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Results for “Cytokine Receptor gp130”

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At least 19 recordsLinked to original sources

PubMed1998

The specification of sympathetic neurotransmitter phenotype depends on gp130 cytokine receptor signaling.

Sympathetic ganglia are composed of noradrenergic and cholinergic neurons. The differentiation of cholinergic sympathetic neurons is characterized by the expression of choline acetyltransferase (ChAT) and vasoactive intestinal peptide (VIP), induced in vitro by a subfamily of cytokines, including LIF, CNTF, GPA, OSM and cardiotrophin-1 (CT-1). To interfere with the function of these neuropoietic cytokines in vivo, antisense RNA for gp130, the common signal-transducing receptor subunit for neuropoietic cytokines, was expressed in chick sympathetic neurons, using retroviral vectors. A strong reduction in the number of VIP-expressing cells, but not of cells expressing ChAT or the adrenergic marker tyrosine hydroxylase (TH), was observed. These results reveal a physiological role of neuropoietic cytokines for the control of VIP expression during the development of cholinergic sympathetic neurons.

Amino Acid Sequence↗

PubMed2000

Identification of a gp130 cytokine receptor critical site involved in oncostatin M response.

Gp130 cytokine receptor is involved in the formation of multimeric functional receptors for interleukin-6 (IL-6), IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor, and cardiotrophin-1. Cloning of the epitope recognized by an OSM-neutralizing anti-gp130 monoclonal antibody identified a portion of gp130 receptor localized in the EF loop of the cytokine binding domain. Site-directed mutagenesis of the corresponding region was carried out by alanine substitution of residues 186-198. To generate type 1 or type 2 OSM receptors, gp130 mutants were expressed together with either LIF receptor beta or OSM receptor beta. When positions Val-189/Tyr-190 and Phe-191/Val-192 were alanine-substituted, Scatchard analyses indicated a complete abrogation of OSM binding to both type receptors. Interestingly, binding of LIF to type 1 receptor was not affected, corroborating the notion that in this case gp130 mostly behaves as a converter protein rather than a binding receptor. The present study demonstrates that positions 189-192 of gp130 cytokine binding domain are essential for OSM binding to both gp130/LIF receptor beta and gp130/OSM receptor beta heterocomplexes.

Alanine↗

PubMed2003

The cytokine receptor gp130: faithfully promiscuous.

Diverse cytokines can signal through receptor complexes containing the gp130 subunit. These cytokines, which include interleukin (IL)-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), and CLC (cardiotrophin-like cytokine), are implicated in inflammatory and immune responses, heart development, and fertility. The gp130 receptor-ligand complexes are contrasted with the complex formed by erythropoietin (Epo) and its receptor, EpoR. Also discussed are insights provided by the structural analysis of IL-6, its alpha receptor (IL6Ralpha), and the signal transducer gp130 for understanding receptor-ligand assembly, for predicting the structures of ligand-receptor complexes of the other IL-6-type cytokines, and for rational drug design.

Antigens, CD↗

PubMed2005

Dimerization of the cytokine receptors gp130 and LIFR analysed in single cells.

The cytokine receptor gp130 is the shared signalling subunit of the IL-6-type cytokines. Interleukin-6 (IL-6) signals through gp130 homodimers whereas leukaemia inhibitory factor (LIF) exerts its action through a heterodimer of gp130 and the LIF receptor (LIFR). Related haematopoietic receptors such as the erythropoietin receptor have been described as preformed dimers in the plasma membrane. Here we investigated gp130 homodimerization and heterodimerization with the LIFR by fluorescence resonance energy transfer (FRET) and bimolecular fluorescence complementation (BiFC). We detected a FRET signal between YFP- and CFP-tagged gp130 at the plasma membrane of unstimulated cells that does not increase upon IL-6 stimulation. However, FRET between YFP-tagged gp130 and CFP-tagged LIFR considerably increased upon LIF stimulation. Using a BiFC approach that detects stable interactions we show that fluorescence complementation of gp130 constructs tagged with matching 'halves' of fluorescent proteins increases upon IL-6 stimulation. Taken together, these findings suggest that transient gp130 homodimers on the plasma membrane are stabilized by IL-6 whereas heterodimerization of gp130 with the LIFR is mainly triggered by the ligand. This view is supported by the observation that the simultaneous action of two IL-6 binding domains on two gp130 molecules is required to efficiently recruit a fluorescent IL-6 (YFP-IL-6) to the plasma membrane.

