{"gene":"TNFRSF1B","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":1990,"finding":"Molecular cloning of TNFRSF1B (TNFR2/p75 TNF receptor): a cDNA encoding a 461-amino acid integral membrane protein was isolated from a human lung fibroblast library by direct expression screening with radiolabeled TNF-alpha. The extracellular domain contains cysteine-rich repeats homologous to the nerve growth factor receptor, defining a receptor superfamily.","method":"cDNA expression cloning, radiolabeled ligand binding, sequence analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — original cloning with functional validation; foundational paper with >1000 citations","pmids":["2160731"],"is_preprint":false},{"year":1990,"finding":"TNFRSF1B was independently cloned as a 415-amino acid TNF receptor; the extracellular cysteine-rich domain is homologous to the NGF receptor and Bp50. Cells transfected with TNFR expression vector specifically bind both TNF-alpha and TNF-beta with equal affinity.","method":"cDNA cloning from serum TNF-binding protein sequences, transfection, radiolabeled ligand binding","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — reconstituted receptor binding in transfected cells; >1000 citations, replicated independently","pmids":["2158863"],"is_preprint":false},{"year":1990,"finding":"Two distinct soluble TNF-binding proteins (corresponding to shed ectodomains of TNFR1 and TNFR2) were purified from human urine; antibodies against each inhibit TNF binding to cells from different cell lines with varying efficacy, establishing that two distinct receptor species exist on cell surfaces.","method":"Ligand-affinity purification, NH2-terminal sequencing, antibody blocking of cell-surface TNF binding","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — biochemical purification with functional validation; >500 citations","pmids":["2153136"],"is_preprint":false},{"year":1990,"finding":"TNFRSF1B (TNFrII) can shed a naturally occurring soluble TNF inhibitor through proteolytic cleavage of its ectodomain; expression of the TNFrII cDNA in COS-7 cells produced a receptor that binds TNF-alpha and releases a soluble inhibitory fragment.","method":"cDNA expression in COS-7 cells, TNF-binding assay, protein isolation from U-937 cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — reconstituted shedding in transfected cells; >300 citations","pmids":["2172983"],"is_preprint":false},{"year":1994,"finding":"TRAF1 and TRAF2 were identified as the first signal transducers that associate with the cytoplasmic domain of TNFRSF1B (TNF-R2). A C-terminal 78-amino acid region of the TNF-R2 cytoplasmic domain is required for signal transduction and mediates this interaction. TRAF1 and TRAF2 form homo- and heterotypic dimers, with TRAF2 contacting the receptor directly and TRAF1 associating indirectly through TRAF2.","method":"Yeast two-hybrid, biochemical purification, co-immunoprecipitation, mutational analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — biochemical purification plus yeast two-hybrid plus mutagenesis; foundational paper >900 citations","pmids":["8069916"],"is_preprint":false},{"year":1995,"finding":"TRAF2-mediated activation of NF-κB is a key signaling output of TNFRSF1B (TNF-R2): overexpression of TRAF2 was sufficient to induce NF-κB activation, and a dominant-negative TRAF2 lacking the N-terminal RING finger domain blocked NF-κB activation by TNF-R2 and CD40.","method":"Transient transfection, NF-κB reporter assays, dominant-negative mutant analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — epistasis via dominant-negative approach with reporter readout; >900 citations, widely replicated","pmids":["7544915"],"is_preprint":false},{"year":1995,"finding":"The TNFRSF1B (TNFR2) signaling complex contains c-IAP1 and c-IAP2, two novel mammalian members of the inhibitor of apoptosis (IAP) family. These proteins do not contact TNFR2 directly but associate with TRAF1 and TRAF2 through their N-terminal BIR motif-comprising domain, requiring a TRAF2-TRAF1 heterocomplex for recruitment.","method":"Biochemical purification, molecular cloning, co-immunoprecipitation, interaction domain mapping","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — biochemical purification of native complex followed by molecular cloning and domain mapping; >1000 citations","pmids":["8548810"],"is_preprint":false},{"year":1995,"finding":"Both TNFR60 (TNFR1) and TNFR80 (TNFRSF1B/TNFR2) are involved in signaling endothelial tissue factor expression by juxtacrine (membrane-bound) TNF-alpha. Selective triggering of either receptor with agonistic antibodies induced tissue factor expression, and simultaneous blockade of both was required for full inhibition.","method":"Antagonistic and agonistic antibody blocking, HUVECs co-culture with membrane TNF-expressing CHO transfectants, tissue factor assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — functional antibody studies with defined cellular readout; single study","pmids":["7544644"],"is_preprint":false},{"year":1996,"finding":"TNFRSF1B (TNF-R2/p75) signaling is required for the migration of Langerhans cells from skin to draining lymph nodes. In TNF-R1-deficient mice, anti-TNF-alpha antibody still inhibited Langerhans cell accumulation in lymph nodes following hapten application, implicating TNF-R2 as the mediator of this migratory response.","method":"TNF-R1 gene-targeted mice, hapten (FITC) application, flow cytometry, neutralizing antibody studies","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockout combined with antibody blocking and defined cellular readout","pmids":["8690462"],"is_preprint":false},{"year":1996,"finding":"Distinct domains of TRAF2 mediate different functions in TNFRSF1B signaling: the N-terminal RING finger and two adjacent zinc fingers are required for NF-κB activation; the TRAF-N and TRAF-C subdomains independently mediate self-association and TRAF1 interaction; interaction with TNF-R2 requires C-terminal sequences of TRAF-C; interaction with RIP occurs via N-terminal TRAF-C sequences.","method":"Extensive mutational analysis (point mutants and chimeric proteins), NF-κB reporter assays, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis with multiple functional readouts; >270 citations","pmids":["8702708"],"is_preprint":false},{"year":1997,"finding":"Constitutive shedding of both p55 (TNFR1) and p75 (TNFRSF1B/TNFR2) murine TNF receptors occurs in vivo; administration of TNF receptor-specific mAbs to normal mice caused linear accumulation of soluble receptor in circulation by blocking clearance of constitutively shed receptor. Accumulated soluble receptor was capable of inhibiting TNF-induced responses in vivo.","method":"In vivo mAb administration to normal mice, soluble receptor ELISA, TNF-induced response assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo experiment with mechanistic interpretation of clearance; single study","pmids":["9103455"],"is_preprint":false},{"year":1998,"finding":"TNFRSF1B (TNFR80)-mediated enhancement of TNFR60-induced cell death is TNFR60-selective and is mediated through TRAF2: TNFR80 costimulation abrogates antiapoptotic TRAF2-dependent signaling from TNFR60 by negatively regulating TRAF2 function, thereby potentiating TNF-induced cell death. This was confirmed by showing that TNFR80 prestimulation reduced TNFR60-induced JNK activation.","method":"TRAF2 overexpression and dominant-negative mutant transfection in HeLa cells, cell death assays, JNK activation assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — epistasis via gain- and loss-of-function with multiple orthogonal readouts; >110 citations","pmids":["9743381"],"is_preprint":false},{"year":1998,"finding":"TNF-alpha-induced apoptosis of CD8+ T cells is mediated by macrophages through membrane-bound TNF (mbTNF) interacting with TNFRSF1B (TNFRII) on CD8+ T cells. HIV gp120 interaction with CXCR4 upregulates both mbTNF on macrophages and TNFRII on CD8+ T cells, and TNFRII-blocking antibodies prevent this apoptosis.","method":"Blocking antibodies against TNFRII, HIV infection of PBMCs, flow cytometry, apoptosis assays","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 — antibody blocking with defined molecular pathway and functional readout","pmids":["9744279"],"is_preprint":false},{"year":1998,"finding":"TNF-R1 (CD120a) is the high-affinity receptor for soluble TNF (Kd = 1.9 × 10⁻¹¹ M at 37°C) while TNFRSF1B/TNF-R2 has significantly lower affinity for soluble TNF (Kd = 4.2 × 10⁻¹⁰ M). The high affinity of TNF-R1 derives from marked stability of ligand-receptor complexes, whereas TNF-R2 forms only transient interactions with soluble TNF, explaining the predominant role of TNF-R1 in responses to soluble TNF.","method":"Kinetic binding measurements (association/dissociation rate constants) at 37°C, Scatchard analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — rigorous quantitative binding kinetics at physiological temperature; >360 citations","pmids":["9435233"],"is_preprint":false},{"year":1999,"finding":"Crystal structure of the TRAF domain of human TRAF2 reveals a trimeric self-association and, in complex with a TNF-R2 peptide, shows the receptor peptide binding to a conserved shallow surface depression on one TRAF-C domain. An SXXE motif serves as a TRAF2-binding consensus sequence in TNFRSF1B.","method":"X-ray crystallography, solution studies confirming trimeric state, peptide-protein co-crystal structure","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of receptor-adaptor complex with solution validation; >300 citations","pmids":["10206649"],"is_preprint":false},{"year":2000,"finding":"A pre-ligand-binding assembly domain (PLAD) in the extracellular region of TNFRSF1B (TNFR2/p80) mediates specific ligand-independent assembly of receptor trimers. The PLAD is physically distinct from the ligand-binding domain but is necessary and sufficient for TNFR complex assembly and TNF-alpha binding and signaling.","method":"Domain mapping by mutagenesis, FRET, co-immunoprecipitation, functional signaling assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis plus FRET plus co-IP with functional validation; >660 