{"gene":"CSF2RB","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2010,"finding":"A homozygous single-base deletion at nt 631 in exon 6 of CSF2RB causes deficiency of GM-CSF receptor β-chain (GM-CSF-Rβc) expression and abolishes GM-CSF-stimulated STAT5 phosphorylation in patient blood cells, establishing that CSF2RB is required for GM-CSF-dependent signaling and its loss causes hereditary pulmonary alveolar proteinosis (PAP) in an autosomal recessive manner.","method":"Patient genetic screening, STAT5 phosphorylation assay in primary blood cells, flow cytometry for receptor expression","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay (STAT5 phosphorylation) combined with genetic analysis in patient cells, single lab/case report","pmids":["21075760"],"is_preprint":false},{"year":2016,"finding":"A frameshift mutation in CSF2RB found in Ashkenazi Jewish Crohn's disease patients acts in a dominant-negative manner: cells co-transfected with full-length and mutant CSF2RB showed reduced pSTAT5 after GM-CSF stimulation compared to wild-type alone. Monocytes from heterozygous carriers showed reduced GM-CSF responses and markedly decreased aldehyde dehydrogenase activity, implicating CSF2RB-mediated STAT5 signaling in intestinal immune tolerance.","method":"Transfection of HEK293 cells with WT and mutant CSF2RB followed by pSTAT5 measurement; primary monocyte functional assays; CyTOF analysis of lamina propria leukocytes","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cell transfection functional assay, primary human monocyte assays, mass cytometry), replicated in discovery and validation cohorts","pmids":["27377463"],"is_preprint":false},{"year":2022,"finding":"STUB1 (an E3 ubiquitin ligase) and CHIC2 form a protein complex that binds CSF2RB and promotes its ubiquitination, leading to lysosomal degradation. Genetic inactivation of either STUB1 or CHIC2 reduces CSF2RB ubiquitination and increases its cell-surface abundance, with the greatest effects observed at low cytokine concentrations.","method":"Genetic screens in multiple cellular contexts; co-immunoprecipitation demonstrating STUB1/CHIC2/CSF2RB complex; ubiquitination assays; flow cytometry for cell-surface CSF2RB","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic screens in multiple contexts, ubiquitination assays, multiple orthogonal methods in one study","pmids":["36108743"],"is_preprint":false},{"year":2023,"finding":"CSF2RB overexpression in mesenchymal stromal cells (MSCs) increases STAT5 phosphorylation in response to CSF2, promotes MSC migration and reduces apoptosis. RNF4 (a ubiquitin ligase) binds phosphorylated STAT5 and is required for CSF2RB-dependent antiapoptotic and promigratory effects; RNF4 knockdown reduced STAT5 phosphorylation and these cellular effects.","method":"Adenoviral CSF2RB overexpression, co-immunoprecipitation of RNF4 with pSTAT5, coimmunostaining, RNF4 knockdown functional rescue, RNA sequencing","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional rescue experiments, single lab, multiple orthogonal methods","pmids":["37064880"],"is_preprint":false},{"year":2012,"finding":"CSF2RB (CD131) co-immunoprecipitates and co-localizes with EPOR in endothelial colony-forming cells (ECFCs), suggesting they form a receptor complex. siRNA knockdown of CD131 abolished EPO-induced proliferation, migration, tube formation, and resistance to apoptosis in ECFCs, as well as downstream PI3K-Akt pathway activation, establishing CD131 as a required co-receptor for EPO's proangiogenic effects.","method":"Co-immunoprecipitation, western blotting, siRNA knockdown of CD131, in vitro proliferation/migration/tube formation assays, in vivo hindlimb ischemia model","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus loss-of-function (siRNA) with multiple functional readouts in vitro and in vivo, single lab","pmids":["22738133"],"is_preprint":false},{"year":2016,"finding":"Carbamylated erythropoietin (CEPO) mediates neuroprotection through the CD131/GDNF/AKT pathway: blockage of CD131 reduced CEPO-mediated GDNF production, and GFR receptor blockage or GDNF neutralization inhibited CEPO-induced neurogenesis. CEPO activates AKT through GDNF but does not trigger JAK2, in contrast to EPO which activates JAK2.","method":"CD131 receptor blockade, GDNF neutralization, GFR receptor blockage in primary neurons and hypoxic mouse model; Western blot, immunohistochemistry, RT-PCR","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological inhibition experiments with pathway readouts, single lab","pmids":["27541284"],"is_preprint":false},{"year":2014,"finding":"The EPO/CD131 heteroreceptor complex mediates tissue-protective (non-hematopoietic) EPO signaling. In mesenchymal-derived cells, cellular stress and TNFα promote externalization (surface expression) of CD131 as an immediate response. The