{"gene":"SIRPB1","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2000,"finding":"SIRPB1 associates with the DAP12 signal transduction molecule, and this complex formation is required for efficient cell-surface expression of SIRPB1. Stimulation of the SIRPB1/DAP12 complex induces tyrosine phosphorylation, MAP kinase activation, and cellular activation in monocytes and dendritic cells.","method":"Co-immunoprecipitation, anti-SIRP mAb stimulation assays, tyrosine phosphorylation and MAPK activation readouts","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional stimulation assays, foundational paper with 130 citations replicated across contexts","pmids":["10604985"],"is_preprint":false},{"year":2020,"finding":"SIRPB1 promotes prostate cancer cell proliferation by activating Akt phosphorylation; knockdown induces G0/G1 cell cycle arrest and apoptosis, while overexpression enhances migration, invasion, and tumor xenograft growth, and Akt inhibition abolishes SIRPB1-stimulated proliferation.","method":"siRNA knockdown, overexpression, colony formation assay, wound-healing/transwell assay, cell cycle analysis, xenograft tumor model, western blot for Akt phosphorylation","journal":"The Prostate","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, OE, in vivo xenograft, pharmacological inhibition) in a single study with clear pathway placement","pmids":["31905248"],"is_preprint":false},{"year":2024,"finding":"SIRPB1 activation by specific antibodies induces SYK phosphorylation and subsequent activation of calcium, MAPK, and NF-κB signaling pathways, primarily in myeloid-derived cells. In macrophages, SIRPB1 regulates expression of IL1RA, CCL2, and IL-8; SIRPB1 knockout reduces these cytokines, which are restored by ectopic SIRPB1 re-expression and again suppressed by SYK inhibitor GS9973.","method":"CRISPR/Cas9 knockout, antibody stimulation, ectopic expression, SYK inhibitor treatment, cytokine measurement in co-culture with glioma cells","journal":"Journal of translational medicine","confidence":"High","confidence_rationale":"Tier 2 — CRISPR KO with rescue experiments and pharmacological inhibition confirming SYK as the downstream effector, multiple orthogonal methods","pmids":["38594692"],"is_preprint":false},{"year":2023,"finding":"A rare frameshift variant (c.1143_1144insG; p.Leu381_Leu382fs) in SIRPB1 acts as a gain-of-function mutation that induces tyrosine phosphorylation of Syk, Akt, and Jak2, elevates SIRPB1 mRNA and protein expression, activates DAP12, activates NF-κB in macrophages, and promotes synthesis of pro-inflammatory cytokines IL-1, TNF-α, and IL-6.","method":"Family-based whole-genome sequencing, genetic association in replication cohort, functional assays in macrophages (western blot for phosphorylation, NF-κB activation, cytokine measurement)","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional readouts but single lab, novel frameshift variant with direct mechanistic follow-up","pmids":["37323681"],"is_preprint":false},{"year":2025,"finding":"SIRPB1 promotes cutaneous malignant melanoma tumorigenicity by suppressing SOCS1 expression, thereby releasing negative regulation of STAT3; knockdown upregulates SOCS1 and negatively regulates STAT3, and STAT3 agonists reverse the tumor-inhibitory effect of SIRPB1 knockdown. Transcription factor USF2 binds the SIRPB1 promoter and drives its transcriptional expression.","method":"siRNA knockdown, overexpression, in vitro proliferation/migration/invasion assays, in vivo tumor model, STAT3 agonist rescue, USF2 promoter binding assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, OE, rescue, in vivo) from a single lab establishing SOCS1/STAT3 pathway placement","pmids":["41467177"],"is_preprint":false},{"year":2017,"finding":"In mouse osteoclast differentiation, Sirpb1 is a DAP12-coupled costimulatory receptor involved in calcium signaling required for auto-amplification of Nfatc1; polyphenolic fractions from dried plum suppress Sirpb1 mRNA expression coincident with suppressed calcium signaling and decreased osteoclast formation.","method":"Primary bone marrow-derived osteoclast cultures, mRNA expression analysis, MAPK phosphorylation assays, functional osteoclast differentiation and activity readouts","journal":"Current developments in nutrition","confidence":"Medium","confidence_rationale":"Tier 3 — mRNA expression and functional osteoclast phenotype linked to Sirpb1 downregulation, but indirect (pharmacological treatment model) with no direct KO/KI","pmids":["29955675"],"is_preprint":false},{"year":2018,"finding":"Circular Chromosome Conformation Capture (4C-seq) from the SIRPB1 promoter revealed that the presence or absence of a common copy-number variant (duplication) causes important 3D chromatin modifications at the SIRPB1 locus, and a 3' enhancer shows neural activity in transgenic models, suggesting that the CNV modulates SIRPB1 expression in the central nervous system.","method":"4C-seq (Circular Chromosome Conformation Capture), transgenic enhancer reporter assay in zebrafish","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — 4C-seq with transgenic functional validation of enhancer activity, single