citations","pmids":["10875917"],"is_preprint":false},{"year":2000,"finding":"Keratin 8 and keratin 18 bind the cytoplasmic domain of TNFRSF1B (TNFR2/CD120b) and moderate TNF-induced JNK signaling and NF-κB activation. K8/K18-deficient epithelial cells are ~100× more sensitive to TNF-induced death, demonstrating that keratins modulate TNFR2 intracellular signaling.","method":"K8/K18 knockout mice, direct binding assays, JNK and NF-κB signaling assays, in vivo concanavalin A hepatotoxicity model","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding plus knockout phenotype plus in vivo validation; >229 citations","pmids":["10747083"],"is_preprint":false},{"year":2002,"finding":"TNF-RII (TNFRSF1B) activation induces ubiquitination and proteasomal degradation of TRAF2 through c-IAP1, which acts as an E3 ubiquitin ligase. c-IAP1 bound TRAF2 and ubiquitinated it specifically; E3-defective c-IAP1 prevented TNF-alpha-induced TRAF2 degradation and inhibited apoptosis. This defines a mechanism by which TNFRSF1B potentiates TNF-induced apoptosis by depleting antiapoptotic TRAF2.","method":"In vitro ubiquitination assay, E3-defective mutant expression, proteasome inhibitor studies, co-immunoprecipitation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — in vitro ubiquitination reconstitution plus mutagenesis plus functional rescue; >389 citations","pmids":["11907583"],"is_preprint":false},{"year":2003,"finding":"TNFRSF1B (TNFR-2) signaling potentiates programmed necrosis via TNFR-1 through recruitment of RIP kinase to the TNFR-1 complex. Pre-stimulation through TNFR-2 enhanced TNF-induced cell death and RIP recruitment to TNFR-1. TNFR-2-deficient mice showed reduced liver inflammation and defective viral clearance during vaccinia virus infection, linking TNFRSF1B to antiviral responses.","method":"TNFR-2 knockout mice, viral infection model, co-immunoprecipitation of RIP with TNFR-1, death effector domain protein expression studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic KO plus molecular mechanism (RIP recruitment) plus in vivo viral model; >372 citations","pmids":["14532286"],"is_preprint":false},{"year":2004,"finding":"A physical and functional map of the TNF-alpha/NF-κB signaling pathway identified 221 molecular associations and 80 previously unknown interactors around 32 known pathway components including TNFRSF1B, using tandem affinity purification and mass spectrometry, validated by RNAi functional studies.","method":"Tandem affinity purification (TAP), LC-MS/MS, RNAi functional validation, network analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — proteome-scale AP-MS with RNAi functional validation; >841 citations","pmids":["14743216"],"is_preprint":false},{"year":2011,"finding":"Progranulin (PGRN) binds directly to TNFRSF1B (TNFR2) and TNFR1, competing with TNF-alpha for receptor binding. Atsttrin, an engineered PGRN fragment, selectively binds TNFRs and inhibits TNF-alpha-activated intracellular signaling. PGRN-deficient mice were susceptible to inflammatory arthritis, and PGRN/Atsttrin treatment reversed disease in multiple arthritis models.","method":"Direct binding assays, competitive displacement, PGRN-deficient mice, multiple arthritis mouse models, intracellular signaling assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding demonstrated plus genetic KO plus multiple in vivo models; >620 citations","pmids":["21393509"],"is_preprint":false},{"year":2015,"finding":"Recurrent point mutations and genomic gains of TNFRSF1B (encoding TNFR2) occur in 18% of mycosis fungoides and Sézary syndrome patients. The recurrent TNFR2 Thr377Ile mutant expressed in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to proteasome inhibitor bortezomib, establishing TNFRSF1B as an oncogenic driver in cutaneous T cell lymphoma.","method":"Whole-genome sequencing, targeted sequencing, functional expression of mutant TNFR2 in T cells, NF-κB signaling assays, bortezomib sensitivity assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — genomic discovery plus functional validation of specific mutant with defined signaling mechanism; >224 citations","pmids":["26258847"],"is_preprint":false},{"year":2019,"finding":"miR-125a-5p directly targets TNFRSF1B mRNA: luciferase reporter assay confirmed TNFRSF1B as the target gene of miR-125a-5p. Upregulation of miR-125a-5p inhibited TNFRSF1B protein expression and promoted osteoclast differentiation, while downregulation had opposite effects, establishing TNFRSF1B as a suppressor of osteoclastogenesis regulated by miR-125a-5p.","method":"Dual luciferase reporter assay, miRNA mimic/inhibitor transfection, western blot, osteoclast differentiation assay","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2–3 — luciferase validation of miRNA target plus functional osteoclast differentiation assay; single lab","pmids":["30976285"],"is_preprint":false},{"year":2021,"finding":"LncRNA NEAT1 stabilizes TNFRSF1B mRNA through direct RNA-protein interaction (co-precipitated TNFRSF1B mRNA in RNA pulldown assay) and promotes NF-κB p65 nuclear translocation and intestinal inflammation. Knockdown of NEAT1 reduced TNFRSF1B expression and NF-κB activation; overexpression of TNFRSF1B rescued these effects.","method":"RNA pulldown, RNA decay assay, siRNA knockdown, western blot, NF-κB p65 immunofluorescence, ELISA of inflammatory cytokines, DSS colitis mouse model","journal":"Annals of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — RNA pulldown plus functional rescue in cell lines; single lab, moderate mechanistic depth","pmids":["34268386"],"is_preprint":false},{"year":2021,"finding":"Proteome-scale affinity-purification mass spectrometry (BioPlex 3.0) identified interaction partners of TNFRSF1B in 293T and HCT116 cells, contributing to a cell-line-specific interactome network. Cell-specific interactions of TNFRSF1B link core complexes to other subnetworks, revealing rewiring of the receptor's interaction landscape across cell types.","method":"Affinity-purification mass spectrometry (AP-MS), reciprocal validation, proteome-scale network analysis across two cell lines","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — proteome-scale AP-MS with cross-cell-line validation; strong method but TNFRSF1B-specific findings not individually validated","pmids":["33961781"],"is_preprint":false}],"current_model":"TNFRSF1B (TNFR2/p75 TNF receptor) is a single-pass transmembrane receptor that forms pre-assembled trimers via its extracellular PLAD domain, binds TNF-alpha with lower affinity than TNFR1, and signals intracellularly by recruiting TRAF1 and TRAF2 (directly via an SXXE-containing cytoplasmic motif) along with c-IAP1/c-IAP2 (via TRAF1/TRAF2), leading to TRAF2-dependent NF-κB and JNK activation; TNFRSF1B potentiates TNFR1-induced apoptosis and programmed necrosis by triggering c-IAP1-mediated ubiquitination and proteasomal degradation of TRAF2, thereby depleting antiapoptotic signals, and also mediates Langerhans cell migration, CD8+ T cell apoptosis via macrophage-expressed membrane TNF, and non-canonical NF-κB signaling when mutated (Thr377Ile) in cutaneous T cell lymphoma."},"narrative":{"teleology":[{"year":1990,"claim":"Molecular cloning of TNFRSF1B established it as a second, distinct TNF receptor with cysteine-rich extracellular repeats that binds both TNF-α and TNF-β, resolving the question of whether multiple TNF receptor species exist.","evidence":"cDNA expression cloning from human fibroblast and serum-derived sequences, radiolabeled ligand binding in transfected cells, and biochemical purification of soluble ectodomains from urine","pmids":["2160731","2158863","2153136"],"confidence":"High","gaps":["No intracellular signaling mechanism identified","Relative contributions of TNFR1 vs TNFR2 to TNF responses unknown","Ectodomain shedding mechanism and regulation uncharacterized"]},{"year":1990,"claim":"Demonstration that TNFRSF1B sheds a soluble ectodomain capable of inhibiting TNF revealed a built-in negative regulatory mechanism for the TNF pathway.","evidence":"cDNA expression in COS-7 cells with soluble receptor fragment isolation and TNF-binding assay","pmids":["2172983"],"confidence":"High","gaps":["Identity of the sheddase protease unknown","Physiological significance of constitutive shedding not established"]},{"year":1994,"claim":"Identification of TRAF1 and TRAF2 as the first signal transducers recruited to the TNFRSF1B cytoplasmic domain answered how a death-domain-lacking receptor signals, establishing that a C-terminal 78-residue region mediates adaptor recruitment.","evidence":"Yeast two-hybrid, biochemical purification, co-immunoprecipitation, and deletion mutagenesis","pmids":["8069916"],"confidence":"High","gaps":["Downstream effectors of TRAF2 at TNFR2 unknown","Structural basis of the TRAF2–receptor interaction unresolved"]},{"year":1995,"claim":"TRAF2 was established as the direct mediator of NF-κB activation downstream of TNFRSF1B, and c-IAP1/c-IAP2 were identified as TRAF1/TRAF2-dependent components of the receptor signaling complex, defining the core adaptor architecture.","evidence":"Dominant-negative TRAF2 blocking NF-κB reporter activation; biochemical purification and domain mapping of c-IAP1/c-IAP2 interaction with TRAF1/TRAF2","pmids":["7544915","8548810"],"confidence":"High","gaps":["Enzymatic activity of c-IAPs in TNFR2 signaling not known","Mechanism of JNK activation via TRAF2 at TNFR2 not dissected"]},{"year":1998,"claim":"The discovery that TNFRSF1B co-stimulation depletes TRAF2 and thereby potentiates TNFR1-induced apoptosis resolved the paradox of how a receptor lacking a death domain enhances cell death, and quantitative binding kinetics explained why TNFR2 preferentially responds to membrane-bound rather than soluble TNF.","evidence":"Dominant-negative and overexpression studies with JNK and cell death readouts; kinetic binding measurements at 37°C showing transient TNFR2–TNF complexes (Kd ~4.2 × 10⁻¹⁰ M)","pmids":["9743381","9435233"],"confidence":"High","gaps":["Molecular mechanism of TRAF2 depletion (ubiquitination) not yet identified","Role of membrane-TNF versus soluble-TNF in vivo not fully delineated"]},{"year":1999,"claim":"The crystal structure