specific CD131 agonist peptide ARA290 overcomes TNFα-mediated inhibition of stress-related transcription factors (SRF, HSF1, AP1), indicating that CD131-mediated signaling modulates pro-inflammatory pathways.","method":"Cell fractionation/surface expression assay for CD131 externalization, western blotting for transcription factor activation, pharmacological modulation with ARA290","journal":"Journal of molecular medicine (Berlin, Germany)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single set of pharmacological experiments without genetic confirmation of CD131 involvement","pmids":["25373867"],"is_preprint":false},{"year":2013,"finding":"CD131 (β-common receptor, βcR) is required for the anti-allodynic effect of both ARA290 and ketamine in a spared nerve injury neuropathic pain model: CD131 knockout mice showed no pain relief from either drug, while acute analgesic effects of ketamine and psychomotor side effects were unaffected, demonstrating that an intact βcR/innate repair receptor is specifically required for neuropathic pain relief.","method":"CD131 knockout mice, spared nerve injury model, behavioral assessment of allodynia and acute nociception, mRNA expression analysis of NMDAR, microglia, astrocytes, CCL2","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with specific behavioral and molecular phenotype, loss-of-function with clear pathway distinction","pmids":["23936499"],"is_preprint":false},{"year":2021,"finding":"A somatic missense mutation S230I in CSF2RB found in a breast cancer patient and the KAIMRC1 cell line confers ligand-independent signaling through JAK2/STAT5 and PI3K/mTOR pathways, enabling cell survival and proliferation under cytokine-starvation conditions.","method":"Exome sequencing, immunoblot analysis for JAK2/STAT5 and PI3K/mTOR pathway activation under ligand-starvation, small molecule kinase inhibitor library screen","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays (Western blot for pathway activation, growth under starvation) combined with mutation identification, single lab","pmids":["34729943"],"is_preprint":false},{"year":2016,"finding":"ApoA-I treatment shifts CD131 from lipid raft to non-raft fractions of the plasma membrane in immune cells by reducing microdomain cholesterol content, and this redistribution is associated with reduced CD131-expressing cell numbers in atherosclerotic plaques.","method":"Lipid raft fractionation of plasma membrane, flow cytometry for CD131-expressing cells, Ldlr-/- mouse atherosclerosis model","journal":"Journal of the American Heart Association","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, lipid raft fractionation without direct functional validation of raft-associated signaling changes","pmids":["27821400"],"is_preprint":false},{"year":2025,"finding":"Pegmolesatide suppresses formation of the EPOR-CD131 heterodimer (demonstrated by co-immunoprecipitation) and inhibits downstream JAK2/STAT3 signaling, thereby reducing indoxyl sulfate-induced cardiomyocyte hypertrophy. Rescue experiments with the CD131 agonist ARA290 or STAT3 activator reversed these protective effects, confirming that suppression of EPOR-CD131/JAK2/STAT3 axis is the mechanism.","method":"Co-immunoprecipitation for EPOR-CD131 heterodimerization, Western blot for JAK2/STAT3 activation, pharmacological rescue with ARA290 and Stattic, phalloidin staining for cell size","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating heterodimerization plus functional rescue experiments with multiple pharmacological tools, single lab","pmids":["41092772"],"is_preprint":false},{"year":2025,"finding":"Bispecific proteins (tandem scFv or bispecific antibody format) bridging EPOR and CD131 are sufficient to selectively activate STAT5 phosphorylation downstream of the EPO-R/CD131 complex without engaging EPO-R/EPO-R homodimers. Equimolar mixtures of individual scFvs were insufficient, indicating that physical crosslinking of EPOR and CD131 is required for receptor activation. A structural model of the EPO-R/CD131 complex was constructed and validated by linker length/arrangement experiments.","method":"Bispecific protein engineering, STAT5 phosphorylation assay, structural modeling with experimental validation via linker length/binding domain arrangement","journal":"Protein engineering, design & selection : PEDS","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of signaling with defined bispecific agonists and mutagenesis-equivalent domain arrangement experiments, single lab","pmids":["41206499"],"is_preprint":false},{"year":2025,"finding":"E2F transcription factor promotes myeloid fate in hematopoietic stem and progenitor cells (HSPCs) in part by enhancing the signaling activity of CD131 (CSF2RB), the common β-chain receptor for IL-3 and GM-CSF. Dual inhibition of EZH2 and β-cytokine signaling (via CD131) suppressed