lab","pmids":["29518122"],"is_preprint":false},{"year":2014,"finding":"A common copy-number variant within SIRPB1 intron 1 is associated with impulsive-disinhibited personality; the deleted allele haplotype is associated with higher SIRPB1 mRNA levels, and the deleted region contains functional insulator elements confirmed by reporter assays in zebrafish embryos, indicating the CNV modulates SIRPB1 expression.","method":"Genome-wide CNV analysis, eQTL analysis, zebrafish insulator functional assay","journal":"Genes, brain, and behavior","confidence":"Medium","confidence_rationale":"Tier 2 — eQTL plus functional insulator validation in zebrafish, single lab","pmids":["25039969"],"is_preprint":false},{"year":2020,"finding":"An allele-specific chromatin conformation capture approach demonstrated that a common deletion mapping between the SIRPB1 promoter and a downstream enhancer directly impacts DNA interactions between cis-regulatory regions and the SIRPB1 promoter.","method":"Allele-specific chromatin conformation capture (4C variant)","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — direct measurement of 3D chromatin contacts, proof-of-concept study focused specifically on SIRPB1 locus","pmids":["32998049"],"is_preprint":false},{"year":2013,"finding":"In the context of DAP12-coupled receptor signaling, SIRPB1 (SIRPb1) is expressed in normal mouse eyes alongside DAP12, and DAP12 deficiency alters the cytokine response profile of lymphocytes, demonstrating that DAP12-coupled receptors including SIRPb1 regulate immune activation in ocular tissues.","method":"Quantitative RT-PCR in mouse eye tissue, DAP12 knockout mouse model, in vitro lymphocyte stimulation with cytokine profiling","journal":"Immunology","confidence":"Low","confidence_rationale":"Tier 3 — SIRPb1 expression quantified but functional role inferred indirectly from DAP12 KO phenotype; SIRPB1 not directly manipulated","pmids":["23906311"],"is_preprint":false}],"current_model":"SIRPB1 is a DAP12-associated activating receptor expressed on myeloid cells whose short cytoplasmic tail lacks SHP-1/SHP-2 recruitment motifs; it requires DAP12 association for cell-surface expression and signals through SYK phosphorylation to activate calcium, MAPK, and NF-κB pathways, regulating inflammatory cytokine production in macrophages, and in cancer contexts promotes proliferation, migration, and invasion via Akt activation and SOCS1/STAT3 signaling, while its expression level is controlled by a copy-number variant that alters 3D chromatin contacts between the SIRPB1 promoter and downstream enhancers."},"narrative":{"teleology":[{"year":2000,"claim":"The fundamental signaling partnership of SIRPB1 was established: it requires DAP12 for surface expression and, upon ligation, triggers tyrosine phosphorylation and MAPK activation in monocytes and dendritic cells, resolving how this short-tailed receptor transduces activating signals.","evidence":"Co-immunoprecipitation and anti-SIRP mAb stimulation of monocytes and dendritic cells","pmids":["10604985"],"confidence":"High","gaps":["The proximal kinase (SYK vs ZAP-70) downstream of DAP12 in the SIRPB1 complex was not identified","Natural ligand for SIRPB1 remains unknown","Functional consequences for cytokine output were not measured"]},{"year":2014,"claim":"A common copy-number variant in SIRPB1 intron 1 was shown to function as a cis-regulatory element—containing insulator activity and acting as an eQTL—demonstrating that structural variation controls SIRPB1 expression levels and linking this to impulsive-disinhibited personality traits.","evidence":"Genome-wide CNV association, eQTL analysis, and zebrafish insulator reporter assay","pmids":["25039969"],"confidence":"Medium","gaps":["Causal relationship between SIRPB1 expression and behavioral phenotype was not established by direct manipulation","Cell-type specificity of the eQTL (myeloid vs neuronal) was not resolved"]},{"year":2018,"claim":"3D chromatin topology studies revealed that the intron-1 CNV reshapes promoter–enhancer contacts at the SIRPB1 locus, and a downstream enhancer drives neural expression, explaining how the structural variant mechanistically alters transcriptional output.","evidence":"4C-seq from SIRPB1 promoter and transgenic enhancer reporter in zebrafish","pmids":["29518122","32998049"],"confidence":"Medium","gaps":["Whether altered 3D contacts quantitatively change SIRPB1 protein levels in human tissues was not shown","Identity of transcription factors mediating enhancer activity was unknown at the time"]},{"year":2020,"claim":"SIRPB1 was shown to function as an oncogenic driver in prostate cancer, promoting proliferation, migration, invasion, and xenograft growth through Akt phosphorylation, with Akt inhibition abolishing these effects—extending SIRPB1 signaling beyond immune cells to a cancer-intrinsic growth pathway.","evidence":"siRNA knockdown, overexpression, xenograft tumor model, pharmacological Akt inhibition in prostate cancer cell lines","pmids":["31905248"],"confidence":"High","gaps":["Whether SIRPB1 signals through DAP12 in epithelial cancer cells was not addressed","The upstream trigger for SIRPB1 activation in the tumor