of the TRAF2 TRAF domain in complex with a TNFR2 peptide revealed the SXXE motif as the TRAF2-binding consensus and showed receptor binding to a shallow surface depression on a trimeric TRAF scaffold, providing the first atomic-level view of TNFRSF1B signal transduction.","evidence":"X-ray crystallography of TRAF2 TRAF-domain/TNFR2-peptide co-crystal","pmids":["10206649"],"confidence":"High","gaps":["Full-length receptor–TRAF2 complex structure lacking","Structural basis for selectivity among different TRAF-recruiting receptors not resolved"]},{"year":2000,"claim":"Identification of the pre-ligand assembly domain (PLAD) showed that TNFRSF1B forms trimers before ligand binding, revealing that receptor pre-assembly is a prerequisite for TNF-α binding and signaling.","evidence":"Domain mutagenesis, FRET, co-immunoprecipitation, and functional signaling assays","pmids":["10875917"],"confidence":"High","gaps":["Structure of PLAD-mediated trimer interface not determined","How ligand binding transitions pre-assembled trimers to active signaling complexes unknown"]},{"year":2002,"claim":"The mechanism by which TNFRSF1B potentiates apoptosis was resolved: c-IAP1 functions as an E3 ubiquitin ligase that ubiquitinates TRAF2 for proteasomal degradation upon TNFR2 activation, depleting antiapoptotic signals.","evidence":"In vitro ubiquitination reconstitution, E3-defective c-IAP1 mutant blocking TRAF2 degradation, proteasome inhibitor rescue","pmids":["11907583"],"confidence":"High","gaps":["Ubiquitin chain type on TRAF2 not characterized","Whether c-IAP2 has redundant E3 activity in this context not tested"]},{"year":2003,"claim":"TNFRSF1B was shown to potentiate TNFR1-dependent programmed necrosis by enhancing RIP kinase recruitment to TNFR1, and TNFR2-deficient mice showed defective antiviral inflammatory responses, linking receptor crosstalk to innate immunity.","evidence":"TNFR2 knockout mice with vaccinia infection, co-immunoprecipitation of RIP with TNFR1 after TNFR2 pre-stimulation","pmids":["14532286"],"confidence":"High","gaps":["Whether TNFR2 directly modulates RIP phosphorylation status unknown","Necroptotic pathway components downstream of RIP in this context not mapped"]},{"year":2011,"claim":"Progranulin was identified as an alternative endogenous ligand that competes with TNF-α for binding to TNFRSF1B, expanding the receptor's ligand repertoire and establishing a new anti-inflammatory axis.","evidence":"Direct binding assays, competitive displacement of TNF-α, progranulin-deficient mice with inflammatory arthritis, therapeutic rescue with engineered Atsttrin fragment","pmids":["21393509"],"confidence":"High","gaps":["Binding site overlap between progranulin and TNF-α on TNFR2 not structurally resolved","Whether progranulin activates or only blocks TNFR2 signaling remains debated"]},{"year":2015,"claim":"Recurrent somatic TNFRSF1B mutations, especially Thr377Ile, were identified as oncogenic drivers in cutaneous T-cell lymphoma, demonstrating that gain-of-function TNFR2 signaling activates non-canonical NF-κB and is targetable with proteasome inhibition.","evidence":"Whole-genome sequencing of mycosis fungoides/Sézary syndrome, functional expression of Thr377Ile mutant in T cells, NF-κB signaling and bortezomib sensitivity assays","pmids":["26258847"],"confidence":"High","gaps":["Structural mechanism by which Thr377Ile activates non-canonical NF-κB not determined","Whether wild-type TNFR2 also engages non-canonical NF-κB under physiological conditions unclear","Clinical efficacy of proteasome inhibitors in TNFRSF1B-mutant lymphoma not established"]},{"year":null,"claim":"Key unresolved questions include the full-length structure of the TNFR2 signaling complex, the precise mechanism of PLAD-mediated pre-assembly transition to active signaling, whether TNFR2-selective agonism versus antagonism can be therapeutically harnessed, and the contribution of non-canonical NF-κB signaling through wild-type TNFR2 in normal immune homeostasis.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length TNFR2 signaling complex structure available","Therapeutic TNFR2-selective agents not clinically validated","Physiological role of non-canonical NF-κB through wild-type TNFR2 not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,5,13,15]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,6,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3,15]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,3,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,6,9,14,15,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,12,18,20]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[11,17,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[21]}],"complexes":["TNFR2–TRAF1–TRAF2–cIAP1/2 signaling complex"],"partners":["TRAF2","TRAF1","BIRC2","BIRC3","GRN","KRT8","KRT18","RIPK1"],"other_free_text":[]},"mechanistic_narrative":"TNFRSF1B (TNFR2/p75) is a TNF receptor superfamily member that transduces TNF-α signals to regulate NF-κB activation, JNK signaling, cell survival, and programmed cell death in immune and epithelial cells. The receptor forms pre-ligand trimers via an extracellular PLAD domain, binds TNF-α with lower affinity than TNFR1 (Kd ~4.2 × 10⁻¹⁰ M), and signals by recruiting TRAF2 directly through a cytoplasmic SXXE motif, with TRAF1 and c-IAP1/c-IAP2 assembling indirectly via TRAF2 [PMID:8069916, PMID:8548810, PMID:10206649, PMID:10875917, PMID:9435233]. TNFRSF1B potentiates TNFR1-mediated apoptosis and programmed necrosis by triggering c-IAP1-dependent ubiquitination and proteasomal degradation of TRAF2, thereby depleting antiapoptotic signaling capacity [PMID:11907583, PMID:14532286, PMID:9743381]. Recurrent gain-of-function mutations in TNFRSF1B, notably Thr377Ile, drive non-canonical NF-κB activation and are found in ~18% of cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome) cases [PMID:26258847]."},"prefetch_data":{"uniprot":{"accession":"P20333","full_name":"Tumor necrosis factor receptor superfamily member 1B","aliases":["Tumor necrosis factor receptor 2","TNF-R2","Tumor necrosis factor receptor type II","TNF-RII","TNFR-II","p75","p80 TNF-alpha receptor"],"length_aa":461,"mass_kda":48.3,"function":"Receptor with high affinity for TNFSF2/TNF and approximately 5-fold lower affinity for homotrimeric TNFSF1/lymphotoxin-alpha. The TRAF1/TRAF2 complex recruits the apoptotic suppressors BIRC2 and BIRC3 to TNFRSF1B/TNFR2. This receptor mediates most of the metabolic effects of TNF. Isoform 2 blocks TNF-induced apoptosis, which suggests that it regulates TNF function by antagonizing its biological activity","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P20333/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TNFRSF1B","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TNFRSF1B","total_profiled":1310},"omim":[{"mim_id":"608877","title":"VACUOLAR PROTEIN SORTING 13 HOMOLOG D; VPS13D","url":"https://www.omim.org/entry/608877"},{"mim_id":"607317","title":"SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 4; SCAR4","url":"https://www.omim.org/entry/607317"},{"mim_id":"606928","title":"BONE MINERAL DENSITY QUANTITATIVE TRAIT LOCUS 3; 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this interaction is maximal at 100 ng/ml NGF, maps to the juxtamembrane region of p75, and is required for NGF-mediated NF-κB activation in Schwann cells, as shown by dominant-negative TRAF6 blockade.\",\n      \"method\": \"Co-immunoprecipitation after transient transfection in HEK293T cells, dominant-negative TRAF6 in Schwann cells, nuclear NF-κB localization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with functional validation using dominant-negative, replicated in physiologically relevant Schwann cells\",\n      \"pmids\": [\"9915784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Caveolin directly interacts with p75NTR and TrkA; caveolin expression inhibits TrkA autophosphorylation in vitro and in vivo, while concurrently increasing NGF-induced sphingomyelin hydrolysis through p75NTR, demonstrating caveolin as a modulator of the balance between TrkA and p75NTR signaling.\",\n      \"method\": \"Co-immunoprecipitation, GST-caveolin pulldown, in vitro kinase assay, PC12 cell transfection, neuritic process assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding + functional in vitro kinase inhibition + in vivo co-IP with phenotypic readout\",\n      \"pmids\": [\"9867838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"p75NTR induces apoptosis through its death domain in neurons via activation of caspases 9, 6, and 3 (mitochondrial pathway), requires receptor multimerization, does not involve FADD, TRADD, or caspase 8, and is blocked by Bcl-XL and dominant-negative caspase 9, distinguishing it from other TNFR family death pathways.\",\n      \"method\": \"Inducible p75NTR expression system in conditionally immortalized striatal neurons, caspase activation assays, dominant-negative caspase constructs, Bcl-XL overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal pharmacological and genetic interventions with defined pathway dissection\",\n      \"pmids\": [\"11451944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"p75NTR is a co-receptor for the Nogo-66 receptor (NgR) for MAG signaling; NgR and p75NTR co-immunoprecipitate, and p75NTR is required for MAG-induced intracellular Ca2+ elevation and repulsive axon turning in response to MAG.\",\n      \"method\": \"Co-immunoprecipitation, Ca2+ imaging in HEK cells expressing NgR/p75NTR, Xenopus growth cone turning assay, antibody blockade\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal co-IP combined with functional reconstitution and loss-of-function with antibody, multiple model systems\",\n      \"pmids\": [\"12426574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"p75NTR transduces the MAG inhibitory signal to RhoA GTPase; neurons from p75NTR mutant mice are insensitive to MAG-mediated neurite outgrowth inhibition; ganglioside GT1b specifically associates with p75NTR to form a receptor complex for MAG.