stress myelopoiesis and restored colon homeostasis in a preclinical colitis model, placing CSF2RB downstream of E2F in the regulation of stress myelopoiesis.","method":"Genetic inactivation of E2F in HSPCs, combined pharmacological inhibition of EZH2 and β-cytokine signaling in colitis model, gene expression analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, primarily genetic epistasis with limited direct mechanistic dissection of CSF2RB's role","pmids":["bio_10.1101_2025.06.16.659412"],"is_preprint":true},{"year":2025,"finding":"CD131 (CSF2RB) signaling is required for macrophage infiltration in ulcerative colitis: CD131-deficient mice showed reduced DSS-induced colitis, with decreased macrophage and T-cell chemotaxis. CD131 promotes chemotaxis of macrophages and T cells into the colon through CCL4.","method":"CD131-deficient mouse DSS colitis model, immune cell infiltration analysis, CCL4 measurement","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined cellular phenotype and molecular mediator (CCL4) identified, single lab","pmids":["40586774"],"is_preprint":false},{"year":1992,"finding":"The CSF2RB gene was mapped to chromosome 22q12.2→q13.1 by PCR analysis of somatic cell hybrids and in situ hybridization.","method":"PCR of human-rodent somatic cell hybrids, in situ hybridization to chromosome 22 translocations","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal localization by two independent methods, single lab","pmids":["1424804"],"is_preprint":false}],"current_model":"CSF2RB (CD131) encodes the common β-chain shared by the GM-CSF, IL-3, and IL-5 receptors, and is responsible for initiating downstream signaling (primarily JAK2/STAT5 and PI3K/AKT) upon cytokine binding; its cell-surface abundance is regulated by STUB1/CHIC2-mediated ubiquitination and lysosomal degradation, loss-of-function mutations cause hereditary pulmonary alveolar proteinosis through abrogated STAT5 signaling, gain-of-function mutations confer ligand-independent JAK2/STAT5 and PI3K/mTOR activation, and CD131 also functions as an obligate co-receptor in an EPOR/CD131 heterodimeric complex that mediates tissue-protective EPO signaling through AKT/GDNF rather than JAK2."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1992,"claim":"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","pmids":["1424804"],"confidence":"Medium","gaps":["No functional or mechanistic information","Does not address receptor activity or partners"]},{"year":2010,"claim":"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","pmids":["21075760"],"confidence":"Medium","gaps":["Single case report","Mechanism of STAT5 coupling not dissected at molecular level"]},{"year":2012,"claim":"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","pmids":["22738133"],"confidence":"Medium","gaps":["Stoichiometry and structure of EPOR/CD131 complex not resolved","Single lab"]},{"year":2013,"claim":"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","pmids":["23936499"],"confidence":"Medium","gaps":["Downstream signaling in neurons not fully mapped","Cell type mediating effect not defined"]},{"year":2014,"claim":"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","pmids":["25373867"],"confidence":"Low","gaps":["No genetic confirmation of CD131 involvement","Single lab pharmacological experiments only"]},{"year":2016,"claim":"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","pmids":["27377463"],"confidence":"High","gaps":["Causal contribution to Crohn's disease not established beyond association","Mechanism of tolerance defect at tissue level incomplete"]},{"year":2016,"claim":"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","pmids":["27541284"],"confidence":"Medium","gaps":["Pharmacological blockade rather than genetic ablation","Direct receptor coupling to GDNF induction not shown"]},{"year":2016,"claim":"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","pmids":["27821400"],"confidence":"Low","gaps":["No direct functional validation of raft-dependent signaling change","Single lab"]},{"year":2021,"claim":"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","pmids":["34729943"],"confidence":"Medium","gaps":["Structural basis of constitutive activation not solved","Single cell line/patient"]},{"year":2022,"claim":"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","pmids":["36108743"],"confidence":"High","gaps":["Ubiquitin linkage type and exact acceptor sites not defined","In vivo relevance of this turnover not tested"]},{"year":2023,"claim":"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","pmids":["37064880"],"confidence":"Medium","gaps":["Whether RNF4 acts catalytically on STAT5 not established","Single lab, overexpression-based"]},{"year":2025,"claim":"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","pmids":["41206499"],"confidence":"Medium","gaps":["Endogenous