microenvironment was not identified"]},{"year":2023,"claim":"A rare gain-of-function frameshift variant in SIRPB1 was found to hyperactivate DAP12, SYK, Akt, JAK2, and NF-κB in macrophages, driving excessive IL-1, TNF-α, and IL-6 production—demonstrating that SIRPB1 variants can cause pathological inflammatory signaling in humans.","evidence":"Family-based WGS, replication cohort, functional macrophage assays for phosphorylation and cytokine output","pmids":["37323681"],"confidence":"Medium","gaps":["The mechanism by which a frameshift increases receptor expression and signaling is unclear (stabilization vs. trafficking effect)","Not independently replicated in a second laboratory","Clinical phenotype associated with this variant was not fully characterized"]},{"year":2024,"claim":"CRISPR knockout and rescue experiments definitively placed SYK as the essential proximal kinase downstream of SIRPB1, showing that SIRPB1 activation drives calcium, MAPK, and NF-κB signaling to regulate IL1RA, CCL2, and IL-8 in macrophages, a pathway fully blocked by the SYK inhibitor GS9973.","evidence":"CRISPR/Cas9 KO, ectopic re-expression, SYK inhibitor GS9973, cytokine profiling in macrophage–glioma co-culture","pmids":["38594692"],"confidence":"High","gaps":["Natural ligand on glioma cells engaging SIRPB1 was not identified","Relative contribution of SIRPB1 vs other DAP12-paired receptors in tumor-associated macrophages is unresolved"]},{"year":2025,"claim":"In melanoma, SIRPB1 was shown to promote tumorigenicity through a distinct mechanism—suppressing SOCS1 to de-repress STAT3—and USF2 was identified as a transcription factor driving SIRPB1 expression, adding a second cancer-relevant signaling axis beyond Akt.","evidence":"siRNA knockdown, overexpression, in vivo tumor model, STAT3 agonist rescue, USF2 promoter binding assay in melanoma cells","pmids":["41467177"],"confidence":"Medium","gaps":["How SIRPB1 suppresses SOCS1 (transcriptional vs post-transcriptional) is not defined","Whether USF2-driven transcription operates in myeloid cells or is cancer-specific is unknown"]},{"year":null,"claim":"The natural ligand for SIRPB1 remains unidentified, and it is unknown whether immune and cancer signaling functions use the same or distinct proximal mechanisms (DAP12-dependent vs DAP12-independent).","evidence":"","pmids":[],"confidence":"High","gaps":["No natural ligand has been identified for SIRPB1","Whether SIRPB1 signals independently of DAP12 in epithelial cancer cells has not been tested","No structural model of the SIRPB1 extracellular domain–ligand interface exists"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,3,4]}],"complexes":["SIRPB1–DAP12 complex"],"partners":["TYROBP","SYK","AKT1","SOCS1","STAT3","USF2"],"other_free_text":[]},"mechanistic_narrative":"SIRPB1 is a DAP12-coupled activating receptor on myeloid cells that transduces signals through SYK, MAPK, NF-κB, and calcium pathways to regulate inflammatory cytokine production and osteoclast differentiation. Association with DAP12 is required for efficient SIRPB1 surface expression, and antibody-mediated or gain-of-function stimulation of the SIRPB1–DAP12 complex induces SYK and Akt phosphorylation, leading to production of IL-1, TNF-α, IL-6, CCL2, and IL-8 in macrophages [PMID:10604985, PMID:38594692, PMID:37323681]. In cancer contexts, SIRPB1 promotes proliferation, migration, and invasion through Akt activation in prostate cancer and through SOCS1 suppression and consequent STAT3 de-repression in melanoma [PMID:31905248, PMID:41467177]. SIRPB1 expression is modulated by a common intron-1 copy-number variant that alters 3D chromatin contacts between the promoter and downstream enhancer/insulator elements [PMID:25039969, PMID:29518122, PMID:32998049]."},"prefetch_data":{"uniprot":{"accession":"O00241","full_name":"Signal-regulatory protein beta-1","aliases":["CD172 antigen-like family member B"],"length_aa":398,"mass_kda":43.2,"function":"Immunoglobulin-like cell surface receptor involved in the negative regulation of receptor tyrosine kinase-coupled signaling processes. Also participates in the recruitment of tyrosine kinase SYK. Triggers activation of myeloid cells when associated with TYROBP (PubMed:10604985)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O00241/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SIRPB1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SIRPB1","total_profiled":1310},"omim":[{"mim_id":"605466","title":"SIGNAL REGULATORY PROTEIN, GAMMA; SIRPG","url":"https://www.omim.org/entry/605466"},{"mim_id":"603889","title":"SIGNAL REGULATORY PROTEIN, BETA-1; SIRPB1","url":"https://www.omim.org/entry/603889"},{"mim_id":"602461","title":"SIGNAL REGULATORY PROTEIN, ALPHA; SIRPA","url":"https://www.omim.org/entry/602461"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":49.3},{"tissue":"lung","ntpm":18.3},{"tissue":"lymphoid tissue","ntpm":27.0}],"url":"https://www.proteinatlas.org/search/SIRPB1"},"hgnc":{"alias_symbol":["SIRP-BETA-1","CD172b","SIRB1"],"prev_symbol":[]},"alphafold":{"accession":"Q5TFQ8","domains":[{"cath_id":"2.60.40.10","chopping":"36-145","consensus_level":"high","plddt":94.7687,"start":36,"end":145},{"cath_id":"2.60.40.10","chopping":"149-248","consensus_level":"high","plddt":96.4888,"start":149,"end":248},{"cath_id":"2.60.40.10","chopping":"255-346","consensus_level":"high","plddt":89.5685,"start":255,"end":346}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5TFQ8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5TFQ8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5TFQ8-F1-predicted_aligned_error_v6.png","plddt_mean":85.