Animals↗

PubMed2005

Signaling conformations of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6 receptor.

gp130 is a shared cytokine signaling receptor and the founding member of the 'tall' class of cytokine receptors. A crystal structure of the ligand-binding domains of gp130 in complex with human interleukin-6 (IL-6) and its a-receptor (IL-6Ralpha) revealed a hexameric architecture in which the gp130 membrane-distal regions were approximately 100 A apart, in contrast to the close apposition seen between short cytokine receptor complexes. Here we used single-particle EM to visualize the entire extracellular hexameric IL-6-IL-6Ralpha-gp130 complex, containing all six gp130 domains. The structure reveals that gp130 is bent such that the membrane-proximal domains of gp130 are close together at the cell surface, enabling activation of intracellular signaling. Variation in the receptor bend angles suggests a possible conformational transition from open to closed states upon ligand binding; this transition is probably representative of the other tall cytokine receptors.

Antigens, CD↗

PubMed2001

Structure of an extracellular gp130 cytokine receptor signaling complex.

The activation of gp130, a shared signal-transducing receptor for a family of cytokines, is initiated by recognition of ligand followed by oligomerization into a higher order signaling complex. Kaposi's sarcoma-associated herpesvirus encodes a functional homolog of human interleukin-6 (IL-6) that activates human gp130. In the 2.4 angstrom crystal structure of the extracellular signaling assembly between viral IL-6 and human gp130, two complexes are cross-linked into a tetramer through direct interactions between the immunoglobulin domain of gp130 and site III of viral IL-6, which is necessary for receptor activation. Unlike human IL-6 (which uses many hydrophilic residues), the viral cytokine largely uses hydrophobic amino acids to contact gp130, which enhances the complementarity of the viral IL-6-gp130 binding interfaces. The cross-reactivity of gp130 is apparently due to a chemical plasticity evident in the amphipathic gp130 cytokine-binding sites.

Antigens, CD↗

PubMed2003

Long term association of the cytokine receptor gp130 and the Janus kinase Jak1 revealed by FRAP analysis.

Signal transduction through cytokine receptors is mediated mainly by non-covalently associated Jak tyrosine kinases. By confocal microscopy, the cytokine receptor gp130 and Jak1, fused with either yellow (YFP) or cyan (CFP) fluorescent protein, were found to be colocalized predominantly at intracellular vesicular structures and at the plasma membrane. Quantitative fluorescence recovery after photobleaching (FRAP) analysis at the plasma membrane revealed equal mobilities for gp130-YFP and Jak1-YFP. Thus, Jak1-YFP diffuses like a transmembrane protein indicating that membrane-bound Jak1 does not exchange rapidly with cytosolic Jaks. Applying a novel dual-color FRAP approach we found that immobilization of gp130-CFP by a pair of monoclonal antibodies led to a corresponding immobilization of co-transfected Jak1-YFP. We conclude from these findings that Jak1, once bound to a gp130 molecule, does not exchange between different receptors at the plasma membrane neither via the cytoplasmic compartment nor via a membrane-associated state.

Animals↗

PubMed1999

Activation of Stat3 by cytokine receptor gp130 ventralizes Xenopus embryos independent of BMP-4.

Stat3 is one of the main signaling components of cytokine receptors, including gp130. Here we show that activation of cytokine receptor gp130 resulted in a dramatic ventralization of Xenopus embryos and that the ventralization correlated well with Stat3 activation potential of the receptor. This finding led to identification of Xenopus Stat3 (Xstat3), which showed a 95% homology to its murine and human counterparts, at the amino acid level, and was expressed from the one-cell stage throughout development. The mechanism of gp130/XStat3-mediated ventralization proved to be independent of BMP-4. gp130/Xstat3 stimulation inhibited Smad2-induced ectopic axis formation in embryos and Smad2-dependent luciferase activity. A dominant-negative Stat3, in contrast, dorsalized Xenopus embryos, resulting in ectopic axis formation. We propose that Stat3-mediated signaling has the capacity to modify dorsoventral patterning in the early development of Xenopus.

Animals↗

PubMed1998

Gab1 acts as an adapter molecule linking the cytokine receptor gp130 to ERK mitogen-activated protein kinase.

