CSF2RB

CSF2RB (CD131) encodes the common β-chain receptor that transduces β-cytokine (GM-CSF, IL-3, IL-5) signaling, predominantly through JAK2/STAT5 and PI3K/AKT, and is required for cytokine-dependent cellular responses (PMID:21075760, PMID:27377463). Loss of CSF2RB expression abolishes GM-CSF-stimulated STAT5 phosphorylation and causes autosomal-recessive hereditary pulmonary alveolar proteinosis, while a dominant-negative frameshift allele reduces GM-CSF-driven STAT5 signaling and impairs monocyte function, linking CSF2RB-STAT5 signaling to intestinal immune tolerance (PMID:21075760, PMID:27377463). A somatic S230I mutation renders the receptor constitutively active, driving ligand-independent JAK2/STAT5 and PI3K/mTOR signaling that supports survival under cytokine starvation (PMID:34729943). Cell-surface abundance of CSF2RB is set by a STUB1/CHIC2 E3-ligase complex that binds the receptor and promotes its ubiquitination and lysosomal degradation, with the strongest effect at low cytokine concentrations (PMID:36108743); downstream of STAT5 activation, RNF4 binds phosphorylated STAT5 and is required for CSF2RB-driven promigratory and antiapoptotic outputs (PMID:37064880). Beyond its canonical β-cytokine role, CD131 acts as an obligate co-receptor in an EPOR/CD131 heteroreceptor complex that mediates tissue-protective, non-hematopoietic signaling: physical crosslinking of EPOR and CD131 is required for receptor activation, and the complex signals through PI3K/AKT and, depending on context, GDNF/AKT or JAK2/STAT3 rather than canonical EPO-driven JAK2 (PMID:22738133, PMID:27541284, PMID:41206499). Through these pathways CSF2RB contributes to stress myelopoiesis and immune-cell chemotaxis into the colon via CCL4 (PMID:40586774).

1. 1992 Medium

   Establishing the chromosomal location of CSF2RB provided the genomic anchor for later disease-association studies.

   Evidence PCR of somatic cell hybrids and in situ hybridization mapping to 22q12.2→q13.1

   PMID:1424804

   Open questions at the time

   • No functional or mechanistic information
   • Does not address receptor activity or partners
2. 2010 Medium

   It was unknown whether CSF2RB loss could cause human disease; a homozygous deletion abolishing receptor expression and GM-CSF-stimulated STAT5 phosphorylation established CSF2RB as essential for GM-CSF signaling and causative of hereditary PAP.

   Evidence Patient genetics, flow cytometry for receptor expression, STAT5 phosphorylation in primary blood cells

   PMID:21075760

   Open questions at the time

   • Single case report
   • Mechanism of STAT5 coupling not dissected at molecular level
3. 2012 Medium

   Whether CD131 functions outside β-cytokine biology was unclear; Co-IP and siRNA knockdown showed CD131 is a required co-receptor for EPO-driven proangiogenic responses, defining an EPOR/CD131 complex.

   Evidence Co-IP, siRNA knockdown, in vitro angiogenesis assays and in vivo hindlimb ischemia in ECFCs

   PMID:22738133

   Open questions at the time

   • Stoichiometry and structure of EPOR/CD131 complex not resolved
   • Single lab
4. 2013 Medium

   The physiological relevance of CD131 in tissue protection was untested in vivo; CD131 knockout abolished anti-allodynic effects of ARA290 and ketamine, showing an intact βcR is specifically required for neuropathic pain relief.

   Evidence CD131 knockout mice, spared nerve injury model, behavioral and molecular analysis

   PMID:23936499

   Open questions at the time

   • Downstream signaling in neurons not fully mapped
   • Cell type mediating effect not defined
5. 2014 Low

   How CD131-mediated tissue-protective signaling is regulated was unclear; stress and TNFα were shown to induce CD131 surface externalization, and the agonist ARA290 modulated stress transcription factors.

   Evidence Cell fractionation/surface assay, western blotting, pharmacological modulation with ARA290

   PMID:25373867

   Open questions at the time

   • No genetic confirmation of CD131 involvement
   • Single lab pharmacological experiments only
6. 2016 High

   The biochemical consequence of a heterozygous CSF2RB frameshift was unknown; transfection and primary monocyte assays demonstrated dominant-negative reduction of GM-CSF-driven STAT5 signaling, linking the receptor to intestinal immune tolerance.

   Evidence HEK293 WT/mutant co-transfection pSTAT5 assays, monocyte functional assays, CyTOF of lamina propria leukocytes

   PMID:27377463

   Open questions at the time

   • Causal contribution to Crohn's disease not established beyond association
   • Mechanism of tolerance defect at tissue level incomplete
7. 2016 Medium

   The signaling arm used by tissue-protective EPO derivatives was unclear; carbamylated EPO was shown to act via CD131/GDNF/AKT without engaging JAK2, distinguishing it from canonical EPO signaling.

