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

Abstract

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.

Bazedoxifene as a novel GP130 inhibitor for Colon Cancer therapy

“…In classic signaling, IL-11 binds to the membrane-bound IL-11R to initiate signal transduction. Recently, it was found that IL-11 signaling can also be initiated via soluble IL-11R, known as trans-signaling [15]. Upon the formation of IL-11/IL-11R/GP130 hexameric complex, IL-11 mainly mediated cancer development through the induction and activation of the JAK/STAT3 signaling pathway [16–18].…”

Interleukin‐11 (IL‐11) receptor cleavage by the rhomboid protease RHBDL2 induces IL‐11 trans‐signaling

“…Expression plasmids encoding the IL‐11R variants IL‐11R‐KKSS and IL‐11R‐R296W have been described previously 20 . The IL‐11R deletion variants IL‐11R‐ΔV363_L372 and IL‐11R‐ΔH353_S362 have been described previously 23,39 . All other IL‐11R mutants used in this study were generated via splicing by overlapping extension (SOE)‐PCR using pcDNA3.1‐myc‐hIL‐11R as template.…”

“…20 The IL-11R deletion variants IL-11R-ΔV363_L372 and IL-11R-ΔH353_S362 have been described previously. 23,39 All other IL-11R mutants used in this study were generated via splicing by overlapping extension (SOE)-PCR using pcDNA3.1-myc-hIL-11R as template. pcDNA3.1 expression plasmids for hIL-6R have been described previously, 40,41 and a variant with an N-terminal myc-tag was used in this study.…”

Structural Understanding of Interleukin 6 Family Cytokine Signaling and Targeted Therapies: Focus on Interleukin 11

“…IL-6 binds the surface formed by the two Fn3 domains, D2 and D3, comprising the CHR ( 68 ). C-terminal of the structured extracellular domains (D1-D3), there is a long linker region (52 residues), predicted to be disordered, that appears to function as a spacer in the signaling complex between the structured extracellular domains and the membrane ( 116 – 118 ).…”