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SIRPB1","jax_strain_url":"https://www.jax.org/strain/search?query=SIRPB1"},"sequence":{"accession":"Q5TFQ8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5TFQ8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5TFQ8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5TFQ8"}},"corpus_meta":[{"pmid":"10604985","id":"PMC_10604985","title":"Cutting edge: signal-regulatory protein beta 1 is a DAP12-associated activating receptor expressed in myeloid cells.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10604985","citation_count":130,"is_preprint":false},{"pmid":"31242423","id":"PMC_31242423","title":"Mesenchymal Stem/Stromal Cell Engulfment Reveals Metastatic Advantage in Breast Cancer.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31242423","citation_count":73,"is_preprint":false},{"pmid":"35721735","id":"PMC_35721735","title":"Genome-Wide Placental Gene Methylations in Gestational Diabetes Mellitus, Fetal Growth and Metabolic Health Biomarkers in Cord Blood.","date":"2022","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/35721735","citation_count":29,"is_preprint":false},{"pmid":"23405089","id":"PMC_23405089","title":"Genome wide analysis of chromosomal alterations in oral squamous cell carcinomas revealed over expression of MGAM and ADAM9.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23405089","citation_count":28,"is_preprint":false},{"pmid":"22890838","id":"PMC_22890838","title":"High-resolution genomic profiling reveals clonal evolution and competition in gastrointestinal marginal zone B-cell lymphoma and its large cell variant.","date":"2012","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22890838","citation_count":23,"is_preprint":false},{"pmid":"24564241","id":"PMC_24564241","title":"Analysis of schizophrenia and hepatocellular carcinoma genetic network with corresponding modularity and pathways: novel insights to the immune system.","date":"2013","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/24564241","citation_count":20,"is_preprint":false},{"pmid":"30689579","id":"PMC_30689579","title":"Stem Cell-Derived Neurons as Cellular Models of Sporadic Alzheimer's Disease.","date":"2019","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/30689579","citation_count":17,"is_preprint":false},{"pmid":"29713342","id":"PMC_29713342","title":"Copy Number Variation of Immune-Related Genes and Their Association with Iodine in Adults with Autoimmune Thyroid Diseases.","date":"2018","source":"International journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/29713342","citation_count":14,"is_preprint":false},{"pmid":"29955675","id":"PMC_29955675","title":"Osteoclast Differentiation is Downregulated by Select Polyphenolic Fractions from Dried Plum via Suppression of MAPKs and Nfatc1 in Mouse C57BL/6 Primary Bone Marrow Cells.","date":"2017","source":"Current developments in nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/29955675","citation_count":14,"is_preprint":false},{"pmid":"34603322","id":"PMC_34603322","title":"The Immunoregulatory Role of the Signal Regulatory Protein Family and CD47 Signaling Pathway in Type 1 Diabetes.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34603322","citation_count":14,"is_preprint":false},{"pmid":"27058892","id":"PMC_27058892","title":"Read-through transcripts in normal human lung parenchyma are down-regulated in lung adenocarcinoma.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27058892","citation_count":14,"is_preprint":false},{"pmid":"37438770","id":"PMC_37438770","title":"Longitudinal APOE4- and amyloid-dependent changes in the blood transcriptome in cognitively intact older adults.","date":"2023","source":"Alzheimer's research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37438770","citation_count":13,"is_preprint":false},{"pmid":"31905248","id":"PMC_31905248","title":"SIRPB1 promotes prostate cancer cell proliferation via Akt activation.","date":"2020","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/31905248","citation_count":12,"is_preprint":false},{"pmid":"25039969","id":"PMC_25039969","title":"SIRPB1 copy-number polymorphism as candidate quantitative trait locus for impulsive-disinhibited personality.","date":"2014","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/25039969","citation_count":10,"is_preprint":false},{"pmid":"23906311","id":"PMC_23906311","title":"Environmental factors determine DAP12 deficiency to either enhance or suppress immunopathogenic processes.","date":"2013","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23906311","citation_count":10,"is_preprint":false},{"pmid":"38594692","id":"PMC_38594692","title":"SIRPB1 regulates inflammatory factor expression in the glioma microenvironment via SYK: functional and bioinformatics insights.