ligand geometry not directly compared","Single lab"]},{"year":2025,"claim":"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","pmids":["41092772"],"confidence":"Medium","gaps":["JAK2/STAT3 vs AKT/GDNF branch selection not reconciled","Single lab, pharmacological"]},{"year":2025,"claim":"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","pmids":["40586774"],"confidence":"Medium","gaps":["Cell-intrinsic vs extrinsic CD131 requirement not separated","Link between receptor signaling and CCL4 induction not molecularly mapped"]},{"year":2025,"claim":"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)","pmids":["bio_10.1101_2025.06.16.659412"],"confidence":"Low","gaps":["Preprint, not peer-reviewed","Direct mechanistic dissection of CSF2RB regulation limited"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of either active complex","Determinants selecting between STAT5, AKT/GDNF, and JAK2/STAT3 outputs unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,11]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,6,9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,13]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2]}],"complexes":["EPOR/CD131 heteroreceptor complex","STUB1/CHIC2 ubiquitination complex"],"partners":["EPOR","STUB1","CHIC2","RNF4","JAK2","STAT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P32927","full_name":"Cytokine receptor common subunit beta","aliases":["CDw131","GM-CSF/IL-3/IL-5 receptor common beta subunit"],"length_aa":897,"mass_kda":97.3,"function":"Cell surface receptor that plays a role in immune response and controls the production and differentiation of hematopoietic progenitor cells into lineage-restricted cells. Acts by forming an heterodimeric receptor through interaction with different partners such as IL3RA, IL5RA or CSF2RA (PubMed:1495999). In turn, participates in various signaling pathways including interleukin-3, interleukin-5 and granulocyte-macrophage colony-stimulating factor/CSF2 pathways. In unstimulated conditions, interacts constitutively with JAK1 and ligand binding leads to JAK1 stimulation and subsequent activation of the JAK-STAT pathway (PubMed:9516124)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/P32927/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CSF2RB","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CSF2RB","total_profiled":1310},"omim":[{"mim_id":"614370","title":"SURFACTANT METABOLISM DYSFUNCTION, PULMONARY, 5; SMDP5","url":"https://www.omim.org/entry/614370"},{"mim_id":"613936","title":"TRANSMEMBRANE PROTEIN 102; TMEM102","url":"https://www.omim.org/entry/613936"},{"mim_id":"430000","title":"INTERLEUKIN 3 RECEPTOR, Y-CHROMOSOMAL; IL3RA","url":"https://www.omim.org/entry/430000"},{"mim_id":"308385","title":"INTERLEUKIN 3 RECEPTOR, ALPHA; IL3RA","url":"https://www.omim.org/entry/308385"},{"mim_id":"306250","title":"COLONY-STIMULATING FACTOR 2 RECEPTOR, ALPHA; CSF2RA","url":"https://www.omim.org/entry/306250"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":51.4},{"tissue":"lymphoid tissue","ntpm":61.8}],"url":"https://www.proteinatlas.org/search/CSF2RB"},"hgnc":{"alias_symbol":["IL5RB","CD131","betaGMR"],"prev_symbol":["IL3RB"]},"alphafold":{"accession":"P32927","domains":[{"cath_id":"2.60.40.10","chopping":"27-116","consensus_level":"high","plddt":92.0844,"start":27,"end":116},{"cath_id":"2.60.40.10","chopping":"133-157_166-237","consensus_level":"high","plddt":93.2828,"start":133,"end":237},{"cath_id":"2.60.40.10","chopping":"247-326","consensus_level":"high","plddt":92.9515,"start":247,"end":326},{"cath_id":"2.60.40.10","chopping":"336-443","consensus_level":"high","plddt":89.4982,"start":336,"end":443}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P32927","model_url":"https://alphafold.ebi.ac.uk/files/AF-P32927-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P32927-F1-predicted_aligned_error_v6.png","plddt_mean":63.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CSF2RB","jax_strain_url":"https://www.jax.org/strain/search?query=CSF2RB"},"sequence":{"accession":"P32927","fasta_url":"https://rest.uniprot.org/uniprotkb/P32927.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P32927/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P32927"}},"corpus_meta":[{"pmid":"21075760","id":"PMC_21075760","title":"Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in CSF2RB.","date":"2010","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21075760","citation_count":79,"is_preprint":false},{"pmid":"22738133","id":"PMC_22738133","title":"Priming of late endothelial progenitor cells with erythropoietin before transplantation requires the CD131 receptor subunit and enhances their angiogenic potential.","date":"2012","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/22738133","citation_count":58,"is_preprint":false},{"pmid":"27377463","id":"PMC_27377463","title":"A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF.","date":"2016","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/27377463","citation_count":57,"is_preprint":false},{"pmid":"20007544","id":"PMC_20007544","title":"Cbfb/Runx1 repression-independent 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alveolar proteinosis (PAP) in an autosomal recessive manner.