IL-6 Type Cytokine Receptor Complexes: Hexamer, Tetramer or Both?

Grötzinger, Joachim; Kernebeck, Thomas; Kallen, Karl-Josef; Rose-John, Stefan

doi:10.1515/bc.1999.100

Cited by 104 publications

(83 citation statements)

References 78 publications

(84 reference statements)

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“…29,30 Furthermore, gp130 signaling is dependent upon the juxtamembrane fibronectin modules in the extracellular domain of the receptor. 31 Because the role of the transmembrane domain in receptor activation has not been fully characterized, we wished to determine what role this domain might play, if any, in the unexpected cross-talk Leukemia between chimeric receptors and endogenous gp130.…”

Section: Egfr/gp130 Interaction With Endogenous Receptor Is Not Facilmentioning

confidence: 99%

Analysis of IL-6-mediated growth control of myeloma cells using a gp130 chimeric receptor approach

2002

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Interleukin 6 (IL-6) has been shown to be a key growth factor for myeloma cells. To study IL-6 signal transduction in multiple myeloma (MM), we employed chimeric receptors composed of the epidermal growth factor receptor (EGFR) extracellular domain, gp130 transmembrane domain, and full-length or truncated gp130 cytoplasmic domains lacking regions previously shown to be necessary for MAPK, STAT1, and STAT3 activation. The IL-6-dependent KAS-6/1 MM cell line was transfected with various chimeric receptor constructs and assayed for EGF responsiveness. EGF stimulation surprisingly stimulated DNA synthesis in all transfectants, regardless of receptor length. When cell proliferation was assayed instead, only transfectants capable of inducing high levels of STAT3 activation proliferated in response to EGF. Additional studies revealed that EGF stimulation resulted in tyrosine phosphorylation of endogenous gp130 in cells expressing the chimeric receptor. Replacing the gp130 transmembrane region with the EGFR transmembrane domain diminished but did not disrupt this interaction. This receptor interaction was also observed in the IL-6-dependent MM cell line ANBL-6. In summary, although our results suggest that STAT activation is crucial in gp130-mediated proliferation of myeloma cells, these results must be interpreted with caution given our demonstration of the interaction between chimeric and endogenous receptors in myeloma cells. Importantly, this interaction has not been noted in studies utilizing the same gp130 chimeric receptor system in non-MM cells.

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Section: Egfr/gp130 Interaction With Endogenous Receptor Is Not Facilmentioning

confidence: 99%

Analysis of IL-6-mediated growth control of myeloma cells using a gp130 chimeric receptor approach

2002

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“…Although cellular and viral IL-6 proteins show only ϳ25% sequence homology, the crystal structure of a receptor complex demonstrated a strong relationship of the binding epitopes to their receptors (15,44). vIL-6 protein folds, as most cytokines do, into so-called four-helical bundles (7,23).…”

mentioning

confidence: 99%

Abrogation of Viral Interleukin-6 (vIL-6)-Induced Signaling by Intracellular Retention and Neutralization of vIL-6 with an Anti-vIL-6 Single-Chain Antibody Selected by Phage Display

Kovaleva

Bußmeyer

Rabe

et al. 2006

J Virol

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Human herpesvirus 8 (HHV-8) encodes several putative oncogenes, which are homologues to cellular host genes known to function in cell cycle regulation, control of apoptosis, and cytokine signaling. Viral interleukin (vIL-6) is believed to play an important role in the pathogenesis of Kaposi's sarcoma as well as primary effusion lymphoma and multicentric Castleman's disease. Therefore, vIL-6 is a promising target for novel therapies directed against HHV-8-associated diseases. By phage display screening of human synthetic antibody libraries, we have selected a specific recombinant antibody, called monoclonal anti-vIL-6 (MAV), binding to vIL-6. The epitope recognized by MAV was localized on the top of the D helix of the vIL-6 protein, which is a part of receptor binding site III. Consequently, MAV specifically inhibits vIL-6-mediated growth of the primary effusion lymphoma-derived cell line BCBL-1 and blocks STAT3 phosphorylation in the human hepatoma cell line HepG2. Since it was previously found that vIL-6 can also induce signals from within the cell, presumably within the endoplasmic reticulum, we fused the recombinant antibody MAV with the endoplasmic retention sequence KDEL (MAV-KDEL). As a result, COS-7 cells expressing MAV-KDEL and synthesizing vIL-6 ceased to secrete the cytokine. Moreover, we observed that vIL-6 that was bound to MAV-KDEL and retained in the endoplasmic reticulum did not induce STAT3 phosphorylation in HepG2 cells. We conclude that the activity of the intracellularly retained vIL-6 protein is neutralized by MAV-KDEL. Our results might represent a novel therapeutic strategy to neutralize virally encoded growth factors or oncogenes.

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“…In particular, little is known about which domains of the receptors are involved in the interactions in the complex and the nature of the receptor-receptor interactions in the hexameric complex. As the CNTF receptor complex is asymmetric, containing one molecule each of gp130 and LIFR instead of two gp130 molecules as in the IL-6 receptor complex, a tetrameric, rather than hexameric, signaling complex for CNTF is still supported (24,25).…”

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confidence: 99%

Solution Structure of the C-terminal Domain of the Ciliary Neurotrophic Factor (CNTF) Receptor and Ligand Free Associations among Components of the CNTF Receptor Complex

Man

Sze

et al. 2003

Journal of Biological Chemistry

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The functional receptor complex of ciliary neurotrophic factor (CNTF), a member of the gp130 family of cytokines, is composed of CNTF, the CNTF receptor ␣ (CNTFR), gp130, and the leukemia inhibitory factor receptor (LIFR). However, the nature of the receptor-mediated interactions in this complex has not yet been resolved. To address this issue we have determined the solution structure of the C-terminal or BC domain of CNTFR and studied the interactions of CNTFR with LIFR and gp130. We reported previously that the membrane distal cytokine-binding domain (CBD1) of LIFR could interact in vitro with soluble CNTFR (sCNTFR) in the absence of CNTF. Here we show that the CBD of human gp130 can also bind in vitro to sCNTFR in the absence of CNTF. In addition, the gp130 CBD could compete with the LIFR CBD1 for the binding of sCNTFR. Substitution of residues in the gp130 CBD, the LIFR CBD1, and the CNTFR BC domain that are expected to be involved in receptor-receptor interactions significantly reduced their interactions. An NMR chemical shift perturbation study of the interaction between the BC domains of CNTFR and gp130 further mapped the interaction surface. These data suggest that both the gp130 CBD and the LIFR CBD1 interact with CNTFR in a similar way and provide insights into the nature of the CNTF receptor complex.

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IL-6 Type Cytokine Receptor Complexes: Hexamer, Tetramer or Both?

Cited by 104 publications

References 78 publications

Analysis of IL-6-mediated growth control of myeloma cells using a gp130 chimeric receptor approach

Analysis of IL-6-mediated growth control of myeloma cells using a gp130 chimeric receptor approach

Abrogation of Viral Interleukin-6 (vIL-6)-Induced Signaling by Intracellular Retention and Neutralization of vIL-6 with an Anti-vIL-6 Single-Chain Antibody Selected by Phage Display

Solution Structure of the C-terminal Domain of the Ciliary Neurotrophic Factor (CNTF) Receptor and Ligand Free Associations among Components of the CNTF Receptor Complex

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