Modular organization of Interleukin-6 and Interleukin-11 α-receptors

Nitz, Rebecca; Lokau, Juliane; Aparicio-Siegmund, Samadhi; Scheller, Jürgen; Garbers, Christoph

doi:10.1016/j.biochi.2015.11.005

Cited by 25 publications

(32 citation statements)

References 28 publications

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“…Furthermore, the recently solved crystal structure of IL-11 revealed differences in the gp130 interaction site compared to that of IL-6, indicating that the two cytokines might bind to gp130 in a different manner (22). However, we have previously shown that chimeric receptors of the IL-11R and IL-6R are indistinguishable in their biological activity (15), pointing towards similar formation of the signaling complexes.…”

Section: Il-11 Signal Transduction Is Mediated Via a Complex Of Il-11mentioning

confidence: 92%

“…Construction of plasmids -pcDNA3.1 expression plasmids for myc-tagged hIL-11R have been described previously (15). Deletions within the IL-11R stalk have been constructed by splicing by overlapping extensions PCR as described previously (19).…”

Section: Methodsmentioning

confidence: 99%

“…Ba/F3-gp130 cell lines, which have been transduced with biologically active variants of the IL-11R, do not express IL-11 themselves but are responsive to IL-11 (15). We further used the synthetic cytokine Hyper-IL-6 (Hy-IL-6), which consists of IL-6 connected by a linker to the soluble IL-6R.…”

Section: Deletion Of the Il-11r Stalk Region Prevents Classic Il-11 Smentioning

confidence: 99%

“…Concentration and purity of the extracted RNA was analyzed using a NanoDrop2000 spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA). For gene expression analysis, 1 µg total RNA was reversely transcribed into cDNA with OligodT 15 …”

Section: Stimulation Of Cells and Western Blotting -mentioning

confidence: 99%

“…The IL-11R consists of three extracellular domains (D1-D3), which are connected to a transmembrane region and an intracellular part through a 55 amino-acid residues long stalk region (15). For binding of IL-11, the fibronectin-type III (FNIII)-like domains D2 and D3, which harbor the cytokine binding module, are essential, while the Ig-like D1 domain has been reported to be negligible for signaling (16,17).…”

Section: Introductionmentioning

confidence: 99%

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The length of the interleukin-11 receptor stalk determines its capacity for classic signaling

Lokau

Garbers

2018

Journal of Biological Chemistry

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Interleukin (IL)-11 is a multifunctional cytokine that was traditionally recognized for its hematopoietic and antiinflammatory functions, but has recently been shown also to be involved in tumorigenesis. IL-11 signaling is initiated by binding of the cytokine to the IL-11 receptor (IL-11R), which is not directly involved in signaling, but required for IL-11 binding to the signal-transducing receptor glycoprotein (gp)130. In classic signaling, IL-11 binds to the membranebound IL-11R in order to initiate signal transduction.Additionally, IL-11 signaling can be initiated via soluble IL-11R, known as trans-signaling, and this pathway only requires the three extracellular domains of the IL-11R, but neither stalk, transmembrane or intracellular region. Here, we analyzed the role of the IL-11R stalk region -a 55 amino acid stretch connecting the extracellular domains with the transmembrane helix -in classic IL-11 signaling with the help of cytokinedependent cell lines. We showed that the stalk region is crucial for IL-11 signaling via the membrane-bound IL-11R. Using different deletion variants, we found that a minimal length of 23 amino-acid residues is required for efficient signal transduction. We further found that classic IL-11 signaling depended solely on the length, but not the sequence of the IL-11R stalk region, suggesting that the stalk functions as a spacer in the signaling complex. We previously described the IL-11R stalk region as determinant of proteolysis and regulator of IL-11 transsignaling. The results presented here reveal an additional function in classic IL-11 signaling, highlighting the importance of the IL-11R stalk in IL-11 signaling.

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Section: Il-11 Signal Transduction Is Mediated Via a Complex Of Il-11mentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Deletion Of the Il-11r Stalk Region Prevents Classic Il-11 Smentioning

confidence: 99%

Section: Stimulation Of Cells and Western Blotting -mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The length of the interleukin-11 receptor stalk determines its capacity for classic signaling

Lokau

Garbers

2018

Journal of Biological Chemistry

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Interleukin‐6–interleukin‐11 receptor chimeras reveal ionomycin‐induced proteolysis beyond ADAM10

Lokau

Garbers

2021

FEBS Letters

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Interleukin-6 (IL-6) and interleukin-11 are two important pleiotropic cytokines, both of which signal through a homodimer of the b-receptor gp130. Specificity is gained through the unique, nonsignaling a-receptors IL-6R and IL-11R. Soluble variants of IL-6R and IL-11R also exist. Both membrane-bound receptors can be cleaved by the metalloprotease ADAM10. Here, we use ten different chimeric receptors consisting of different parts of IL-6R and IL-11R and analyze their susceptibility toward cleavage by ADAM10. As expected, all chimeras are substrates of ADAM10. However, we observed that cleavage of chimeric receptors containing the stalk region of the IL-11R could be blocked by the protease inhibitor GI (selective for ADAM10), but not by the protease inhibitor GW (selective for both ADAM10 and ADAM17), suggesting that another protease besides ADAM10 is involved in cleavage of these chimeras.

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Interleukin-11: A Multifunctional Cytokine with Intrinsically Disordered Regions

Permyakov

Uversky

Permyakov

2016

Cell Biochem Biophys

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Cytokine interleukin-11 (IL-11) is a multifunctional protein with diverse roles in the normal cell signaling and in various pathologies. The structure of IL-11 is characterized by a four-helix bundle motif comprising two pairs of antiparallel α-helices arranged in an up-up-down-down configuration. Evaluation of the intrinsic disorder predisposition of human IL-11 by several computational tools clearly shows that this protein is predicted to have functional disordered regions potentially involved in interaction with natural binding partners. Signaling by IL-11 proceeds via an interaction of the protein with its membrane-specific receptor IL-11Rα and a subsequent interaction of the complex with the transmembrane signal-transducing receptor GP130. Cytoplasmic domain of IL-11Rα is predicted to be very disordered, and noticeable amount of disorder is present even in the large extracellular domain of the protein. GP130 is also predicted to have long disordered region that is located at the C-terminal of the protein and is expected to have several disorder-based binding sites. It shows that intrinsic disorder might play an important role in functioning of this signaling machine. A specific subset of the calcium sensor proteins (calmodulin, S100P, S100B, NCS-1, GCAP-1/2) exhibits metal-dependent binding of IL-11 with dissociation constants in a range of 1-19 μM, and the structural features of their hinge regions likely ensure selectivity and calcium sensitivity of IL-11 binding to the EF-hand proteins studied. IL-11 exhibits multiple effects on hematopoietic and non-hematopoietic systems. It plays a major role in orchestrating complex processes of tumor development and progression.

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Modular organization of Interleukin-6 and Interleukin-11 α-receptors

Cited by 25 publications

References 28 publications

The length of the interleukin-11 receptor stalk determines its capacity for classic signaling

The length of the interleukin-11 receptor stalk determines its capacity for classic signaling

Interleukin‐6–interleukin‐11 receptor chimeras reveal ionomycin‐induced proteolysis beyond ADAM10

Interleukin-11: A Multifunctional Cytokine with Intrinsically Disordered Regions

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