Signaling mechanisms through gp130: A model of the cytokine system

doi:10.1016/S1359-6101(98)80005-1

Cytokine & Growth Factor Reviews

Volume 8, Issue 4, December 1997, Pages 241-252

https://doi.org/10.1016/S1359-6101(98)80005-1 Get rights and content

Abstract

The interleukin-6 cytokine family plays roles in a wide variety of tissues and organs, including the immune hematopoietic and nervous systems. Gp130 is a signal-transducing subunit shared by the receptors for the IL-6 family of cytokines. The binding of a ligand to its receptor induces the dimerization of gp 130, leading to the activation of JAK tyrosine kinase and tyrosine phosphorylation of gpl30. These events lead to the activation of multiple signal-transduction pathways, such as the STAT, Ras-MAPK and PI-3 kinase pathways whose activation is controlled by distinct regions of gp130. We propose a model showing that the outcome of the signal transduction depends on the balance or interplay among the contradictory signal transduction pathways that are simultaneously generated through a cytokine receptor in a given target cell.

References (139)

P.H. Patterson et al.
Neuronal differentiation factors/cytokines and synaptic plasticity
Cell
(1993)
D. Pennica et al.
Cardiotrophin-1: a multifunctional cytokine that signals via LIF receptor-gp130 dependent pathways
Cytokine Growth Factor Rev.
(1996)
T. Kishimoto et al.
Interleukin-6 family of cytokines and gp 130
Blood
(1995)
D.J. Hilton
LIF: lots of interesting functions
Trends Biochem. Sci.
(1992)
D.P. Gearing
The leukemia inhibitory factor and its receptor
Adv. Immunol.
(1993)
J.N. Ihle et al.
Signaling by the cytokine receptor superfamily: JAKs and STATs
Trends Biochem. Sci.
(1994)
S. Davis et al.
The molecular biology of the CNTF receptor
Curv. Opin. Cell Biol.
(1993)
T. Taga et al.
Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130
Cell
(1989)
M. Hibi et al.
Molecular cloning and expression of an IL-6 signal transducer, gpl30
Cell
(1990)
J.F. Bazan
Haemopoietic receptors and helical cytokines
Immunol. Today
(1990)

D.P. Gearing et al.

Homology of the p40 subunit of natural killer cell stimulatory factor (NKSF) with the extracellular domain of the interleukin-6 receptor

Cell

(1991)

S. Jing et al.

GDNF-induced activation of the Ret protein tyrosine kinase is mediated by GDNFR-α, a novel receptor for GDNF

Cell

(1996)

L. Velazquez et al.

A protein tyrosine kinase in the interferon a/b signaling pathway

Cell

(1992)

B.A. Witthuhn et al.

Jak2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin

Cell

(1993)

L.S. Argetsinger et al.

Identification of Jak2 as a growth hormone receptor-associated tyrosine kinase

Cell

(1993)

T. Matsuda et al.

Interleukin-6-induced tyrosine phosphorylation of multiple proteins in murine hematopoietic lineage cells

Biochem. Biophys. Res. Commun.

(1994)

L.C. Berger et al.

Tyrosine phosphorylation of JAKTYK kinases in malignant plasma cell lines growth-stimulated by interleukins 6 and 11

Biochem. Biophys. Res. Commun.

(1994)

S. Akira et al.

Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91related transcription factor involved in the gpl30mediated signaling pathway

Cell

(1994)

Y. Fujitani et al.

Transcriptional activation of the IL-6 response element in the junB promoter is mediated by multiple Stat family proteins

Biochem. Biophys. Res. Commun.

(1994)

V. Poli et al.

IL-6DBP, a nuclear protein involved in interleukin-6 signal transduction, defines a new family of leucine zipper proteins related to C/EBP

Cell

(1990)

Z. Wen et al.

Maximal activation of transcription by Statl and Stat3 requires both tyrosine and serine phosphorylation

Cell

(1995)

T. Fukada et al.

Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis

Immunity

(1996)

T. Yin et al.

Mitogen-activated protein kinases and ribosomal S6 protein kinases are involved in signaling pathways shared by interleukin-11, interleukin-6, leukemia inhibitory factor, and oncostatin M in mouse 3T3-LI cells

J. Biol. Chem.

(1994)

L.C. Berger et al.

Interferon-beta interrupts interleukin-6-dependent signaling events in myeloma cells

Blood

(1997)

A.D. Keegan et al.

An IL-4 receptor regin containing an insulin receptor motif is important for IL-4-mediated IRS-I phosphorylation and cell growth

Cell

(1994)

T. Hirano et al.

Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin

Nature

(1986)

A. Zilberstein et al.

Structure and expression of cDNA and genes for human interferon-beta-2, a distinct species inducible by growth-stimulatory cytokines

EMBO J.

(1986)

G. Haegeman et al.

Structural analysis of the sequence encoding for an inducible 26-kDa protein in human fibroblasts

Eur. J. Biochem.

(1986)

L.T. May et al.