Gab1 has structural similarities with Drosophila DOS (daughter of sevenless), which is a substrate of the protein tyrosine phosphatase Corkscrew. Both Gab1 and DOS have a pleckstrin homology domain and tyrosine residues, potential binding sites for various SH2 domain-containing adapter molecules when they are phosphorylated. We found that Gab1 was tyrosine phosphorylated in response to various cytokines, such as interleukin-6 (IL-6), IL-3, alpha interferon (IFN-alpha), and IFN-gamma. Upon the stimulation of IL-6 or IL-3, Gab1 was found to form a complex with phosphatidylinositol (PI)-3 kinase and SHP-2, a homolog of Corkscrew. Mutational analysis of gp130, the common subunit of IL-6 family cytokine receptors, revealed that neither tyrosine residues of gp130 nor its carboxy terminus was required for tyrosine phosphorylation of Gab1. Expression of Gab1 enhanced gp130-dependent mitogen-activated protein (MAP) kinase ERK2 activation. A mutation of tyrosine 759, the SHP-2 binding site of gp130, abrogated the interactions of Gab1 with SHP-2 and PI-3 kinase as well as ERK2 activation. Furthermore, ERK2 activation was inhibited by a dominant negative p85 PI-3 kinase, wortmannin, or a dominant negative Ras. These observations suggest that Gab1 acts as an adapter molecule in transmitting signals to ERK MAP kinase for the cytokine receptor gp130 and that SHP-2, PI-3 kinase, and Ras are involved in Gab1-mediated ERK activation.

Adaptor Proteins, Signal Transducing↗

PubMed2004

The cytokine receptor gp130 and its soluble form are under hormonal control in human endometrium and decidua.

The transmembrane protein gp130 plays a central role in cytokine action as a signal transducing receptor subunit common to all interleukin-6 type cytokines. Endometrial tissue obtained from women with a normal menstrual cycle and decidua obtained from women in the first or second trimester of pregnancy were assessed for gp130 by western blotting, immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) analysis. By immunoblotting, two forms of gp130 were detected: one-the soluble form-of approximately 100 kDa and a larger membrane-bound form of approximately 150 kDa. The latter became clearly visible in the mid to late secretory phase and was more pronounced in decidual tissue of second trimester compared to first trimester. Immunohistochemically, gp130 was located in glandular epithelial cells during the mid to late secretory phase, whereas staining in the proliferative phase was rather weak. In first and second trimester decidua, glandular cells were also positively stained. In addition, the invading trophoblast cells were gp130 positive. Soluble gp130 release was measured in the supernatants from primary endometrial and decidual cell cultures by ELISA and reached maximum values in cell cultures without addition of hormones. In cultured endometrial epithelial cells obtained during the proliferative phase of the cycle, the soluble gp130 release increased significantly under combined estradiol/progesterone supplementation which mimics the secretory phase conditions compared to estradiol supplementation alone. In cultured epithelial cells derived from decidual tissue of first trimester of pregnancy, similar effects of hormonal regulation were observed. Our results suggest that the balance between soluble gp130 and its membrane-bound form may play an important role in regulating cytokine action necessary for blastocyst implantation and for further interaction between the decidualized endometrium and the invading trophoblast.

Antigens, CD↗

PubMed2002

Tyrosine 759 of the cytokine receptor gp130 is involved in Listeria monocytogenes susceptibility.

Interleukin-6 family cytokines have been implicated in adaptive and innate immunity, hematopoiesis, and inflammation. This cytokine family shares a signal-transducing receptor subunit called gp130. gp130(F759/F759) knockin mice carry a point mutation at the SHP2-binding site of gp130 due to the replacement of tyrosine-759 (Y759 for human gp130) with phenylalanine (F). To explore the effect of this point mutation on the host response to bacterial infection, gp130(F759/F759) knockin mice were infected with Listeria monocytogenes. gp130(F759/F759) knockin mice began to die at 3 to 4 days post infection (p.i.) and showed higher mortality than did controls. Listeria titers at 3 days p.i. in the peritoneal cavity, spleen, and liver were significantly higher in gp130(F759/F759)knockin mice than in controls. Nitric oxide production, upregulation of the mRNA levels of a variety of cytokines, and listericidal activity in gp130(F759/F759) macrophages were unchanged. However, gp130(F759/F759) knockin mice displayed significantly lower levels of interferon (IFN)gamma in serum and in the culture supernatant from peritoneal exudate cells and splenocytes, in response to Listeria infection. These results suggest that the Y759 point mutation in gp130 attenuates the early phase of defense against Listeria infection, possibly owing to insufficient elevation of IFNgamma levels, and thus gp130 is a possible candidate gene for Listeria susceptibility.