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38594692","citation_count":7,"is_preprint":false},{"pmid":"35967305","id":"PMC_35967305","title":"A Cross-Tissue Transcriptome-Wide Association Study Identifies Novel Susceptibility Genes for Juvenile Idiopathic Arthritis in Asia and Europe.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35967305","citation_count":7,"is_preprint":false},{"pmid":"38283146","id":"PMC_38283146","title":"Genome-wide survey reveals the genetic background of Xinjiang Brown cattle in China.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38283146","citation_count":7,"is_preprint":false},{"pmid":"31349540","id":"PMC_31349540","title":"Deletions in Genes Participating in Innate Immune Response Modify the Clinical Course of Andes Orthohantavirus Infection.","date":"2019","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/31349540","citation_count":6,"is_preprint":false},{"pmid":"39113081","id":"PMC_39113081","title":"FOSL1-mediated LINC01566 negatively regulates CD4+ T-cell activation in myasthenia gravis.","date":"2024","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/39113081","citation_count":5,"is_preprint":false},{"pmid":"40723400","id":"PMC_40723400","title":"Molecular and Genetic Pathogenesis of Oral Cancer: A Basis for Customized Diagnosis and Treatment.","date":"2025","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40723400","citation_count":5,"is_preprint":false},{"pmid":"39920152","id":"PMC_39920152","title":"Retrotrans-genomics identifies aberrant THE1B endogenous retrovirus fusion transcripts in the pathogenesis of sarcoidosis.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39920152","citation_count":5,"is_preprint":false},{"pmid":"25752595","id":"PMC_25752595","title":"Nature and nurture: a case of transcending haematological pre-malignancies in a pair of monozygotic twins adding possible clues on the pathogenesis of B-cell proliferations.","date":"2015","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/25752595","citation_count":5,"is_preprint":false},{"pmid":"22110671","id":"PMC_22110671","title":"SNPs array karyotyping reveals a novel recurrent 20p13 amplification in primary myelofibrosis.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22110671","citation_count":5,"is_preprint":false},{"pmid":"29518122","id":"PMC_29518122","title":"A common copy-number variant within SIRPB1 correlates with human Out-of-Africa migration after genetic drift correction.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29518122","citation_count":4,"is_preprint":false},{"pmid":"37323681","id":"PMC_37323681","title":"A frameshift variant in the SIRPB1 gene confers susceptibility to Crohn's disease in a Chinese population.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37323681","citation_count":3,"is_preprint":false},{"pmid":"26239731","id":"PMC_26239731","title":"Genotyping of common SIRPB1 copy number variant using Paralogue Ratio Test coupled to MALDI-MS quantification.","date":"2015","source":"Molecular and cellular probes","url":"https://pubmed.ncbi.nlm.nih.gov/26239731","citation_count":2,"is_preprint":false},{"pmid":"38552750","id":"PMC_38552750","title":"Knocking out FAM20C in pre-osteoblasts leads to up-regulation of osteoclast differentiation to affect long bone development.","date":"2024","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/38552750","citation_count":2,"is_preprint":false},{"pmid":"40830311","id":"PMC_40830311","title":"A prospective study on the regulation of osteoarthritis risk through inflammatory pathways in clonal hematopoiesis.","date":"2025","source":"GeroScience","url":"https://pubmed.ncbi.nlm.nih.gov/40830311","citation_count":1,"is_preprint":false},{"pmid":"39497634","id":"PMC_39497634","title":"In silico and functional analysis identifies key gene networks and novel gene candidates in obesity-linked human visceral fat.","date":"2024","source":"Obesity (Silver Spring, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/39497634","citation_count":1,"is_preprint":false},{"pmid":"41467177","id":"PMC_41467177","title":"SIRPB1 is transcriptionally regulated by USF2 and promotes cutaneous malignant melanoma tumorigenicity through SOCS1/STAT3 signaling.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41467177","citation_count":0,"is_preprint":false},{"pmid":"41333034","id":"PMC_41333034","title":"Multi-Omics Mendelian Randomization Identifies Therapeutic Targets for Sjögren's Disease with Clinical and Bayesian Validation.","date":"2025","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/41333034","citation_count":0,"is_preprint":false},{"pmid":"41886420","id":"PMC_41886420","title":"Genetic variations associated with immediate hypersensitivity reactions to iodinated contrast media: A whole exome sequencing study.","date":"2026","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/41886420","citation_count":0,"is_preprint":false},{"pmid":"32998049","id":"PMC_32998049","title":"Straightforward protocol for allele-specific chromatin conformation