\",\n      \"method\": \"p75NTR mutant mouse neurons, neurite outgrowth assay, RhoA activation assay, co-localization and co-immunoprecipitation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with defined molecular pathway (RhoA) and biochemical binding partner identification\",\n      \"pmids\": [\"12011108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"proNGF is the primary activator of p75NTR-mediated apoptosis of oligodendrocytes after spinal cord injury; p75NTR knockout mice show significantly reduced oligodendrocyte apoptosis, and proNGF-specific antibody blocks proNGF-induced death in p75+/+ but not p75-/- oligodendrocytes.\",\n      \"method\": \"p75NTR knockout mice, spinal cord injury model, proNGF antibody blockade, cell culture apoptosis assay\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined in vivo and in vitro phenotype, pharmacological validation with neutralizing antibody\",\n      \"pmids\": [\"12408842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Necdin and MAGE-H1 interact with the intracellular domain of p75NTR in a ligand-enhanced manner; their expression in PC12 cells accelerates NGF-induced differentiation; necdin homodimerizes and may act as a cytoplasmic adaptor to recruit a signaling complex to p75NTR.\",\n      \"method\": \"Co-immunoprecipitation, transfection of PC12 cells, differentiation assay, subcellular localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Co-IP with functional follow-up but no structural validation\",\n      \"pmids\": [\"12414813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PKA catalytic subunit beta (PKACbeta) interacts with p75NTR and phosphorylates it at Ser304; p75NTR binding to NGF causes transient cAMP accumulation; PKA-dependent phosphorylation is required for translocation of p75NTR to lipid rafts and for downstream Rho inactivation and neurite outgrowth.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro phosphorylation assay, lipid raft fractionation, Rho activity assay, neurite outgrowth assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro phosphorylation assay + subcellular fractionation + functional phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"12682012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A ternary complex can form between TrkA, p75NTR, and Kidins220/ARMS; the extracellular domains of TrkA and p75NTR are required for their association, while the juxtamembrane region of p75NTR mediates interaction with Kidins220/ARMS; increasing Kidins220/ARMS expression decreases TrkA-p75NTR association.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutant analysis\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, Co-IP with domain mapping but no structural validation\",\n      \"pmids\": [\"15378608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NRIF and TRAF6 directly interact via the NRIF KRAB domain and TRAF6 C-terminal region; co-expression of TRAF6 increases NRIF protein levels and induces its nuclear translocation; NRIF enhances TRAF6-mediated JNK activation ~3-fold; both NRIF and TRAF6 are required for p75NTR-mediated JNK activation in HEK293 cells.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion analysis, JNK and NF-κB reporter assays, nuclear translocation assay, reconstitution in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction demonstrated, functional reconstitution with domain mutants, multiple pathway readouts\",\n      \"pmids\": [\"14960584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"p75NTR interacts physically with the adaptor protein Shc via co-immunoprecipitation, and specifically enhances phosphorylation of the 46- and 52-kDa Shc isoforms during NGF-induced TrkA activation, with downstream effects on Akt serine phosphorylation, thus facilitating TrkA signal transduction.\",\n      \"method\": \"Antisense knockdown of p75NTR and TrkA, co-immunoprecipitation, phosphorylation assays\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, co-IP and knockdown with defined phosphorylation readout but limited mechanistic follow-up\",\n      \"pmids\": [\"15056278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Truncated TrkB.T1 induces dendritic filopodia via neurotrophin-independent extracellular or intramembrane interaction with p75NTR; a dominant-negative p75NTR lacking intracellular domain and p75NTR-blocking antibody both inhibit this effect, demonstrating p75NTR is required downstream of TrkB.T1.\",\n      \"method\": \"Hippocampal neuron transfection, dominant-negative p75NTR, antibody blockade, fluorescence microscopy of filopodia\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss-of-function with two independent methods, defined cellular phenotype\",\n      \"pmids\": [\"15507485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"p75NTR forms disulfide-linked dimers through Cys257 in the transmembrane domain independent of neurotrophin binding; Cys257 mutation abolishes neurotrophin-dependent receptor activity but not MAG/NgR/Lingo-1 signaling; FRET shows NGF binding transiently disrupts intracellular domain association via conformational rearrangement, proposing a scissor-like activation mechanism.\",\n      \"method\": \"Mutagenesis, cross-linking, FRET, biochemical signaling assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with FRET structural analysis and functional signaling readouts, strong mechanistic dissection\",\n      \"pmids\": [\"19376068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"p75NTR is required for signal transduction by PIR-B; p75NTR interacts with PIR-B upon ligand (MAG) binding and is required for MAG-induced SHP phosphatase activation; p75NTR mutant mice show promoted axonal regeneration after optic nerve injury.\",\n      \"method\": \"Co-immunoprecipitation, SHP activation assay, p75NTR mutant mouse optic nerve crush model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with in vivo phenotype, biochemical co-IP and signaling assay\",\n      \"pmids\": [\"21881600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p75NTR forms a complex with Rab5 and Rab31 GTPases via helix 4 of the p75NTR death domain in adipocytes; this interaction inhibits insulin-stimulated GLUT4 translocation and glucose uptake; p75NTR KO increases Rab5 activity and Akt-independent glucose disposal.\",\n      \"method\": \"Knockout mice, euglycemic clamp, shRNA knockdown in adipocytes/myoblasts, co-immunoprecipitation, GLUT4 translocation assay, dominant-negative Rab5\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO + shRNA + co-IP with domain mapping + functional rescue with dominant-negative, multiple orthogonal approaches\",\n      \"pmids\": [\"22460790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"p75NTR localizes asymmetrically into a single undifferentiated neurite in response to local neurotrophin exposure and is required for axon specification; p75NTR knockout/knockdown results in failure to initiate axon formation in newborn neurons both in vitro and in developing cortex and adult hippocampus.\",\n      \"method\": \"Live imaging, p75NTR KO and shRNA knockdown, immunofluorescence, in vivo cortical development and adult hippocampal neurogenesis analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and shRNA loss-of-function with defined polarization phenotype in vitro and in vivo, direct localization with functional consequence\",\n      \"pmids\": [\"24685135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of the p75NTR death domain (DD) in complex with RhoGDI (activating the RhoA pathway) and with the CARD domain of RIP2 kinase (activating NF-κB) reveal partially overlapping binding epitopes with >100-fold affinity difference; RIP2 recruitment displaces RhoGDI upon ligand binding; p75NTR DD forms low-affinity symmetric homodimers whose interface overlaps with RIP2-CARD but not RhoGDI binding sites, supporting a model where receptor activation requires DD separation.\",\n      \"method\": \"X-ray crystallography, NMR, biochemical binding assays, mutagenesis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with functional validation, competitive binding with affinity measurements, mechanistic model supported by structural and biochemical data\",\n      \"pmids\": [\"26646181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NMR structure of the p75NTR transmembrane domain reveals disulfide-linked dimers via Cys257; under reducing conditions monomer-dimer equilibrium exists; AXXXG motif on the opposite helix face mediates the functionally inactive C257A dimer but is not on the WT dimer interface; AXXXG mutagenesis reveals its role in regulated intramembrane proteolysis by γ-secretase rather than dimerization.\",\n      \"method\": \"NMR structural determination, biochemical cross-linking, mutagenesis, γ-secretase cleavage assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure combined with mutagenesis and functional proteolysis assay\",\n      \"pmids\": [\"27056327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"TNFR80 (p75/TNFRSF1B) costimulation strongly enhances TNFR60-induced cell death specifically and not other death receptor pathways; this enhancement is mediated by TRAF2, whereby TNFR80 signaling abrogates the antiapoptotic TRAF2-dependent functions initiated by TNFR60.\",\n      \"method\": \"TRAF2 overexpression and dominant-negative mutants in HeLa cells, selective TNFR antibody costimulation, JNK and NF-κB activation assays, cell death assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic constructs with defined pathway dissection, receptor specificity demonstrated\",\n      \"pmids\": [\"9743381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Direct association between p75NTR and TrkA demonstrated in Sf9 cells co-expressing both receptors; both intracellular and extracellular domains of each receptor contribute to the interaction; p75NTR modulates NGF endocytosis, as NGF is internalized in TrkA-expressing cells but not p75-expressing cells, and is regulated by the intracellular domain of p75.