   Evidence CD131 blockade, GDNF neutralization, GFR blockade in primary neurons and hypoxic mouse model

   PMID:27541284

   Open questions at the time

   • Pharmacological blockade rather than genetic ablation
   • Direct receptor coupling to GDNF induction not shown
8. 2016 Low

   Membrane organization of CD131 in immune cells was uncharacterized; ApoA-I was shown to shift CD131 out of cholesterol-rich lipid rafts, associated with fewer CD131+ cells in plaques.

   Evidence Lipid raft fractionation, flow cytometry, Ldlr-/- atherosclerosis model

   PMID:27821400

   Open questions at the time

   • No direct functional validation of raft-dependent signaling change
   • Single lab
9. 2021 Medium

   Whether CSF2RB could be oncogenic was untested; a somatic S230I mutation was shown to drive ligand-independent JAK2/STAT5 and PI3K/mTOR activation supporting growth under starvation.

   Evidence Exome sequencing, immunoblot under ligand starvation, kinase inhibitor library screen

   PMID:34729943

   Open questions at the time

   • Structural basis of constitutive activation not solved
   • Single cell line/patient
10. 2022 High

    How surface levels of CSF2RB are controlled was unknown; genetic screens and Co-IP identified a STUB1/CHIC2 complex that ubiquitinates CSF2RB and drives lysosomal degradation, most impactful at low cytokine concentrations.

    Evidence Genetic screens, reciprocal Co-IP, ubiquitination assays, flow cytometry across multiple cell contexts

    PMID:36108743

    Open questions at the time

    • Ubiquitin linkage type and exact acceptor sites not defined
    • In vivo relevance of this turnover not tested
11. 2023 Medium

    Downstream effectors required for CSF2RB-STAT5 cellular outputs were unclear; RNF4 was shown to bind phosphorylated STAT5 and to be required for CSF2RB-driven MSC migration and survival.

    Evidence Adenoviral overexpression, reciprocal Co-IP of RNF4 with pSTAT5, knockdown rescue, RNA-seq

    PMID:37064880

    Open questions at the time

    • Whether RNF4 acts catalytically on STAT5 not established
    • Single lab, overexpression-based
12. 2025 Medium

    Whether physical crosslinking of EPOR and CD131 is sufficient for activation was untested; engineered bispecific proteins bridging the two receptors selectively activated STAT5, while equimolar single scFvs did not, and a validated structural model was built.

    Evidence Bispecific protein engineering, STAT5 phosphorylation assays, structural modeling with linker-arrangement validation

    PMID:41206499

    Open questions at the time

    • Endogenous ligand geometry not directly compared
    • Single lab
13. 2025 Medium

    The therapeutic and signaling consequences of disrupting EPOR-CD131 were unclear; pegmolesatide was shown to suppress EPOR-CD131 heterodimer formation and JAK2/STAT3 signaling, reducing cardiomyocyte hypertrophy, with ARA290/STAT3-activator rescue confirming the axis.

    Evidence Co-IP for heterodimerization, western blot, pharmacological rescue with ARA290 and Stattic

    PMID:41092772

    Open questions at the time

    • JAK2/STAT3 vs AKT/GDNF branch selection not reconciled
    • Single lab, pharmacological
14. 2025 Medium

    The role of CD131 in colonic immune-cell recruitment was undefined; CD131-deficient mice showed reduced DSS colitis with impaired macrophage and T-cell chemotaxis mediated through CCL4.

    Evidence CD131-deficient mouse DSS colitis model, immune infiltration analysis, CCL4 measurement

    PMID:40586774

    Open questions at the time

    • Cell-intrinsic vs extrinsic CD131 requirement not separated
    • Link between receptor signaling and CCL4 induction not molecularly mapped
15. 2025 Low

    How CSF2RB is positioned in transcriptional control of myelopoiesis was unclear; E2F was placed upstream of CD131 signaling in driving stress myelopoiesis, with combined EZH2/β-cytokine inhibition restoring colon homeostasis.

    Evidence Genetic inactivation of E2F in HSPCs, combined pharmacological inhibition in colitis model, expression analysis (preprint)

    PMID:bio_10.1101_2025.06.16.659412

    Open questions at the time

    • Preprint, not peer-reviewed
    • Direct mechanistic dissection of CSF2RB regulation limited

• How CSF2RB partitions between canonical β-cytokine JAK2/STAT5 signaling and the EPOR/CD131 tissue-protective branches (AKT/GDNF vs JAK2/STAT3) at the structural and regulatory level remains unresolved.
• No high-resolution structure of either active complex
• Determinants selecting between STAT5, AKT/GDNF, and JAK2/STAT3 outputs unknown