capture.","date":"2020","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/32998049","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.14.638349","title":"Integrative Analysis of Single-cell and Bulk RNA Sequencing Reveals Macrophage Heterogeneity in Lyme Arthritis","date":"2025-02-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.14.638349","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20649,"output_tokens":2558,"usd":0.050159},"stage2":{"model":"claude-opus-4-6","input_tokens":5881,"output_tokens":2285,"usd":0.129795},"total_usd":0.179954,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"SIRPB1 associates with the DAP12 signal transduction molecule, and this complex formation is required for efficient cell-surface expression of SIRPB1. Stimulation of the SIRPB1/DAP12 complex induces tyrosine phosphorylation, MAP kinase activation, and cellular activation in monocytes and dendritic cells.\",\n      \"method\": \"Co-immunoprecipitation, anti-SIRP mAb stimulation assays, tyrosine phosphorylation and MAPK activation readouts\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional stimulation assays, foundational paper with 130 citations replicated across contexts\",\n      \"pmids\": [\"10604985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SIRPB1 promotes prostate cancer cell proliferation by activating Akt phosphorylation; knockdown induces G0/G1 cell cycle arrest and apoptosis, while overexpression enhances migration, invasion, and tumor xenograft growth, and Akt inhibition abolishes SIRPB1-stimulated proliferation.\",\n      \"method\": \"siRNA knockdown, overexpression, colony formation assay, wound-healing/transwell assay, cell cycle analysis, xenograft tumor model, western blot for Akt phosphorylation\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, OE, in vivo xenograft, pharmacological inhibition) in a single study with clear pathway placement\",\n      \"pmids\": [\"31905248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRPB1 activation by specific antibodies induces SYK phosphorylation and subsequent activation of calcium, MAPK, and NF-κB signaling pathways, primarily in myeloid-derived cells. In macrophages, SIRPB1 regulates expression of IL1RA, CCL2, and IL-8; SIRPB1 knockout reduces these cytokines, which are restored by ectopic SIRPB1 re-expression and again suppressed by SYK inhibitor GS9973.\",\n      \"method\": \"CRISPR/Cas9 knockout, antibody stimulation, ectopic expression, SYK inhibitor treatment, cytokine measurement in co-culture with glioma cells\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with rescue experiments and pharmacological inhibition confirming SYK as the downstream effector, multiple orthogonal methods\",\n      \"pmids\": [\"38594692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A rare frameshift variant (c.1143_1144insG; p.Leu381_Leu382fs) in SIRPB1 acts as a gain-of-function mutation that induces tyrosine phosphorylation of Syk, Akt, and Jak2, elevates SIRPB1 mRNA and protein expression, activates DAP12, activates NF-κB in macrophages, and promotes synthesis of pro-inflammatory cytokines IL-1, TNF-α, and IL-6.\",\n      \"method\": \"Family-based whole-genome sequencing, genetic association in replication cohort, functional assays in macrophages (western blot for phosphorylation, NF-κB activation, cytokine measurement)\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional readouts but single lab, novel frameshift variant with direct mechanistic follow-up\",\n      \"pmids\": [\"37323681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIRPB1 promotes cutaneous malignant melanoma tumorigenicity by suppressing SOCS1 expression, thereby releasing negative regulation of STAT3; knockdown upregulates SOCS1 and negatively regulates STAT3, and STAT3 agonists reverse the tumor-inhibitory effect of SIRPB1 knockdown. Transcription factor USF2 binds the SIRPB1 promoter and drives its transcriptional expression.\",\n      \"method\": \"siRNA knockdown, overexpression, in vitro proliferation/migration/invasion assays, in vivo tumor model, STAT3 agonist rescue, USF2 promoter binding assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, OE, rescue, in vivo) from a single lab establishing SOCS1/STAT3 pathway placement\",\n      \"pmids\": [\"41467177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In mouse osteoclast differentiation, Sirpb1 is a DAP12-coupled costimulatory receptor involved in calcium signaling required for auto-amplification of Nfatc1; polyphenolic fractions from dried plum suppress Sirpb1 mRNA expression coincident with suppressed calcium signaling and decreased osteoclast formation.\",\n      \"method\": \"Primary bone marrow-derived osteoclast cultures, mRNA expression analysis, MAPK phosphorylation assays, functional osteoclast differentiation and activity readouts\",\n      \"journal\": \"Current developments in nutrition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — mRNA expression and functional osteoclast phenotype linked to Sirpb1 downregulation, but indirect (pharmacological treatment model) with no direct KO/KI\",\n      \"pmids\": [\"29955675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Circular Chromosome Conformation Capture (4C-seq) from the SIRPB1 promoter revealed that the presence or absence of a common copy-number variant (duplication) causes important 3D chromatin modifications at the SIRPB1 locus, and a 3' enhancer shows neural activity in transgenic models, suggesting that the CNV modulates SIRPB1 expression in the central nervous system.