\",\n      \"method\": \"Patient genetic screening, STAT5 phosphorylation assay in primary blood cells, flow cytometry for receptor expression\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay (STAT5 phosphorylation) combined with genetic analysis in patient cells, single lab/case report\",\n      \"pmids\": [\"21075760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A frameshift mutation in CSF2RB found in Ashkenazi Jewish Crohn's disease patients acts in a dominant-negative manner: cells co-transfected with full-length and mutant CSF2RB showed reduced pSTAT5 after GM-CSF stimulation compared to wild-type alone. Monocytes from heterozygous carriers showed reduced GM-CSF responses and markedly decreased aldehyde dehydrogenase activity, implicating CSF2RB-mediated STAT5 signaling in intestinal immune tolerance.\",\n      \"method\": \"Transfection of HEK293 cells with WT and mutant CSF2RB followed by pSTAT5 measurement; primary monocyte functional assays; CyTOF analysis of lamina propria leukocytes\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cell transfection functional assay, primary human monocyte assays, mass cytometry), replicated in discovery and validation cohorts\",\n      \"pmids\": [\"27377463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STUB1 (an E3 ubiquitin ligase) and CHIC2 form a protein complex that binds CSF2RB and promotes its ubiquitination, leading to lysosomal degradation. Genetic inactivation of either STUB1 or CHIC2 reduces CSF2RB ubiquitination and increases its cell-surface abundance, with the greatest effects observed at low cytokine concentrations.\",\n      \"method\": \"Genetic screens in multiple cellular contexts; co-immunoprecipitation demonstrating STUB1/CHIC2/CSF2RB complex; ubiquitination assays; flow cytometry for cell-surface CSF2RB\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic screens in multiple contexts, ubiquitination assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"36108743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CSF2RB overexpression in mesenchymal stromal cells (MSCs) increases STAT5 phosphorylation in response to CSF2, promotes MSC migration and reduces apoptosis. RNF4 (a ubiquitin ligase) binds phosphorylated STAT5 and is required for CSF2RB-dependent antiapoptotic and promigratory effects; RNF4 knockdown reduced STAT5 phosphorylation and these cellular effects.\",\n      \"method\": \"Adenoviral CSF2RB overexpression, co-immunoprecipitation of RNF4 with pSTAT5, coimmunostaining, RNF4 knockdown functional rescue, RNA sequencing\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional rescue experiments, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37064880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CSF2RB (CD131) co-immunoprecipitates and co-localizes with EPOR in endothelial colony-forming cells (ECFCs), suggesting they form a receptor complex. siRNA knockdown of CD131 abolished EPO-induced proliferation, migration, tube formation, and resistance to apoptosis in ECFCs, as well as downstream PI3K-Akt pathway activation, establishing CD131 as a required co-receptor for EPO's proangiogenic effects.\",\n      \"method\": \"Co-immunoprecipitation, western blotting, siRNA knockdown of CD131, in vitro proliferation/migration/tube formation assays, in vivo hindlimb ischemia model\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus loss-of-function (siRNA) with multiple functional readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"22738133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Carbamylated erythropoietin (CEPO) mediates neuroprotection through the CD131/GDNF/AKT pathway: blockage of CD131 reduced CEPO-mediated GDNF production, and GFR receptor blockage or GDNF neutralization inhibited CEPO-induced neurogenesis. CEPO activates AKT through GDNF but does not trigger JAK2, in contrast to EPO which activates JAK2.\",\n      \"method\": \"CD131 receptor blockade, GDNF neutralization, GFR receptor blockage in primary neurons and hypoxic mouse model; Western blot, immunohistochemistry, RT-PCR\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological inhibition experiments with pathway readouts, single lab\",\n      \"pmids\": [\"27541284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The EPO/CD131 heteroreceptor complex mediates tissue-protective (non-hematopoietic) EPO signaling. In mesenchymal-derived cells, cellular stress and TNFα promote externalization (surface expression) of CD131 as an immediate response. The specific CD131 agonist peptide ARA290 overcomes TNFα-mediated inhibition of stress-related transcription factors (SRF, HSF1, AP1), indicating that CD131-mediated signaling modulates pro-inflammatory pathways.