Anti-β-interferon antibodies inhibit the increased expression of HLA-B7 mRNA in tumor necrosis factor-treated human fibroblasts: Structural studies of the β interferon involved

T. Hirano et al.

Interleukin 6

T. Hirano et al.

Signal transduction through gp130 that is shared among the receptors for the interleukin 6 related cytokine subfamily

Stem Cells

(1994)

D. Gearing et al.

Molecular cloning and expression of cDNA encoding a marine myeloid leukaemia inhibitory factor (LIF)

EMBO J.

(1987)

L.-F.H. Lin et al.

Purification, cloning and expression of ciliary neurotrophic factor (CNTF)

Science

(1989)

N. Malik et al.

Molecular cloning, sequence analysis, and functional expression of a novel growth regulator, oncostatin M

Mol. Cell. Biol.

(1989)

S.R. Paul et al.

Molecular cloning of a cDNA encoding interleukin 11, a stromal cell-derived lymphopoietic and hematopoietic cytokine

D. Pennica et al.

Expression cloning of cardiotrophin-1, a cytokine that induces cardiac myocyte hypertrophy

Hirano, T., Interleukin 6 and its receptor: ten years later. Intern Rev. Immunol., in...

D. Metcalf

The leukemia inhibitory factor (LIF)

Int. J. Cell Cloning

(1991)

T. Hirano

The biology of interleukin-6

Chem. Immunol.

(1992)

Y.C. Yang

Interleukin 11: an overview

Stem Cells

(1993)

N.Y. lp et al.

The neurotrophins and CNTF: two families of collaborative neurotrophic factors

Ann. Rev. Neurosci.

(1996)

M. Hibi et al.

IL-6 cytokine family and signal transduction: a model of the cytokine system

J. Mol. Med.

(1996)

J.J. Darnell et al.

Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins

Science

(1994)

C. Schindler et al.

Transcriptional responses to polypeptide ligands: The JAK-STAT pathway

Annu. Rev. Biochem.

(1995)

J.N. Ihle et al.

Signaling through the hematopoietic cytokine receptors

Anna. Rev. Immunol.

(1995)

K. Yamasaki et al.

Cloning and expression of the human interleukin-6 (BSF-2,'IFN beta 2) receptor

Science

(1988)

T. Sugita et al.

Functional murine interleukin 6 receptor with the intracisternal A particle gene product at is cytoplasmic domain

L.D. Ward et al.

High affinity interleukin-6 receptor is a hexameric complex consisting of two molecules each of interleukin-6, interleukin-6 receptor, and gp-130

J. Biol. Chem.

(1994)

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¹: [email protected]; http:// www.med.osaka-u.ac.jp/pub/molonc/www/Eindex.html

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Mini reviewSignaling mechanisms through gp130: A model of the cytokine system

Abstract

Cell

Cytokine Growth Factor Rev.

Blood

Trends Biochem. Sci.

Adv. Immunol.

Trends Biochem. Sci.

Curv. Opin. Cell Biol.

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Immunol. Today

Cell

Cell

Cell

Cell

Cell

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Biochem. Biophys. Res. Commun.

Cell

Biochem. Biophys. Res. Commun.

Cell

Cell

Immunity

J. Biol. Chem.

Blood

Cell

Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin

Nature

Structure and expression of cDNA and genes for human interferon-beta-2, a distinct species inducible by growth-stimulatory cytokines

EMBO J.

Structural analysis of the sequence encoding for an inducible 26-kDa protein in human fibroblasts

Eur. J. Biochem.

Anti-β-interferon antibodies inhibit the increased expression of HLA-B7 mRNA in tumor necrosis factor-treated human fibroblasts: Structural studies of the β interferon involved

Interleukin 6

Signal transduction through gp130 that is shared among the receptors for the interleukin 6 related cytokine subfamily

Stem Cells

Molecular cloning and expression of cDNA encoding a marine myeloid leukaemia inhibitory factor (LIF)

EMBO J.

Purification, cloning and expression of ciliary neurotrophic factor (CNTF)

Science

Molecular cloning, sequence analysis, and functional expression of a novel growth regulator, oncostatin M

Mol. Cell. Biol.

Molecular cloning of a cDNA encoding interleukin 11, a stromal cell-derived lymphopoietic and hematopoietic cytokine

Expression cloning of cardiotrophin-1, a cytokine that induces cardiac myocyte hypertrophy

The leukemia inhibitory factor (LIF)

Int. J. Cell Cloning

The biology of interleukin-6

Chem. Immunol.

Interleukin 11: an overview

Stem Cells

The neurotrophins and CNTF: two families of collaborative neurotrophic factors

Ann. Rev. Neurosci.

IL-6 cytokine family and signal transduction: a model of the cytokine system

J. Mol. Med.

Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins

Science

Transcriptional responses to polypeptide ligands: The JAK-STAT pathway

Annu. Rev. Biochem.

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Science

Functional murine interleukin 6 receptor with the intracisternal A particle gene product at is cytoplasmic domain

High affinity interleukin-6 receptor is a hexameric complex consisting of two molecules each of interleukin-6, interleukin-6 receptor, and gp-130

J. Biol. Chem.

Mini review
Signaling mechanisms through gp130: A model of the cytokine system