\",\n      \"method\": \"Baculovirus co-expression in Sf9 insect cells, co-immunoprecipitation, domain deletion analysis, NGF endocytosis assay\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein interaction in reconstituted system with domain mapping and functional endocytosis readout\",\n      \"pmids\": [\"9379485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"TNF receptor II (TNFRSF1B/p75) signaling is required for Langerhans cell migration from skin to draining lymph nodes; in TNF-RI-deficient mice, anti-TNF-α antibody significantly inhibited Langerhans cell accumulation in lymph nodes, indicating TNFR2-dependent TNF signaling mediates this migration.\",\n      \"method\": \"TNF-RI knockout mice, hapten application, flow cytometry of draining lymph nodes, neutralizing anti-TNF-α antibody\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and antibody blockade with defined cellular migration phenotype, but TNFR2 involvement inferred rather than directly shown\",\n      \"pmids\": [\"8690462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Both TNFR60 and TNFR80 (TNFRSF1B) are involved in signaling endothelial tissue factor expression; selective triggering of either receptor alone can induce tissue factor expression in HUVECs, and simultaneous blockade of both is required for full inhibition; membrane-bound TNF-α engages both receptors with synergistic effect.\",\n      \"method\": \"Agonistic and antagonistic receptor-specific antibodies, coculture with membrane TNF-expressing CHO cells, tissue factor expression assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — selective receptor triggering and blockade with defined functional readout\",\n      \"pmids\": [\"7544644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Both p55 and p75 TNF receptors are constitutively shed in vivo; administration of receptor-specific non-blocking mAb to normal mice causes linear accumulation of soluble receptor by abrogating its clearance, demonstrating constitutive shedding as a mechanism for regulating TNF activity.\",\n      \"method\": \"In vivo mAb administration in mice, ELISA for soluble receptor levels, TNF bioactivity assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-clearance experiment with mechanistic interpretation\",\n      \"pmids\": [\"9103455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p75NTR mediates Aβ-induced tau hyperphosphorylation via CDK5 and GSK3β; genetic knockout of p75NTR in both wild-type and P301L tau transgenic mice significantly reduces Aβ-induced tau phosphorylation, synaptic disorder, and neuronal loss; soluble p75ECD-Fc (blocking Aβ binding to p75NTR) suppresses tau hyperphosphorylation.\",\n      \"method\": \"p75NTR knockout mice, P301L tau transgenic mouse model, kinase inhibitors (CDK5, GSK3β), p75ECD-Fc pharmacological blockade, Western blot for p-tau\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO in two mouse models plus pharmacological blockade with defined mechanistic pathway (CDK5/GSK3β)\",\n      \"pmids\": [\"31394202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p75NTR interacts with BACE1; this interaction is enhanced by Aβ; co-presence of Aβ and p75NTR increases colocalization of BACE1 and APP in early endosomes; JNK-mediated phosphorylation of APP-Thr668 and BACE1-Ser498 in the presence of Aβ and p75NTR drives this endosomal localization.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, endosomal fractionation, phosphorylation assays in cortical neurons\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, co-IP and colocalization with mechanistic follow-up on phosphorylation\",\n      \"pmids\": [\"28869759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"p75NTR-mediated glioma invasion requires PKA-dependent phosphorylation at S303 and an intact C-terminal PDZ-binding motif (SPV); PDLIM1 is a novel signaling adaptor that interacts with p75NTR in a phosphorylation-regulated manner via S425; shRNA knockdown of PDLIM1 completely ablates p75NTR-mediated invasion in vitro and in vivo.\",\n      \"method\": \"Phosphomimetic and deletion mutagenesis, peptide pulldown, co-immunoprecipitation, shRNA in vitro and in vivo invasion assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple mutagenesis strategies, biochemical interaction defined, in vivo validation with shRNA\",\n      \"pmids\": [\"26119933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TrkB associates with p75NTR in hippocampal neurons after BDNF binding and requires TrkB phosphorylation; the complex forms in early endosomes after internalization; p75NTR interaction with TrkB is specifically required for PI3K-Akt but not Erk signaling, and is necessary for BDNF-mediated survival in trophic deprivation.\",\n      \"method\": \"Co-immunoprecipitation, endosomal fractionation, PI3K-Akt and Erk pathway assays, trophic deprivation survival assay in p75NTR null neurons\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP with subcellular fractionation and defined signaling readout, genetic absence of p75NTR with functional consequence\",\n      \"pmids\": [\"31736712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LncRNA NEAT1 stabilizes TNFRSF1B mRNA through direct physical association (RNA pulldown), increasing TNFRSF1B protein levels, which promotes NF-κB p65 nuclear translocation and intestinal inflammation; NEAT1 knockdown reduces TNFRSF1B expression and NF-κB activation, effects reversed by TNFRSF1B overexpression.\",\n      \"method\": \"RNA pulldown, RNA decay assay, siRNA knockdown, western blot, immunofluorescence for NF-κB p65 translocation, ELISA for cytokines\",\n      \"journal\": \"Annals of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNA pulldown for direct interaction, functional rescue experiment, but single lab\",\n      \"pmids\": [\"34268386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NGF signals via p75NTR in Pdgfra+ mesenchymal osteogenic precursors to regulate their migration into bone injury sites; mice lacking Ngf in myeloid cells or lacking p75NTR in Pdgfra+ cells both show reduced migration of osteogenic precursors and delayed bone healing.\",\n      \"method\": \"Conditional knockout mice (myeloid-specific Ngf KO, Pdgfra-specific p75NTR KO), cranial bone injury model, histology, single-cell transcriptomics\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO in vivo with defined migration phenotype and scRNA-seq pathway analysis\",\n      \"pmids\": [\"35302859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-125a-5p directly targets the 3'UTR of TNFRSF1B (confirmed by dual luciferase reporter assay); miR-125a-5p upregulation inhibits TNFRSF1B protein expression and promotes osteoclast differentiation, while miR-125a-5p inhibition has the opposite effect.\",\n      \"method\": \"Dual luciferase reporter assay, miRNA mimic and inhibitor transfection, western blot, qRT-PCR, osteoclast differentiation assay\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'UTR targeting confirmed by reporter assay with functional validation\",\n      \"pmids\": [\"30976285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NGFR100W (hereditary HSAN V mutation) retains ability to bind and activate TrkA but fails to bind or stimulate p75NTR-mediated signaling (RhoA-Cofilin pathway); intraplantar injection shows NGFR100W cannot induce acute hyperalgesia (p75NTR-dependent) but retains chronic hyperalgesia (TrkA-dependent), demonstrating p75NTR mediates the acute nociceptive component of NGF signaling.\",\n      \"method\": \"Biochemical binding assays, signaling pathway assays, in vivo intraplantar injection and pain behavior testing\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — naturally occurring mutation used to dissect receptor-specific signaling, multiple biochemical and in vivo readouts\",\n      \"pmids\": [\"29483280\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TNFRSF1B (p75NTR/TNFR2) is a multifunctional receptor that operates through ligand-specific activation mechanisms: it forms disulfide-linked transmembrane dimers via Cys257 that undergo conformational rearrangement upon neurotrophin binding to expose the death domain for competitive recruitment of downstream effectors (RhoGDI for RhoA/Rho pathway activation, RIP2-CARD for NF-κB activation), associates with co-receptors (TrkA/B/C, NgR, sortilin, PIR-B, Lingo-1) to diversify signaling outcomes ranging from survival to apoptosis and axon growth inhibition, is regulated by PKA phosphorylation at Ser304 that controls lipid raft translocation and γ-secretase-mediated intramembrane proteolysis, and recruits adaptor proteins including TRAF6, NRIF, Shc, and PDLIM1 to activate JNK, NF-κB, ceramide, and cytoskeletal (RhoA/Rho-Cofilin) signaling cascades; as TNFR2 it specifically mediates TNF-α-dependent functions including Langerhans cell migration and enhancement of TNFR1-induced apoptosis via TRAF2 depletion, and is regulated post-transcriptionally by lncRNA NEAT1-mediated mRNA stabilization and by miR-125a-5p targeting.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract discoveries only from KEEP papers about TNFRSF1B (TNF receptor superfamily member 1B, also known as TNFR2/p75TNFR).\n\n**Classification notes:**\n- Papers [1]-[11], [13], [16]-[22] (first corpus) about p75 neurotrophin receptor (NGFR/TNFRSF16) → EXCLUDE (alias collision - different gene)\n- Papers [12], [14], [15], [26], [28], [33], [82], [88], [93] about LEDGF/p75 → EXCLUDE (different gene, PSIP1)\n- Papers [23], [34], [80] about p75/AIRM1 (SIGLEC10), IL-12p75, Lactobacillus proteins → EXCLUDE\n- Papers [25], [37], [41], [47], [48], [52], [54], [57], [58], [62], [69], [72], [76], [86], [94] — need careful review; some describe TNFRSF1B specifically\n- Gene2pubmed curated papers: most are about TNFR2/TNFRSF1B directly → KEEP\n\n**KEEP papers (about TNFRSF1B/TNFR2):**\n- First corpus: [25], [37], [41], [47], [48], [52], [54], [57], [58], [62], [69], [72], [76], [86], [94]\n- Gene2pubmed: [2], [3], [4], [5], [6], [7], [8], [9], [10], [12], [13], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30]\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1990,\n      \"finding\": \"Molecular cloning of TNFRSF1B (TNFR2/p75 TNF receptor): a cDNA encoding a 461-amino acid integral membrane protein was isolated from a human lung fibroblast library by direct expression screening with radiolabeled TNF-alpha. The extracellular domain contains cysteine-rich repeats homologous to the nerve growth factor receptor, defining a receptor superfamily.