\",\n      \"method\": \"4C-seq (Circular Chromosome Conformation Capture), transgenic enhancer reporter assay in zebrafish\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — 4C-seq with transgenic functional validation of enhancer activity, single lab\",\n      \"pmids\": [\"29518122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A common copy-number variant within SIRPB1 intron 1 is associated with impulsive-disinhibited personality; the deleted allele haplotype is associated with higher SIRPB1 mRNA levels, and the deleted region contains functional insulator elements confirmed by reporter assays in zebrafish embryos, indicating the CNV modulates SIRPB1 expression.\",\n      \"method\": \"Genome-wide CNV analysis, eQTL analysis, zebrafish insulator functional assay\",\n      \"journal\": \"Genes, brain, and behavior\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — eQTL plus functional insulator validation in zebrafish, single lab\",\n      \"pmids\": [\"25039969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"An allele-specific chromatin conformation capture approach demonstrated that a common deletion mapping between the SIRPB1 promoter and a downstream enhancer directly impacts DNA interactions between cis-regulatory regions and the SIRPB1 promoter.\",\n      \"method\": \"Allele-specific chromatin conformation capture (4C variant)\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct measurement of 3D chromatin contacts, proof-of-concept study focused specifically on SIRPB1 locus\",\n      \"pmids\": [\"32998049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In the context of DAP12-coupled receptor signaling, SIRPB1 (SIRPb1) is expressed in normal mouse eyes alongside DAP12, and DAP12 deficiency alters the cytokine response profile of lymphocytes, demonstrating that DAP12-coupled receptors including SIRPb1 regulate immune activation in ocular tissues.\",\n      \"method\": \"Quantitative RT-PCR in mouse eye tissue, DAP12 knockout mouse model, in vitro lymphocyte stimulation with cytokine profiling\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — SIRPb1 expression quantified but functional role inferred indirectly from DAP12 KO phenotype; SIRPB1 not directly manipulated\",\n      \"pmids\": [\"23906311\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SIRPB1 is a DAP12-associated activating receptor expressed on myeloid cells whose short cytoplasmic tail lacks SHP-1/SHP-2 recruitment motifs; it requires DAP12 association for cell-surface expression and signals through SYK phosphorylation to activate calcium, MAPK, and NF-κB pathways, regulating inflammatory cytokine production in macrophages, and in cancer contexts promotes proliferation, migration, and invasion via Akt activation and SOCS1/STAT3 signaling, while its expression level is controlled by a copy-number variant that alters 3D chromatin contacts between the SIRPB1 promoter and downstream enhancers.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SIRPB1 is a DAP12-coupled activating receptor on myeloid cells that transduces signals through SYK, MAPK, NF-κB, and calcium pathways to regulate inflammatory cytokine production and osteoclast differentiation. Association with DAP12 is required for efficient SIRPB1 surface expression, and antibody-mediated or gain-of-function stimulation of the SIRPB1–DAP12 complex induces SYK and Akt phosphorylation, leading to production of IL-1, TNF-α, IL-6, CCL2, and IL-8 in macrophages [PMID:10604985, PMID:38594692, PMID:37323681]. In cancer contexts, SIRPB1 promotes proliferation, migration, and invasion through Akt activation in prostate cancer and through SOCS1 suppression and consequent STAT3 de-repression in melanoma [PMID:31905248, PMID:41467177]. SIRPB1 expression is modulated by a common intron-1 copy-number variant that alters 3D chromatin contacts between the promoter and downstream enhancer/insulator elements [PMID:25039969, PMID:29518122, PMID:32998049].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The fundamental signaling partnership of SIRPB1 was established: it requires DAP12 for surface expression and, upon ligation, triggers tyrosine phosphorylation and MAPK activation in monocytes and dendritic cells, resolving how this short-tailed receptor transduces activating signals.\",\n      \"evidence\": \"Co-immunoprecipitation and anti-SIRP mAb stimulation of monocytes and dendritic cells\",\n      \"pmids\": [\"10604985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The proximal kinase (SYK vs ZAP-70) downstream of DAP12 in the SIRPB1 complex was not identified\",\n        \"Natural ligand for SIRPB1 remains unknown\",\n        \"Functional consequences for cytokine output were not measured\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A common copy-number variant in SIRPB1 intron 1 was shown to function as a cis-regulatory element—containing insulator activity and acting as an eQTL—demonstrating that structural variation controls SIRPB1 expression levels and linking this to impulsive-disinhibited personality traits.