IL11RA

IL11RA encodes the ligand-binding alpha subunit of the IL-11 receptor, which forms a high-affinity receptor complex with gp130 and transduces IL-11 signals to STAT3 (PMID:8808281, PMID:8786120, PMID:24498618). It is the obligate receptor component for IL-11 responses: null mutation abolishes the hematopoietic response to IL-11, although IL-11 receptor signaling is dispensable for adult hematopoiesis under steady-state and stress conditions (PMID:9310465). Loss-of-function mutations in IL11RA dramatically reduce IL-11-mediated STAT3 phosphorylation, and the protein is expressed in cranial mesenchyme around the coronal and lambdoidal suture tips, linking IL11RA to suture development (PMID:24498618). Its role as a functional IL-11 receptor and the requirement of STAT3 nuclear translocation for downstream activity are conserved in Xenopus, where il11ra is also required for tadpole tail regeneration (PMID:35115663). Beyond development and regeneration, IL11RA drives tumor cell behavior: it promotes melanoma cell migration and invasion and supports hepatic metastasis through STAT3 activation and downstream MMP2 expression (PMID:38468436).

1. 1996 Medium

   Establishing the molecular identity of the IL-11 receptor: cloning showed IL-11Rα is a hematopoietic cytokine receptor family member that pairs with gp130 to form a high-affinity IL-11 receptor.

   Evidence Molecular cloning, genomic sequencing, and protein sequence alignment against CNTF and IL-6 receptor alpha chains

   PMID:8786120 PMID:8808281

   Open questions at the time

   • Heterodimer with gp130 inferred from homology rather than direct binding assay
   • No structural determination of the ligand-receptor complex
2. 1997 High

   Testing whether IL11RA is functionally required for IL-11 responses in vivo: gene targeting showed it is essential for the hematopoietic response to IL-11 but dispensable for adult hematopoiesis.

   Evidence Null mutation in mice with hematopoietic colony assays and confirmation of absent compensatory expression

   PMID:9310465

   Open questions at the time

   • Did not address non-hematopoietic roles
   • Downstream signaling effectors not dissected
3. 2013 High

   Connecting IL11RA to human disease and signaling: patient mutations were shown to impair IL-11-driven STAT3 phosphorylation, and the receptor was localized to cranial suture mesenchyme, mechanistically linking IL11RA to craniosynostosis.

   Evidence Coexpression STAT3 phosphorylation assays in HEK293T/COS7, immunofluorescence, zebrafish in situ hybridization, exon trapping

   PMID:24498618

   Open questions at the time

   • Quantitative receptor-ligand binding not measured for each variant
   • Mechanism linking STAT3 loss to suture fusion not resolved
4. 2022 High

   Defining the requirement for STAT3 nuclear translocation and a regeneration role: il11ra loss abolished IL-11-induced nuclear pSTAT3 and impaired tail regeneration, demonstrating conserved receptor function in regeneration.

   Evidence CRISPR knockout and morpholino knockdown in Xenopus cells and tadpoles with pSTAT3 nuclear localization and tail regeneration readouts

   PMID:35115663

   Open questions at the time

   • Conservation to mammalian regeneration not established
   • Downstream regeneration effectors of STAT3 not identified
5. 2024 Medium

   Extending IL11RA to cancer: knockdown and knockout reduced melanoma migration, invasion, and hepatic metastasis through STAT3 activation and MMP2 induction, defining a pro-metastatic STAT3/MMP2 axis.

   Evidence siRNA knockdown in human melanoma lines, Il11ra knockout mice in a B16-F10 hepatic metastasis model, Western blot and RT-qPCR

   PMID:38468436

   Open questions at the time

   • Single-lab study
   • Direct causal link between MMP2 and metastasis not isolated
6. 2025 Low

   Attempting to explain variant pathogenicity structurally: in silico modeling indicated missense variants disrupt hydrogen-bond networks and reduce binding to IL-11 and gp130.

   Evidence 3D protein structure modeling and molecular docking with whole-exome sequencing and Sanger validation

   PMID:40353334

   Open questions at the time

   • Purely computational with no experimental validation of binding affinity
   • Predicted affinity changes not tested in cells

• How IL11RA-mediated signaling integrates into multicellular fibrotic and regenerative communities remains open.
• Cell-cell interaction roles inferred only from spatial transcriptomics without direct IL11RA perturbation
• Mechanism linking pro-fibrotic niche to STAT3 signaling unestablished