Animals↗

PubMed1996

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

gp130 is a common signal transducer for the interleukin-6-related cytokines. To delineate the gp130-mediated growth signal, we established a series of pro-B cell lines expressing chimeric receptors composed of the extracellular domain of the granulocyte colony-stimulating factor receptor and the transmembrane and cytoplasmic domains of gp130. The second tyrosine (from the membrane) of gp130, which was required for the tyrosine phosphorylation of SHP-2, its association with GRB2, and activation of a MAP kinase, was essential for mitogenesis, but not for anti-apoptosis. On the other hand, the tyrosine in the YXXQ motifs essential for STAT3 activation was required for bcl-2 induction and anti-apoptosis. Furthermore, dominant-negative STAT3 inhibited anti-apoptosis. These data demonstrate that two distinct signals, mitogenesis and anti-apoptosis, are required for gp130-induced cell growth and that STAT3 is involved in anti-apoptosis.

Animals↗

PubMed2005

Bone marrow dysfunction in mice lacking the cytokine receptor gp130 in endothelial cells.

In vitro studies suggest that bone marrow endothelial cells contribute to multilineage hematopoiesis, but this function has not been studied in vivo. We used a Cre/loxP-mediated recombination to produce mice that lacked the cytokine receptor subunit gp130 in hematopoietic and endothelial cells. Although normal at birth, the mice developed bone marrow dysfunction that was accompanied by splenomegaly caused by extramedullary hematopoiesis. The hypocellular marrow contained myeloerythroid progenitors and functional repopulating stem cells. However, long-term bone marrow cultures produced few hematopoietic cells despite continued expression of gp130 in most stromal cells. Transplanting gp130-deficient bone marrow into irradiated wild-type mice conferred normal hematopoiesis, whereas transplanting wild-type bone marrow into irradiated gp130-deficient mice did not cure the hematopoietic defects. These data provide evidence that gp130 expression in the bone marrow microenvironment, most likely in endothelial cells, makes an important contribution to hematopoiesis.

Animals↗

PubMed2001

A region encompassing the FERM domain of Jak1 is necessary for binding to the cytokine receptor gp130.

The terminal portion of the Janus kinases (Jaks) contains a divergent FERM (Four-point-one, Ezrin, Radixin, Moesin) homology domain comprising 19 conserved hydrophobic regions. To determine the role of this domain in governing recruitment of Jak1, but not Jak3, to the gp130 subunit of the interleukin-6 family of cytokine receptors, the interaction of three Jak1/Jak3 chimeras with gp130 was investigated. Chimeras 1, 2 and 3 (Jak1 FERM regions 1-19, 1-18 and 1-8/Jak3, respectively) were all enzymically active. Chimeras 1 and 2 interacted with the cytoplasmic domain of gp130, although less efficiently than Jak1. Only chimera 2, however, restored gp130 signalling in Jak1-negative cells. The data are consistent with recruitment of Jak1 to gp130 through the Jak1 FERM domain, but also emphasise the likely requirement for precise Jak/receptor orientation to sustain function.

Amino Acid Sequence↗

PubMed2004

Acquiring signalling specificity from the cytokine receptor gp130.

Repeated use of a relatively small number of intracellular signalling molecules specifies tissue- and cell-type-specific responses to pleiotropic-acting growth factors and cytokines. Currently, gaining a better understanding of these mechanisms is a major challenge. The IL-6 family of cytokines shares a common receptor subunit called gp130. Phenotypic comparisons of mice with amino acid knock-in substitutions that disable individual signalling modules in gp130, with knockout mice lacking ligand-specific gp130 activation or transgenic mice with constitutive gp130 activation, has led to the identification of two molecular mechanisms. One mechanism is based on differential target-gene responsiveness to signalling threshold levels transduced by either the STAT1/3 or the SHP2/ERK cascade, which are under reciprocal negative regulation and together account for the majority of intracellular gp130 signalling. The second mechanism is based on the capacity of certain cell types to integrate the often-conflicting information transduced by these two pathways, and to prevent pathological responses.

Animals↗

PubMed2004

The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTLV-1 pX in promoting rheumatoid arthritis-like arthritis.