\",\n      \"method\": \"cDNA expression cloning, radiolabeled ligand binding, sequence analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning with functional validation; foundational paper with >1000 citations\",\n      \"pmids\": [\"2160731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"TNFRSF1B was independently cloned as a 415-amino acid TNF receptor; the extracellular cysteine-rich domain is homologous to the NGF receptor and Bp50. Cells transfected with TNFR expression vector specifically bind both TNF-alpha and TNF-beta with equal affinity.\",\n      \"method\": \"cDNA cloning from serum TNF-binding protein sequences, transfection, radiolabeled ligand binding\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted receptor binding in transfected cells; >1000 citations, replicated independently\",\n      \"pmids\": [\"2158863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Two distinct soluble TNF-binding proteins (corresponding to shed ectodomains of TNFR1 and TNFR2) were purified from human urine; antibodies against each inhibit TNF binding to cells from different cell lines with varying efficacy, establishing that two distinct receptor species exist on cell surfaces.\",\n      \"method\": \"Ligand-affinity purification, NH2-terminal sequencing, antibody blocking of cell-surface TNF binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical purification with functional validation; >500 citations\",\n      \"pmids\": [\"2153136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"TNFRSF1B (TNFrII) can shed a naturally occurring soluble TNF inhibitor through proteolytic cleavage of its ectodomain; expression of the TNFrII cDNA in COS-7 cells produced a receptor that binds TNF-alpha and releases a soluble inhibitory fragment.\",\n      \"method\": \"cDNA expression in COS-7 cells, TNF-binding assay, protein isolation from U-937 cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted shedding in transfected cells; >300 citations\",\n      \"pmids\": [\"2172983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"TRAF1 and TRAF2 were identified as the first signal transducers that associate with the cytoplasmic domain of TNFRSF1B (TNF-R2). A C-terminal 78-amino acid region of the TNF-R2 cytoplasmic domain is required for signal transduction and mediates this interaction. TRAF1 and TRAF2 form homo- and heterotypic dimers, with TRAF2 contacting the receptor directly and TRAF1 associating indirectly through TRAF2.\",\n      \"method\": \"Yeast two-hybrid, biochemical purification, co-immunoprecipitation, mutational analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical purification plus yeast two-hybrid plus mutagenesis; foundational paper >900 citations\",\n      \"pmids\": [\"8069916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"TRAF2-mediated activation of NF-κB is a key signaling output of TNFRSF1B (TNF-R2): overexpression of TRAF2 was sufficient to induce NF-κB activation, and a dominant-negative TRAF2 lacking the N-terminal RING finger domain blocked NF-κB activation by TNF-R2 and CD40.\",\n      \"method\": \"Transient transfection, NF-κB reporter assays, dominant-negative mutant analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via dominant-negative approach with reporter readout; >900 citations, widely replicated\",\n      \"pmids\": [\"7544915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The TNFRSF1B (TNFR2) signaling complex contains c-IAP1 and c-IAP2, two novel mammalian members of the inhibitor of apoptosis (IAP) family. These proteins do not contact TNFR2 directly but associate with TRAF1 and TRAF2 through their N-terminal BIR motif-comprising domain, requiring a TRAF2-TRAF1 heterocomplex for recruitment.\",\n      \"method\": \"Biochemical purification, molecular cloning, co-immunoprecipitation, interaction domain mapping\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical purification of native complex followed by molecular cloning and domain mapping; >1000 citations\",\n      \"pmids\": [\"8548810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Both TNFR60 (TNFR1) and TNFR80 (TNFRSF1B/TNFR2) are involved in signaling endothelial tissue factor expression by juxtacrine (membrane-bound) TNF-alpha. Selective triggering of either receptor with agonistic antibodies induced tissue factor expression, and simultaneous blockade of both was required for full inhibition.\",\n      \"method\": \"Antagonistic and agonistic antibody blocking, HUVECs co-culture with membrane TNF-expressing CHO transfectants, tissue factor assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional antibody studies with defined cellular readout; single study\",\n      \"pmids\": [\"7544644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"TNFRSF1B (TNF-R2/p75) signaling is required for the migration of Langerhans cells from skin to draining lymph nodes. In TNF-R1-deficient mice, anti-TNF-alpha antibody still inhibited Langerhans cell accumulation in lymph nodes following hapten application, implicating TNF-R2 as the mediator of this migratory response.\",\n      \"method\": \"TNF-R1 gene-targeted mice, hapten (FITC) application, flow cytometry, neutralizing antibody studies\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout combined with antibody blocking and defined cellular readout\",\n      \"pmids\": [\"8690462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Distinct domains of TRAF2 mediate different functions in TNFRSF1B signaling: the N-terminal RING finger and two adjacent zinc fingers are required for NF-κB activation; the TRAF-N and TRAF-C subdomains independently mediate self-association and TRAF1 interaction; interaction with TNF-R2 requires C-terminal sequences of TRAF-C; interaction with RIP occurs via N-terminal TRAF-C sequences.\",\n      \"method\": \"Extensive mutational analysis (point mutants and chimeric proteins), NF-κB reporter assays, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis with multiple functional readouts; >270 citations\",\n      \"pmids\": [\"8702708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Constitutive shedding of both p55 (TNFR1) and p75 (TNFRSF1B/TNFR2) murine TNF receptors occurs in vivo; administration of TNF receptor-specific mAbs to normal mice caused linear accumulation of soluble receptor in circulation by blocking clearance of constitutively shed receptor. Accumulated soluble receptor was capable of inhibiting TNF-induced responses in vivo.\",\n      \"method\": \"In vivo mAb administration to normal mice, soluble receptor ELISA, TNF-induced response assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo experiment with mechanistic interpretation of clearance; single study\",\n      \"pmids\": [\"9103455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"TNFRSF1B (TNFR80)-mediated enhancement of TNFR60-induced cell death is TNFR60-selective and is mediated through TRAF2: TNFR80 costimulation abrogates antiapoptotic TRAF2-dependent signaling from TNFR60 by negatively regulating TRAF2 function, thereby potentiating TNF-induced cell death. This was confirmed by showing that TNFR80 prestimulation reduced TNFR60-induced JNK activation.\",\n      \"method\": \"TRAF2 overexpression and dominant-negative mutant transfection in HeLa cells, cell death assays, JNK activation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via gain- and loss-of-function with multiple orthogonal readouts; >110 citations\",\n      \"pmids\": [\"9743381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"TNF-alpha-induced apoptosis of CD8+ T cells is mediated by macrophages through membrane-bound TNF (mbTNF) interacting with TNFRSF1B (TNFRII) on CD8+ T cells. HIV gp120 interaction with CXCR4 upregulates both mbTNF on macrophages and TNFRII on CD8+ T cells, and TNFRII-blocking antibodies prevent this apoptosis.\",\n      \"method\": \"Blocking antibodies against TNFRII, HIV infection of PBMCs, flow cytometry, apoptosis assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — antibody blocking with defined molecular pathway and functional readout\",\n      \"pmids\": [\"9744279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"TNF-R1 (CD120a) is the high-affinity receptor for soluble TNF (Kd = 1.9 × 10⁻¹¹ M at 37°C) while TNFRSF1B/TNF-R2 has significantly lower affinity for soluble TNF (Kd = 4.2 × 10⁻¹⁰ M). The high affinity of TNF-R1 derives from marked stability of ligand-receptor complexes, whereas TNF-R2 forms only transient interactions with soluble TNF, explaining the predominant role of TNF-R1 in responses to soluble TNF.\",\n      \"method\": \"Kinetic binding measurements (association/dissociation rate constants) at 37°C, Scatchard analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — rigorous quantitative binding kinetics at physiological temperature; >360 citations\",\n      \"pmids\": [\"9435233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Crystal structure of the TRAF domain of human TRAF2 reveals a trimeric self-association and, in complex with a TNF-R2 peptide, shows the receptor peptide binding to a conserved shallow surface depression on one TRAF-C domain. An SXXE motif serves as a TRAF2-binding consensus sequence in TNFRSF1B.\",\n      \"method\": \"X-ray crystallography, solution studies confirming trimeric state, peptide-protein co-crystal structure\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of receptor-adaptor complex with solution validation; >300 citations\",\n      \"pmids\": [\"10206649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A pre-ligand-binding assembly domain (PLAD) in the extracellular region of TNFRSF1B (TNFR2/p80) mediates specific ligand-independent assembly of receptor trimers. The PLAD is physically distinct from the ligand-binding domain but is necessary and sufficient for TNFR complex assembly and TNF-alpha binding and signaling.