\",\n      \"method\": \"Cell fractionation/surface expression assay for CD131 externalization, western blotting for transcription factor activation, pharmacological modulation with ARA290\",\n      \"journal\": \"Journal of molecular medicine (Berlin, Germany)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single set of pharmacological experiments without genetic confirmation of CD131 involvement\",\n      \"pmids\": [\"25373867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD131 (β-common receptor, βcR) is required for the anti-allodynic effect of both ARA290 and ketamine in a spared nerve injury neuropathic pain model: CD131 knockout mice showed no pain relief from either drug, while acute analgesic effects of ketamine and psychomotor side effects were unaffected, demonstrating that an intact βcR/innate repair receptor is specifically required for neuropathic pain relief.\",\n      \"method\": \"CD131 knockout mice, spared nerve injury model, behavioral assessment of allodynia and acute nociception, mRNA expression analysis of NMDAR, microglia, astrocytes, CCL2\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with specific behavioral and molecular phenotype, loss-of-function with clear pathway distinction\",\n      \"pmids\": [\"23936499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A somatic missense mutation S230I in CSF2RB found in a breast cancer patient and the KAIMRC1 cell line confers ligand-independent signaling through JAK2/STAT5 and PI3K/mTOR pathways, enabling cell survival and proliferation under cytokine-starvation conditions.\",\n      \"method\": \"Exome sequencing, immunoblot analysis for JAK2/STAT5 and PI3K/mTOR pathway activation under ligand-starvation, small molecule kinase inhibitor library screen\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays (Western blot for pathway activation, growth under starvation) combined with mutation identification, single lab\",\n      \"pmids\": [\"34729943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ApoA-I treatment shifts CD131 from lipid raft to non-raft fractions of the plasma membrane in immune cells by reducing microdomain cholesterol content, and this redistribution is associated with reduced CD131-expressing cell numbers in atherosclerotic plaques.\",\n      \"method\": \"Lipid raft fractionation of plasma membrane, flow cytometry for CD131-expressing cells, Ldlr-/- mouse atherosclerosis model\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, lipid raft fractionation without direct functional validation of raft-associated signaling changes\",\n      \"pmids\": [\"27821400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Pegmolesatide suppresses formation of the EPOR-CD131 heterodimer (demonstrated by co-immunoprecipitation) and inhibits downstream JAK2/STAT3 signaling, thereby reducing indoxyl sulfate-induced cardiomyocyte hypertrophy. Rescue experiments with the CD131 agonist ARA290 or STAT3 activator reversed these protective effects, confirming that suppression of EPOR-CD131/JAK2/STAT3 axis is the mechanism.\",\n      \"method\": \"Co-immunoprecipitation for EPOR-CD131 heterodimerization, Western blot for JAK2/STAT3 activation, pharmacological rescue with ARA290 and Stattic, phalloidin staining for cell size\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating heterodimerization plus functional rescue experiments with multiple pharmacological tools, single lab\",\n      \"pmids\": [\"41092772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Bispecific proteins (tandem scFv or bispecific antibody format) bridging EPOR and CD131 are sufficient to selectively activate STAT5 phosphorylation downstream of the EPO-R/CD131 complex without engaging EPO-R/EPO-R homodimers. Equimolar mixtures of individual scFvs were insufficient, indicating that physical crosslinking of EPOR and CD131 is required for receptor activation. A structural model of the EPO-R/CD131 complex was constructed and validated by linker length/arrangement experiments.\",\n      \"method\": \"Bispecific protein engineering, STAT5 phosphorylation assay, structural modeling with experimental validation via linker length/binding domain arrangement\",\n      \"journal\": \"Protein engineering, design & selection : PEDS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of signaling with defined bispecific agonists and mutagenesis-equivalent domain arrangement experiments, single lab\",\n      \"pmids\": [\"41206499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"E2F transcription factor promotes myeloid fate in hematopoietic stem and progenitor cells (HSPCs) in part by enhancing the signaling activity of CD131 (CSF2RB), the common β-chain receptor for IL-3 and GM-CSF. Dual inhibition of EZH2 and β-cytokine signaling (via CD131) suppressed stress myelopoiesis and restored colon homeostasis in a preclinical colitis model, placing CSF2RB downstream of E2F in the regulation of stress myelopoiesis.