\",\n      \"evidence\": \"Genome-wide CNV association, eQTL analysis, and zebrafish insulator reporter assay\",\n      \"pmids\": [\"25039969\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal relationship between SIRPB1 expression and behavioral phenotype was not established by direct manipulation\",\n        \"Cell-type specificity of the eQTL (myeloid vs neuronal) was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"3D chromatin topology studies revealed that the intron-1 CNV reshapes promoter–enhancer contacts at the SIRPB1 locus, and a downstream enhancer drives neural expression, explaining how the structural variant mechanistically alters transcriptional output.\",\n      \"evidence\": \"4C-seq from SIRPB1 promoter and transgenic enhancer reporter in zebrafish\",\n      \"pmids\": [\"29518122\", \"32998049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether altered 3D contacts quantitatively change SIRPB1 protein levels in human tissues was not shown\",\n        \"Identity of transcription factors mediating enhancer activity was unknown at the time\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"SIRPB1 was shown to function as an oncogenic driver in prostate cancer, promoting proliferation, migration, invasion, and xenograft growth through Akt phosphorylation, with Akt inhibition abolishing these effects—extending SIRPB1 signaling beyond immune cells to a cancer-intrinsic growth pathway.\",\n      \"evidence\": \"siRNA knockdown, overexpression, xenograft tumor model, pharmacological Akt inhibition in prostate cancer cell lines\",\n      \"pmids\": [\"31905248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether SIRPB1 signals through DAP12 in epithelial cancer cells was not addressed\",\n        \"The upstream trigger for SIRPB1 activation in the tumor microenvironment was not identified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A rare gain-of-function frameshift variant in SIRPB1 was found to hyperactivate DAP12, SYK, Akt, JAK2, and NF-κB in macrophages, driving excessive IL-1, TNF-α, and IL-6 production—demonstrating that SIRPB1 variants can cause pathological inflammatory signaling in humans.\",\n      \"evidence\": \"Family-based WGS, replication cohort, functional macrophage assays for phosphorylation and cytokine output\",\n      \"pmids\": [\"37323681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The mechanism by which a frameshift increases receptor expression and signaling is unclear (stabilization vs. trafficking effect)\",\n        \"Not independently replicated in a second laboratory\",\n        \"Clinical phenotype associated with this variant was not fully characterized\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CRISPR knockout and rescue experiments definitively placed SYK as the essential proximal kinase downstream of SIRPB1, showing that SIRPB1 activation drives calcium, MAPK, and NF-κB signaling to regulate IL1RA, CCL2, and IL-8 in macrophages, a pathway fully blocked by the SYK inhibitor GS9973.\",\n      \"evidence\": \"CRISPR/Cas9 KO, ectopic re-expression, SYK inhibitor GS9973, cytokine profiling in macrophage–glioma co-culture\",\n      \"pmids\": [\"38594692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Natural ligand on glioma cells engaging SIRPB1 was not identified\",\n        \"Relative contribution of SIRPB1 vs other DAP12-paired receptors in tumor-associated macrophages is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In melanoma, SIRPB1 was shown to promote tumorigenicity through a distinct mechanism—suppressing SOCS1 to de-repress STAT3—and USF2 was identified as a transcription factor driving SIRPB1 expression, adding a second cancer-relevant signaling axis beyond Akt.\",\n      \"evidence\": \"siRNA knockdown, overexpression, in vivo tumor model, STAT3 agonist rescue, USF2 promoter binding assay in melanoma cells\",\n      \"pmids\": [\"41467177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How SIRPB1 suppresses SOCS1 (transcriptional vs post-transcriptional) is not defined\",\n        \"Whether USF2-driven transcription operates in myeloid cells or is cancer-specific is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The natural ligand for SIRPB1 remains unidentified, and it is unknown whether immune and cancer signaling functions use the same or distinct proximal mechanisms (DAP12-dependent vs DAP12-independent).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No natural ligand has been identified for SIRPB1\",\n        \"Whether SIRPB1 signals independently of DAP12 in epithelial cancer cells has not been tested\",\n        \"No structural model of the SIRPB1 extracellular domain–ligand interface exists\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4]}\n    ],\n    \"complexes\": [\n      \"SIRPB1–DAP12 complex\"\n    ],\n    \"partners\": [\n      \"TYROBP\",\n      \"SYK\",\n      \"AKT1\",\n      \"SOCS1\",\n      \"STAT3\",\n      \"USF2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}