IL11RA

IL11RA encodes the ligand-binding alpha subunit of the interleukin-11 receptor, which heterodimerizes with gp130 to form the high-affinity IL-11 signaling complex; this architecture is conserved within the hematopoietic cytokine receptor family alongside the CNTF and IL-6 receptor alpha chains (PMID:8808281, PMID:8786120). IL11RA is required for IL-11-induced STAT3 phosphorylation and nuclear translocation, and loss-of-function mutations abolish this signaling, causing autosomal recessive craniosynostosis linked to its specific expression in cranial suture mesenchyme (PMID:24498618). Despite its membership in the hematopoietic cytokine receptor family, IL11Ra-null mice display normal adult hematopoiesis and stress recovery, indicating dispensability for blood cell homeostasis (PMID:9310465). IL11RA-dependent STAT3 signaling also promotes tissue regeneration in Xenopus tadpole tails and drives melanoma cell migration and metastasis through MMP2 expression (PMID:35115663, PMID:38468436).

1. 1996 High

   Determining the molecular composition of the IL-11 receptor established that IL11RA heterodimerizes with gp130, placing it in the shared gp130 cytokine receptor family alongside the CNTF and IL-6 receptor alpha chains.

   Evidence Genomic cloning, exon-intron analysis, and FISH mapping of the IL11RA gene

   PMID:8786120 PMID:8808281

   Open questions at the time

   • No crystal structure of the IL11RA/gp130/IL-11 ternary complex from experiment
   • Stoichiometry of the signaling-competent complex not resolved at the time
   • Post-translational modifications of IL11RA not characterized
2. 1997 High

   Gene-targeted deletion of Il11ra in mice unexpectedly revealed that IL-11 receptor signaling is dispensable for adult steady-state and stress hematopoiesis, redirecting attention toward non-hematopoietic functions.

   Evidence Il11ra knockout mice assessed by colony assays, peripheral blood counts, and hematopoietic stress (5-FU, phenylhydrazine)

   PMID:9310465

   Open questions at the time

   • Embryonic or neonatal hematopoietic roles not fully excluded
   • Potential compensation by other gp130-family receptors not tested
   • Non-hematopoietic phenotypes of the knockout not yet explored
3. 2013 High

   Functional assays of patient-derived IL11RA mutations demonstrated that the receptor is essential for IL-11-mediated STAT3 phosphorylation, and its expression in cranial suture mesenchyme explained why loss-of-function causes craniosynostosis.

   Evidence STAT3 phosphorylation assays in HEK293T/COS7 cells expressing mutant IL11RA, exon trapping, in situ hybridization of cranial sutures

   PMID:24498618

   Open questions at the time

   • Downstream transcriptional targets of IL-11/STAT3 in cranial mesenchyme not identified
   • Mechanism by which lost signaling leads to premature suture fusion not resolved
   • Whether soluble IL11RA isoforms contribute to suture biology not tested
4. 2022 High

   CRISPR knockout and morpholino knockdown in Xenopus demonstrated that IL11RA-dependent STAT3 signaling is required for appendage regeneration, extending the receptor's functional importance beyond skeletal development.

   Evidence CRISPR il11ra.L knockout (phospho-STAT3 nuclear localization assay) and morpholino knockdown (tadpole tail regeneration)

   PMID:35115663

   Open questions at the time

   • Whether mammalian tissue regeneration similarly requires IL11RA/STAT3 not established
   • Cell-autonomous versus non-cell-autonomous mechanisms not fully dissected
   • Identity of regeneration-specific target genes downstream of IL11RA/STAT3 unknown
5. 2024 Medium

   IL11RA was shown to promote melanoma migration, invasion, and hepatic metastasis through STAT3 activation and MMP2 upregulation, revealing a pro-tumorigenic role for the receptor.

   Evidence siRNA knockdown and Il11ra knockout mice with splenic melanoma injection, Western blot and RT-qPCR for STAT3 and MMP2

   PMID:38468436

   Open questions at the time

   • Single-lab study; independent replication needed
   • Whether IL11RA acts cell-autonomously in tumor cells versus stromal cells not resolved
   • Applicability beyond melanoma not tested

• An experimental structure of the IL-11/IL11RA/gp130 signaling complex is lacking, the transcriptional programs downstream of IL11RA/STAT3 in cranial suture and regenerative contexts are uncharacterized, and the relative contributions of membrane-bound versus soluble IL11RA to physiological signaling remain undefined.
• No experimentally determined ternary complex structure
• Downstream transcriptional targets in cranial mesenchyme and regeneration not mapped
• Role of soluble IL11RA shedding in modulating signaling not explored