994) · Science · doi:10.1126/science.8140422 · Cited by 2,070

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The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension
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“Only JAK1 is essential for IL-6 and IL-11 signaling, while JAK2 and Tyk2 modulate the signals [24,27,28] (Figure 2A).”
Background
The Salmonella Secreted Effector SarA/SteE Mimics Cytokine Receptor Signaling to Activate STAT3
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Influential
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Background
Absence of Suppressor of Cytokine Signalling 3 Reduces Self-Renewal and Promotes Differentiation in Murine Embryonic Stem Cells
Forrai, A., Boyle, K., Hart, A. H., Hartley, L., Rakar, S., Willson, T. A., Simpson, K., Roberts, A. W., Alexander, W. S., Voss, A. K., et al. (2005) · Stem Cells · doi:10.1634/stemcells.2005-0323 · Cited by 65
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“Binding of SHP2 to the (p)Y759 motif in gp130 and subsequent phosphorylation by JAKs initiates activation of MAPK by recruiting growth factor-receptor-bound protein/son of sevenless (Grb/SOS) complex and/or Grb2-associated binder-1 (Gab1) to the membrane [15–17].”
BackgroundInfluentialSelf-citation
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Proteolytic control of Interleukin-11 and Interleukin-6 biology
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The Inhibitory Effect of IL-1β on IL-6-Induced α2-Macroglobulin Expression Is Due to Activation of NF-κB
Bode, J. G., Fischer, R., Häussinger, D., Graeve, L., Heinrich, P. C., & Schaper, F. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.3.1469 · Cited by 50
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“Attenuated phosphorylation of the tyrosine-759 motif increases IL-6-dependent STAT3 activity [42,43] and reduces MAPK activity [44,45], which is related to gastric adenomas, autoimmune arthritis and increased Th1 cytokine expression.”
Background
Studies on the Interleukin-6-type Cytokine Signal Transducer gp130 Reveal a Novel Mechanism of Receptor Activation by Monoclonal Antibodies
Müller‐Newen, G., Küster, A., Wijdenes, J., Schaper, F., & Heinrich, P. C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.7.4579 · Cited by 41
Self-citation
Interleukin‐6‐induced proliferation of pre‐B cells mediated by receptor complexes lacking the SHP2/SOCS3 recruitment sites revisited
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Modulation of the Interleukin-6 Receptor Subunit Glycoprotein 130 Complex and Its Signaling by LMO4 Interaction*
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A single amino acid substitution (Trp666→Ala) in the interbox1/2 region of the interleukin-6 signal transducer gp130 abrogates binding of JAK1, and dominantly impairs signal transduction
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Self-citation
Interleukin-6 and Interferon-α Signaling via JAK1–STAT Differentially Regulate Oncolytic versus Cytoprotective Antiviral States
Danziger, O., Pupko, T., Bacharach, E., & Ehrlich, M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00094 · Cited by 35
“Importantly, in spite of JAK1 being a central mediator of IL-6 signaling (43), the lack of JAK1 expression in LNCaP cells [due to genetic mutations and epigenetic silencing (13–15)] was not experimentally addressed in the context of IL-6 signaling.”
Background
Shp2 Inhibits Proliferation of Esophageal Squamous Cell Cancer via Dephosphorylation of Stat3
Chen, Q., Han, T., Tang, H., Huang, K., Min, J., Li, J., Ding, X., & Xu, Z. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18010134 · Cited by 38
“The inhibitory function of Shp2 on Stat3 activity requires Tyr-759 in the cytoplasmatic domain of gp130, an up-stream signal-transduction component of Stat3 [37,38].”
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“Such an approach could encompass the use of myeloid celltargeted lentiviral vectors [196], [197] or nanoparticles [198], which could than deliver silencing RNA for STAT3 [13], [178-180] or genes encoding negative regulators of STAT3 [8-11].”
Background
Zebrafish peptidoglycan recognition protein SC (zfPGRP-SC) mediates multiple intracellular signaling pathways
Chang, M. X., Wang, Y. P., & Nie, P. (2008) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2008.11.007 · Cited by 38
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Leukemia Inhibitory Factor Induces the Chemomigration of Immortalized Gonadotropin-Releasing Hormone Neurons through the Independent Activation of the Janus Kinase/Signal Transducer and Activator of Transcription 3, Mitogen-Activated Protein Kinase/Extracellularly Regulated Kinase 1/2, and Phosphatidylinositol 3-Kinase/Akt Signaling Pathways
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IL6 Promotes a STAT3-PRL3 Feedforward Loop via SHP2 Repression in Multiple Myeloma
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Self-citation
Targeting STAT-3 signaling pathway in cancer for development of novel drugs: Advancements and challenges
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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)
Department of Biochemistry, RWTH-Aachen, Pauwelsstraße 30, D52057 Aachen, Germany
Imperial Cancer Research Fund, 44 Lincoln's Inns Field, London WC2A 3PX, U.K.
Corresponding author: SCHAPER, Fred
GENDO, Cornelia
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: bronze
doi.org
Locations: Biochemical Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Deutscher Akademischer Austauschdienst
Deutsche Forschungsgemeinschaft
Topics: Life Sciences › Immunology and Microbiology › Immunology › 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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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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