Rheumatoid arthritis (RA) is a polygenic autoimmune disease. The autoimmunity develops from synergistic actions of genetic and environmental factors. We generated a double-mutant mouse by crossing two murine models of RA, a gp130 mutant knock-in mouse (gp130F759/F759) and an HTLV-1 pX transgenic mouse (pX-Tg), in a C57BL/6 background, which is resistant to arthritis. The mice spontaneously developed severe arthritis with a much earlier onset than the gp130F759/F759 mice and with a much higher incidence than did the pX-Tg mice. The symptoms of gp130F759/F759 mice, including lymphoadenopathy, splenomegaly, hyper-gamma-globulinemia, autoantibody production, increases in memory/activated T cells and granulocytes in the peripheral lymphoid organs, and a decrease in the class II MHC(bright) CD11c+ population, were augmented in the double mutants. Marked reductions in incidence, severity and immunological abnormalities were seen in the triple mutant, IL-6-/-/gp130F759/F759/pX-Tg, indicating that the arthritis in the double mutant is IL-6 dependent. gp130F759/F759/pX-Tg is a unique mouse model for RA.

Animals↗

PubMed1997

Cytokine-dependent gp130 receptor subunit regulates human fetal pituitary adrenocorticotropin hormone and growth hormone secretion.

We have shown recently that leukemia inhibitory factor (LIF) and oncostatin M (OSM), two members of the gp130-dependent cytokine family, stimulate murine proopiomelanocortin (POMC) transcription and adrenocorticotropin hormone (ACTH) secretion. LIF and corticotropin-releasing hormone (CRH) also synergistically induced in vivo ACTH secretion in fetal nonhuman primates. To elucidate the role of the gp130-related cytokines in human pituitary hormone regulation, we tested expression of gp130-related cytokine receptors in human fetal pituitaries. Using RT-PCR, mRNA expression of receptors for LIF, IL-6, and CRH, and the gp130 subunit, were all detected in fetal pituitaries of 18- and 31-wk gestation. Recombinant human IL-6, LIF, and OSM treatments of primary human fetal pituitary cultures (16-31 wk) increased ACTH secretion by up to 48% (P < 0.05) using doses of 1 nM, and when fetal cultures were cotreated with CRH, ACTH was induced five- to sixfold as compared to CRH alone (three- to fourfold; P = 0.01). Incubation with gp130-specific antibody suppressed basal and cytokine-stimulated ACTH secretion (alone or with CRH) from human fetal cells. Human POMC promoter -879/+6 fused to the luciferase reporter gene and transfected into AtT-20 cells, was stimulated by LIF (7-fold), which also exerted strong (22-fold) synergy with CRH on POMC transcription. Growth hormone (GH) release from fetal cultures was modestly stimulated (15-31%, P < 0.05), while other anterior pituitary hormones were not altered by these cytokines. Thus, physiologic concentrations of the gp130-related cytokines have direct effects on ACTH and GH regulation in the human pituitary, indicating that gp130-dependent signals serve as a paracrine system controlling early human pituitary function.

Adrenocorticotropic Hormone↗

PubMedDate not supplied

Cytokine-dependent gp130 receptor subunit regulates rat modified axial-pattern epigastric flap.

We investigated axial-pattern flap survival by modulating the cytokine receptor component, gp130, to elucidate the mechanism of the cytokine receptor modulation subsequently leading to the initiation of local angiogenesis and blood-flow augmentation. Fifty-two male Wistar rats were divided into four groups. The flap size was 8 x 8 cm, with the medial middle branch of the superficial epigastric artery as the only nutrient supply vessel. Group 1 received only a control vehicle, group 2 received leukemia inhibitory factor(LIF), cDNA treated, group 3 received combined treatment of LIF and anti-gp130 antibody, and group 4 was the anti-gp130-treated group. All groups received 0.1 mL phosphate-buffered saline (PBS) via 30-gauge needle injected into the proximal site of the femoral artery after distal sites of the bifurcated femoral artery to epigastric artery and vein were clamped. All clamps were removed after 10 min of incubation of the injected agents. During the first 3 postoperative days, the flap survival was significantly more improved in the anti-gp130-treated and combined-treated groups than in the control (88 +/- 1.5% and 77 +/- 5.3 vs. 45 +/- 7.8, respectively, p <.01). Laser blood flowmetry on day 3 showed a significant increase of blood flow in three different flap sites in anti-gp130-treated and combined-treated groups than in the other groups (p <.001). Microangiography showed remarkable differences between all four groups. The anti-gp130-treated flap showed augmented vessel formation at the base of the pedicle, which elongated the vessel interconnection up to the distal area. Strong gp130 transcripts and vascular endothelial growth factor (VEGF) expression were observed in all groups, as determined using reverse-transcription polymerase chain reaction (RT-PCR). The intensity of VEGF expression was the strongest in the anti-gp130-treated group. Attenuation of the gp130 receptor subunit can improve axial-pattern flap survival along with angiogenesis.

Animals↗