\",\n      \"method\": \"Domain mapping by mutagenesis, FRET, co-immunoprecipitation, functional signaling assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis plus FRET plus co-IP with functional validation; >660 citations\",\n      \"pmids\": [\"10875917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Keratin 8 and keratin 18 bind the cytoplasmic domain of TNFRSF1B (TNFR2/CD120b) and moderate TNF-induced JNK signaling and NF-κB activation. K8/K18-deficient epithelial cells are ~100× more sensitive to TNF-induced death, demonstrating that keratins modulate TNFR2 intracellular signaling.\",\n      \"method\": \"K8/K18 knockout mice, direct binding assays, JNK and NF-κB signaling assays, in vivo concanavalin A hepatotoxicity model\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding plus knockout phenotype plus in vivo validation; >229 citations\",\n      \"pmids\": [\"10747083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TNF-RII (TNFRSF1B) activation induces ubiquitination and proteasomal degradation of TRAF2 through c-IAP1, which acts as an E3 ubiquitin ligase. c-IAP1 bound TRAF2 and ubiquitinated it specifically; E3-defective c-IAP1 prevented TNF-alpha-induced TRAF2 degradation and inhibited apoptosis. This defines a mechanism by which TNFRSF1B potentiates TNF-induced apoptosis by depleting antiapoptotic TRAF2.\",\n      \"method\": \"In vitro ubiquitination assay, E3-defective mutant expression, proteasome inhibitor studies, co-immunoprecipitation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro ubiquitination reconstitution plus mutagenesis plus functional rescue; >389 citations\",\n      \"pmids\": [\"11907583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TNFRSF1B (TNFR-2) signaling potentiates programmed necrosis via TNFR-1 through recruitment of RIP kinase to the TNFR-1 complex. Pre-stimulation through TNFR-2 enhanced TNF-induced cell death and RIP recruitment to TNFR-1. TNFR-2-deficient mice showed reduced liver inflammation and defective viral clearance during vaccinia virus infection, linking TNFRSF1B to antiviral responses.\",\n      \"method\": \"TNFR-2 knockout mice, viral infection model, co-immunoprecipitation of RIP with TNFR-1, death effector domain protein expression studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus molecular mechanism (RIP recruitment) plus in vivo viral model; >372 citations\",\n      \"pmids\": [\"14532286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A physical and functional map of the TNF-alpha/NF-κB signaling pathway identified 221 molecular associations and 80 previously unknown interactors around 32 known pathway components including TNFRSF1B, using tandem affinity purification and mass spectrometry, validated by RNAi functional studies.\",\n      \"method\": \"Tandem affinity purification (TAP), LC-MS/MS, RNAi functional validation, network analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — proteome-scale AP-MS with RNAi functional validation; >841 citations\",\n      \"pmids\": [\"14743216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Progranulin (PGRN) binds directly to TNFRSF1B (TNFR2) and TNFR1, competing with TNF-alpha for receptor binding. Atsttrin, an engineered PGRN fragment, selectively binds TNFRs and inhibits TNF-alpha-activated intracellular signaling. PGRN-deficient mice were susceptible to inflammatory arthritis, and PGRN/Atsttrin treatment reversed disease in multiple arthritis models.\",\n      \"method\": \"Direct binding assays, competitive displacement, PGRN-deficient mice, multiple arthritis mouse models, intracellular signaling assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding demonstrated plus genetic KO plus multiple in vivo models; >620 citations\",\n      \"pmids\": [\"21393509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Recurrent point mutations and genomic gains of TNFRSF1B (encoding TNFR2) occur in 18% of mycosis fungoides and Sézary syndrome patients. The recurrent TNFR2 Thr377Ile mutant expressed in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to proteasome inhibitor bortezomib, establishing TNFRSF1B as an oncogenic driver in cutaneous T cell lymphoma.\",\n      \"method\": \"Whole-genome sequencing, targeted sequencing, functional expression of mutant TNFR2 in T cells, NF-κB signaling assays, bortezomib sensitivity assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genomic discovery plus functional validation of specific mutant with defined signaling mechanism; >224 citations\",\n      \"pmids\": [\"26258847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-125a-5p directly targets TNFRSF1B mRNA: luciferase reporter assay confirmed TNFRSF1B as the target gene of miR-125a-5p. Upregulation of miR-125a-5p inhibited TNFRSF1B protein expression and promoted osteoclast differentiation, while downregulation had opposite effects, establishing TNFRSF1B as a suppressor of osteoclastogenesis regulated by miR-125a-5p.\",\n      \"method\": \"Dual luciferase reporter assay, miRNA mimic/inhibitor transfection, western blot, osteoclast differentiation assay\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — luciferase validation of miRNA target plus functional osteoclast differentiation assay; single lab\",\n      \"pmids\": [\"30976285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LncRNA NEAT1 stabilizes TNFRSF1B mRNA through direct RNA-protein interaction (co-precipitated TNFRSF1B mRNA in RNA pulldown assay) and promotes NF-κB p65 nuclear translocation and intestinal inflammation. Knockdown of NEAT1 reduced TNFRSF1B expression and NF-κB activation; overexpression of TNFRSF1B rescued these effects.\",\n      \"method\": \"RNA pulldown, RNA decay assay, siRNA knockdown, western blot, NF-κB p65 immunofluorescence, ELISA of inflammatory cytokines, DSS colitis mouse model\",\n      \"journal\": \"Annals of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RNA pulldown plus functional rescue in cell lines; single lab, moderate mechanistic depth\",\n      \"pmids\": [\"34268386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Proteome-scale affinity-purification mass spectrometry (BioPlex 3.0) identified interaction partners of TNFRSF1B in 293T and HCT116 cells, contributing to a cell-line-specific interactome network. Cell-specific interactions of TNFRSF1B link core complexes to other subnetworks, revealing rewiring of the receptor's interaction landscape across cell types.\",\n      \"method\": \"Affinity-purification mass spectrometry (AP-MS), reciprocal validation, proteome-scale network analysis across two cell lines\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteome-scale AP-MS with cross-cell-line validation; strong method but TNFRSF1B-specific findings not individually validated\",\n      \"pmids\": [\"33961781\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TNFRSF1B (TNFR2/p75 TNF receptor) is a single-pass transmembrane receptor that forms pre-assembled trimers via its extracellular PLAD domain, binds TNF-alpha with lower affinity than TNFR1, and signals intracellularly by recruiting TRAF1 and TRAF2 (directly via an SXXE-containing cytoplasmic motif) along with c-IAP1/c-IAP2 (via TRAF1/TRAF2), leading to TRAF2-dependent NF-κB and JNK activation; TNFRSF1B potentiates TNFR1-induced apoptosis and programmed necrosis by triggering c-IAP1-mediated ubiquitination and proteasomal degradation of TRAF2, thereby depleting antiapoptotic signals, and also mediates Langerhans cell migration, CD8+ T cell apoptosis via macrophage-expressed membrane TNF, and non-canonical NF-κB signaling when mutated (Thr377Ile) in cutaneous T cell lymphoma.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TNFRSF1B encodes p75NTR, a multifunctional transmembrane receptor of the TNFR superfamily that serves as a signaling hub integrating neurotrophin, myelin-associated inhibitor, and TNF-α signals to determine cell fate outcomes including survival, apoptosis, axon specification, and migration. The receptor forms constitutive disulfide-linked dimers via transmembrane Cys257 and undergoes a scissor-like conformational rearrangement upon neurotrophin binding that separates intracellular death domains, enabling competitive recruitment of effectors—RhoGDI for RhoA pathway activation and RIP2-CARD for NF-κB signaling—as resolved by crystal structures showing partially overlapping binding epitopes on the death domain [PMID:26646181, PMID:19376068]. p75NTR assembles into co-receptor complexes with TrkA/B (modulating PI3K-Akt survival signaling and ceramide generation), NgR/Lingo-1 (transducing MAG-mediated axon growth inhibition via RhoA), and PIR-B (activating SHP phosphatases), and recruits intracellular adaptors TRAF6 and NRIF for JNK activation, with PKA phosphorylation at Ser304 controlling lipid raft translocation and γ-secretase-mediated intramembrane proteolysis [PMID:9915784, PMID:14960584, PMID:12682012, PMID:27056327, PMID:12426574, PMID:21881600]. In the immune system, TNFR2 (p75) signaling enhances TNFR1-induced apoptosis by depleting the anti-apoptotic adaptor TRAF2, mediates Langerhans cell migration, and its expression is post-transcriptionally regulated by lncRNA NEAT1-mediated mRNA stabilization and miR-125a-5p targeting [PMID:9743381, PMID:8690462, PMID:34268386, PMID:30976285].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that p75NTR acts as a co-receptor modulating TrkA responsiveness to NGF resolved the paradox of how a receptor lacking intrinsic kinase activity contributes to neurotrophin signaling, and identified ceramide as an independent p75-initiated second messenger.\",\n      \"evidence\": \"Co-expression studies, pharmacologic and mutagenesis experiments in cell culture\",\n      \"pmids\": [\"7571013\", \"8580709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of TrkA-p75NTR physical interaction unknown\", \"Ceramide pathway downstream effectors uncharacterized\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrating TNFR2-dependent Langerhans cell migration in TNF-RI knockout mice established that TNFRSF1B has non-redundant immune functions distinct from TNFR1, particularly in dendritic cell trafficking.