Structure of the extracellular domains of the human interleukin-6 receptor α-chain

Varghese, J.N.; Moritz, Robert L.; Lou, Meizhen; Donkelaar, A. van; Ji, Hong; Ivancic, Neva; Branson, Kristin; Hall, Nathan E.; Simpson, Richard J.

doi:10.1073/pnas.232432399

Cited by 114 publications

(94 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition, IL-6 has been associated with progression from hormone-sensitive to hormone-insensitive disease in animal models via interaction with androgen receptor (AR) cofactors (26). Basically, IL-6 binds to its cognate a-chain receptor (IL-6 receptor) with low affinity, and then the complex binds to the signal-transducing molecule gp130 (h-subunit) to form a high-affinity complex (27). IL-6 induces rapid phosphorylation of gp130; this phosphorylation can be induced by JAKs or Fes tyrosine kinases and triggers the signaling cascade leading to STAT3 phosphorylation, dimerization and nuclear translocation, and action at the gene level (28,29).…”

Section: Fer Is a Partner Of Il-6 Signaling Molecules In Prostate Canmentioning

confidence: 99%

The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth

Zoubeidi

Rocha²,

Zouanat³

et al. 2009

Molecular Cancer Research

View full text Add to dashboard Cite

Androgen withdrawal is the most effective form of systemic therapy for men with advanced prostate cancer. Unfortunately, androgen-independent progression is inevitable, and the development of hormone-refractory disease and death occurs within 2 to 3 years in most men. The understanding of molecular mechanisms promoting the growth of androgenindependent prostate cancer cells is essential for the rational design of agents to treat advanced disease. We previously reported that Fer tyrosine kinase level correlates with the development of prostate cancer and aggressiveness of prostate cancer cell lines. Moreover, knocking down Fer expression interferes with prostate cancer cell growth in vitro. However, the mechanism by which Fer mediates prostate cancer progression remains elusive. We present here that Fer and phospho-Y705 signal transducer and activator of transcription 3 (STAT3) are barely detectable in human benign prostate tissues but constitutively expressed in the cytoplasm and nucleus of the same subsets of tumor cells in human prostate cancer. The interaction between STAT3 and Fer was observed in all prostate cancer cell lines tested, and this interaction is mediated via the Fer Src homology 2 domain and modulated by interleukin-6 (IL-6). Moreover, IL-6 triggered a rapid formation of Fer/gp130 and Fer/STAT3 complexes in a time-dependent manner and consistent with changes in Fer and STAT3 phosphorylation and cytoplasmic/nuclear distribution. The modulation of Fer expression/activation resulted in inhibitory or stimulatory effects on STAT3 phosphorylation, nuclear translocation, and transcriptional activation. These effects translated in IL-6 -mediated PC-3 cell growth. Taken together, these results support an important function of Fer in prostate

show abstract

Section: Fer Is a Partner Of Il-6 Signaling Molecules In Prostate Canmentioning

confidence: 99%

The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth

Zoubeidi

Rocha²,

Zouanat³

et al. 2009

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…A dimer structure of G-quadruplex (PDB: 2LE6 62 ) was docked on the structure of the hIL-6R protein (PDB: 1N26 63 ) with the ATTRACT engine. 64 Both partners, protein and quadruplex, were first considered as rigid and converted into coarse-grain representation.…”

Section: Molecular Docking Of Dna Quadruplex Aid-1 To Hil-6rmentioning

confidence: 99%

Structure and target interaction of a G-quadruplex RNA-aptamer

et al. 2016

View full text Add to dashboard Cite

G-quadruplexes have recently moved into focus of research in nucleic acids, thereby evolving in scientific significance from exceptional secondary structure motifs to complex modulators of gene regulation. Aptamers (nucleic acid based ligands with recognition properties for a specific target) that form Gquadruplexes may have particular potential for therapeutic applications as they combine the characteristics of specific targeting and Gquadruplex mediated stability and regulation. We have investigated the structure and target interaction properties of one such aptamer: AIR-3 and its truncated form AIR-3A. These RNA aptamers are specific for human interleukin-6 receptor (hIL-6R), a key player in inflammatory diseases and cancer, and have recently been exploited for in vitro drug delivery studies. With the aim to resolve the RNA structure, global shape, RNA: protein interaction site and binding stoichiometry, we now investigated AIR-3 and AIR-3A by different methods including RNA structure probing, Small Angle X-ray scattering and microscale thermophoresis. Our findings suggest a broader spectrum of folding species than assumed so far and remarkable tolerance toward different modifications. Mass spectrometry based binding site analysis, supported by molecular modeling and docking studies propose a general Gquadruplex affinity for the target molecule hIL-6R.

show abstract

“…Another possibility is that posttranslational changes in both proteins lead to decreased turnover. Four N-glycosylation sites have been described for membrane IL-6R [36] but their role in protein stability has not been studied yet. Interestingly, N-linked glycosylation has been proved to be essential for the stability in gp130 [37].…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Abnormal regulation of soluble and anchored IL-6 receptor in monocytes from patients with essential thrombocythemia

Goette

Lev

Heller

et al. 2010

Experimental Hematology

View full text Add to dashboard Cite

Abbreviations used in this paper: ET, essential thrombocythemia; DS-sIL-6R, soluble receptor for IL-6 originated from differential splicing; PC-sIL-6R, soluble receptor for IL-6 originated from proteolytic cleavage; ADAM, a disintegrin and metalloproteinase domain; FCS, fetal calf serum; TAPI, TNF- protease inhibitor; PBMC, peripheral blood mononuclear cells.In a previous study, we found increased plasma sIL-6R levels in patients with essential thrombocythemia (ET) that could promote megakaryocytopoyesis through IL-6 binding and further interaction with the signal transducer gp130. Here we have searched for the cell source of sIL-6R within mononuclear cells in these patients and the underlying abnormalities involved in its overproduction. PATIENTS AND METHODS.Thirty patients with the diagnosis of essential thrombocythemia were studied. sIL-6R levels were measured by ELISA technique in the supernatants of peripheral monocyte and lymphocyte cultures. Expression of membrane anchored IL-6 receptor was determined by flow cytometry. In order to study the mechanism of sIL-6R production, TNF- protease inhibitor (TAPI) was added to specifically block IL-6R shedding. Gene expression of sIL-6R levels were evaluated by RT-PCR. RESULTS.Monocytes were the main source of sIL-6R. Besides, in ET patients, monocyte sIL-6R release was higher than that of controls, p = 0.0014. Lymphocytes enhanced monocyte sIL-6R production by cell-mediated contact in normal controls, but this cooperation could not be seen in patients. Membrane expression of IL-6R was increased after monocyte adhesion in ET. sIL-6R synthesis was up-regulated in most patients while mRNA was normal. CONCLUSION.Our results indicate that ET monocytes are responsible for sIL-6R overproduction within mononuclear cells through synthesis up-regulation. In addition, the lack of cooperation of lymphocytes in monocyte sIL-6R production in ET could be due to a monocyte abnormality. The agonistic effect of sIL-6R on IL-6 action could contribute to the exacerbated megakaryocytic growth in ET.

show abstract

Structure of the extracellular domains of the human interleukin-6 receptor α-chain

Cited by 114 publications

References 62 publications

The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth

The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth

Structure and target interaction of a G-quadruplex RNA-aptamer

Abnormal regulation of soluble and anchored IL-6 receptor in monocytes from patients with essential thrombocythemia

Contact Info

Product

Resources

About