\",\n      \"method\": \"Genetic inactivation of E2F in HSPCs, combined pharmacological inhibition of EZH2 and β-cytokine signaling in colitis model, gene expression analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, primarily genetic epistasis with limited direct mechanistic dissection of CSF2RB's role\",\n      \"pmids\": [\"bio_10.1101_2025.06.16.659412\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CD131 (CSF2RB) signaling is required for macrophage infiltration in ulcerative colitis: CD131-deficient mice showed reduced DSS-induced colitis, with decreased macrophage and T-cell chemotaxis. CD131 promotes chemotaxis of macrophages and T cells into the colon through CCL4.\",\n      \"method\": \"CD131-deficient mouse DSS colitis model, immune cell infiltration analysis, CCL4 measurement\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined cellular phenotype and molecular mediator (CCL4) identified, single lab\",\n      \"pmids\": [\"40586774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The CSF2RB gene was mapped to chromosome 22q12.2→q13.1 by PCR analysis of somatic cell hybrids and in situ hybridization.\",\n      \"method\": \"PCR of human-rodent somatic cell hybrids, in situ hybridization to chromosome 22 translocations\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal localization by two independent methods, single lab\",\n      \"pmids\": [\"1424804\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CSF2RB (CD131) encodes the common β-chain shared by the GM-CSF, IL-3, and IL-5 receptors, and is responsible for initiating downstream signaling (primarily JAK2/STAT5 and PI3K/AKT) upon cytokine binding; its cell-surface abundance is regulated by STUB1/CHIC2-mediated ubiquitination and lysosomal degradation, loss-of-function mutations cause hereditary pulmonary alveolar proteinosis through abrogated STAT5 signaling, gain-of-function mutations confer ligand-independent JAK2/STAT5 and PI3K/mTOR activation, and CD131 also functions as an obligate co-receptor in an EPOR/CD131 heterodimeric complex that mediates tissue-protective EPO signaling through AKT/GDNF rather than JAK2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CSF2RB (CD131) encodes the common \\u03b2-chain receptor that transduces \\u03b2-cytokine (GM-CSF, IL-3, IL-5) signaling, predominantly through JAK2/STAT5 and PI3K/AKT, and is required for cytokine-dependent cellular responses [#0, #1]. 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 [#0, #1]. A somatic S230I mutation renders the receptor constitutively active, driving ligand-independent JAK2/STAT5 and PI3K/mTOR signaling that supports survival under cytokine starvation [#8]. 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 [#2]; downstream of STAT5 activation, RNF4 binds phosphorylated STAT5 and is required for CSF2RB-driven promigratory and antiapoptotic outputs [#3]. Beyond its canonical \\u03b2-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 [#4, #5, #11]. Through these pathways CSF2RB contributes to stress myelopoiesis and immune-cell chemotaxis into the colon via CCL4 [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing the chromosomal location of CSF2RB provided the genomic anchor for later disease-association studies.\",\n      \"evidence\": \"PCR of somatic cell hybrids and in situ hybridization mapping to 22q12.2\\u2192q13.1\",\n      \"pmids\": [\"1424804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or mechanistic information\", \"Does not address receptor activity or partners\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"Patient genetics, flow cytometry for receptor expression, STAT5 phosphorylation in primary blood cells\",\n      \"pmids\": [\"21075760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case report\", \"Mechanism of STAT5 coupling not dissected at molecular level\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Whether CD131 functions outside \\u03b2-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.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, in vitro angiogenesis assays and in vivo hindlimb ischemia in ECFCs\",\n      \"pmids\": [\"22738133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structure of EPOR/CD131 complex not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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 \\u03b2cR is specifically required for neuropathic pain relief.\",\n      \"evidence\": \"CD131 knockout mice, spared nerve injury model, behavioral and molecular analysis\",\n      \"pmids\": [\"23936499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling in neurons not fully mapped\", \"Cell type mediating effect not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"How CD131-mediated tissue-protective signaling is regulated was unclear; stress and TNF\\u03b1 were shown to induce CD131 surface externalization, and the agonist ARA290 modulated stress transcription factors.\",\n      \"evidence\": \"Cell fractionation/surface assay, western blotting, pharmacological modulation with ARA290\",\n      \"pmids\": [\"25373867\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genetic confirmation of CD131 involvement\", \"Single lab pharmacological experiments only\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"HEK293 WT/mutant co-transfection pSTAT5 assays, monocyte functional assays, CyTOF of lamina propria leukocytes\",\n      \"pmids\": [\"27377463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal contribution to Crohn's disease not established beyond association\", \"Mechanism of tolerance defect at tissue level incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"CD131 blockade, GDNF neutralization, GFR blockade in primary neurons and hypoxic mouse model\",\n      \"pmids\": [\"27541284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological blockade rather than genetic ablation\", \"Direct receptor coupling to GDNF induction not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Lipid raft fractionation, flow cytometry, Ldlr-/- atherosclerosis model\",\n      \"pmids\": [\"27821400\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct functional validation of raft-dependent signaling change\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Exome sequencing, immunoblot under ligand starvation, kinase inhibitor library screen\",\n      \"pmids\": [\"34729943\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of constitutive activation not solved\", \"Single cell line/patient\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genetic screens, reciprocal Co-IP, ubiquitination assays, flow cytometry across multiple cell contexts\",\n      \"pmids\": [\"36108743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin linkage type and exact acceptor sites not defined\", \"In vivo relevance of this turnover not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Adenoviral overexpression, reciprocal Co-IP of RNF4 with pSTAT5, knockdown rescue, RNA-seq\",\n      \"pmids\": [\"37064880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RNF4 acts catalytically on STAT5 not established\", \"Single lab, overexpression-based\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Bispecific protein engineering, STAT5 phosphorylation assays, structural modeling with linker-arrangement validation\",\n      \"pmids\": [\"41206499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous ligand geometry not directly compared\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP for heterodimerization, western blot, pharmacological rescue with ARA290 and Stattic\",\n      \"pmids\": [\"41092772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"JAK2/STAT3 vs AKT/GDNF branch selection not reconciled\", \"Single lab, pharmacological\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"CD131-deficient mouse DSS colitis model, immune infiltration analysis, CCL4 measurement\",\n      \"pmids\": [\"40586774\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-intrinsic vs extrinsic CD131 requirement not separated\", \"Link between receptor signaling and CCL4 induction not molecularly mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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/\\u03b2-cytokine inhibition restoring colon homeostasis.\",\n      \"evidence\": \"Genetic inactivation of E2F in HSPCs, combined pharmacological inhibition in colitis model, expression analysis (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.06.16.659412\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Direct mechanistic dissection of CSF2RB regulation limited\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CSF2RB partitions between canonical \\u03b2-cytokine JAK2/STAT5 signaling and the EPOR/CD131 tissue-protective branches (AKT/GDNF vs JAK2/STAT3) at the structural and regulatory level remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of either active complex\", \"Determinants selecting between STAT5, AKT/GDNF, and JAK2/STAT3 outputs unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 11]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 6, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"EPOR/CD131 heteroreceptor complex\", \"STUB1/CHIC2 ubiquitination complex\"],\n    \"partners\": [\"EPOR\", \"STUB1\", \"CHIC2\", \"RNF4\", \"JAK2\", \"STAT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}