\",\n      \"evidence\": \"TNF-RI knockout mice with hapten application, anti-TNF-α antibody blockade, flow cytometry of draining lymph nodes\",\n      \"pmids\": [\"8690462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TNFR2 involvement inferred indirectly from TNFR1-KO rather than demonstrated with TNFR2-specific ablation\", \"Downstream signaling pathway mediating migration not identified\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showing that both TNF receptors are constitutively shed in vivo and that p75NTR physically associates with TrkA via both extracellular and intracellular domains established receptor ectodomain shedding as a regulatory mechanism and defined the molecular architecture of the p75-Trk co-receptor complex.\",\n      \"evidence\": \"In vivo mAb clearance experiment for shedding; baculovirus co-expression in Sf9 cells with co-IP and domain deletion for TrkA interaction\",\n      \"pmids\": [\"9103455\", \"9379485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protease(s) mediating constitutive shedding not identified\", \"Whether Sf9-derived interactions reflect native neuronal complexes\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Two key signaling principles were established: TrkA suppresses p75-mediated JNK-dependent apoptosis while preserving p75-mediated NF-κB activation (explaining cell-context-dependent survival/death decisions), and TNFR2 enhances TNFR1-induced apoptosis through TRAF2 depletion (establishing TNFR2 as a pro-apoptotic amplifier).\",\n      \"evidence\": \"TrkA transfection into oligodendrocytes with kinase and reporter assays; TRAF2 overexpression/dominant-negative in HeLa cells with selective TNFR costimulation\",\n      \"pmids\": [\"9547236\", \"9743381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TrkA selectively inhibits JNK but not NF-κB branch mechanistically unclear\", \"Whether TRAF2 depletion model operates in primary immune cells\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identification of TRAF6 as a direct ligand-dependent interactor of p75NTR's juxtamembrane region required for NF-κB activation, and caveolin as a modulator that suppresses TrkA while enhancing p75NTR sphingomyelin hydrolysis, defined the first molecular adaptors mediating distinct p75NTR signaling branches.\",\n      \"evidence\": \"Reciprocal co-IP with dominant-negative TRAF6 in Schwann cells; GST-pulldown and in vitro kinase assay with caveolin in PC12 cells\",\n      \"pmids\": [\"9915784\", \"9867838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRAF6 discriminates between NF-κB and JNK branches at p75NTR\", \"Whether caveolin interaction is direct or scaffolded\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defining p75NTR-induced apoptosis as proceeding through the mitochondrial pathway (caspases 9→6→3) independently of FADD/TRADD/caspase-8 distinguished the p75NTR death mechanism from classical TNFR family death-domain signaling.\",\n      \"evidence\": \"Inducible p75NTR expression in conditionally immortalized striatal neurons with dominant-negative caspases and Bcl-XL overexpression\",\n      \"pmids\": [\"11451944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the BH3-only protein linking p75NTR to mitochondrial permeabilization unknown\", \"How death domain recruits the mitochondrial arm without FADD\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"A major functional expansion was achieved by showing p75NTR serves as a co-receptor for the NgR/MAG inhibitory signaling complex, transducing myelin inhibitor signals to RhoA activation and neurite outgrowth inhibition, and that proNGF (not mature NGF) is the physiological ligand driving p75NTR-mediated oligodendrocyte apoptosis after spinal cord injury.\",\n      \"evidence\": \"Co-IP of NgR and p75NTR, Ca²⁺ imaging, Xenopus turning assay; p75NTR mutant mouse neurons insensitive to MAG; p75NTR KO mice with reduced post-SCI oligodendrocyte death and proNGF antibody blockade\",\n      \"pmids\": [\"12426574\", \"12011108\", \"12408842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of p75NTR-NgR interaction unknown\", \"How p75NTR selectively activates RhoA in MAG vs. neurotrophin contexts\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery that PKA phosphorylates p75NTR at Ser304 and that this modification controls lipid raft translocation and downstream Rho inactivation established post-translational regulation as a gating mechanism for p75NTR signaling compartmentalization.\",\n      \"evidence\": \"Yeast two-hybrid for PKACβ interaction, in vitro phosphorylation, lipid raft fractionation, Rho activity and neurite outgrowth assays\",\n      \"pmids\": [\"12682012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase that reverses Ser304 phosphorylation not identified\", \"Whether raft translocation is required for all p75NTR signaling outputs\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The NRIF-TRAF6 interaction was shown to be required for p75NTR-mediated JNK activation, with TRAF6 stabilizing NRIF and promoting its nuclear translocation, establishing a cooperative adaptor mechanism for the pro-apoptotic JNK branch distinct from the NF-κB branch.\",\n      \"evidence\": \"Co-IP with domain deletion, JNK and NF-κB reporter assays, nuclear translocation assay in HEK293 cells\",\n      \"pmids\": [\"14960584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear targets of NRIF not identified\", \"Whether NRIF-TRAF6 complex assembles on endosomal or plasma membrane p75NTR\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Structural and biophysical demonstration that p75NTR forms constitutive Cys257-linked transmembrane dimers that undergo scissor-like conformational rearrangement upon neurotrophin binding—separating intracellular domains—provided the first activation mechanism for a death-domain receptor that does not involve ligand-induced dimerization.\",\n      \"evidence\": \"Mutagenesis of Cys257, cross-linking, FRET measurements of intracellular domain proximity, signaling assays distinguishing neurotrophin vs. MAG/NgR pathways\",\n      \"pmids\": [\"19376068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length receptor structure not available\", \"How conformational change is transmitted across the membrane\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Crystal structures of the p75NTR death domain in complex with RhoGDI and RIP2-CARD revealed partially overlapping binding sites with >100-fold affinity difference, establishing that competitive displacement of RhoGDI by RIP2 upon ligand binding switches signaling from RhoA to NF-κB, providing the structural basis for p75NTR's binary signaling switch.\",\n      \"evidence\": \"X-ray crystallography, NMR, quantitative binding assays, mutagenesis\",\n      \"pmids\": [\"26646181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How neurotrophin binding allosterically changes death domain accessibility to favor RIP2\", \"Whether additional effectors compete for the same surface in vivo\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of PDLIM1 as a phosphorylation-dependent adaptor binding p75NTR's PDZ-binding motif, required for glioma cell invasion, revealed a PKA-regulated signaling axis through which p75NTR drives pathological cell migration.\",\n      \"evidence\": \"Phosphomimetic mutagenesis, peptide pulldown, co-IP, shRNA knockdown in vitro and in vivo invasion models\",\n      \"pmids\": [\"26119933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream cytoskeletal effectors of PDLIM1 in invasion not mapped\", \"Whether PDLIM1 interaction occurs in non-pathological contexts\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"NMR structure of the p75NTR transmembrane domain confirmed Cys257-mediated disulfide dimer and revealed that the AXXXG motif on the opposite helix face regulates γ-secretase-mediated intramembrane proteolysis rather than dimerization, separating dimerization from regulated proteolysis at atomic resolution.\",\n      \"evidence\": \"NMR structural determination, mutagenesis, γ-secretase cleavage assays\",\n      \"pmids\": [\"27056327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How γ-secretase cleavage is triggered by ectodomain shedding\", \"Fate and function of the released intracellular domain fragment\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The naturally occurring NGFR100W mutation (HSAN V) that abolishes p75NTR binding while retaining TrkA activation dissected receptor-specific contributions to nociception, establishing p75NTR as the mediator of acute NGF-induced hyperalgesia via the RhoA-Cofilin pathway.\",\n      \"evidence\": \"Biochemical binding assays, RhoA-Cofilin signaling, intraplantar injection with pain behavior testing\",\n      \"pmids\": [\"29483280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RhoA-Cofilin is sufficient or whether additional p75NTR effectors contribute to acute nociception\", \"Cell type(s) in which p75NTR mediates acute hyperalgesia not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"p75NTR was shown to mediate Aβ-induced tau hyperphosphorylation through CDK5 and GSK3β in two mouse models, positioning p75NTR as a receptor linking amyloid pathology to tauopathy.\",\n      \"evidence\": \"p75NTR knockout in WT and P301L tau transgenic mice, kinase inhibitors, p75ECD-Fc pharmacological blockade\",\n      \"pmids\": [\"31394202\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding site for Aβ on p75NTR not structurally defined\", \"How p75NTR activates CDK5 mechanistically\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Cell-type-specific conditional knockout demonstrated p75NTR functions in Pdgfrα+ mesenchymal osteogenic precursors to mediate NGF-dependent migration into bone injury sites, extending p75NTR's role beyond the nervous system to skeletal repair.\",\n      \"evidence\": \"Myeloid-specific Ngf KO and Pdgfrα-specific p75NTR KO in cranial bone injury model, single-cell transcriptomics\",\n      \"pmids\": [\"35302859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathway (RhoA vs. NF-κB vs. other) mediating osteogenic precursor migration not determined\", \"Whether this mechanism operates in long bone repair\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A full-length structure of p75NTR showing how ectodomain ligand binding transmits conformational change through the transmembrane dimer to the death domain, and how the competitive effector switch (RhoGDI vs. RIP2) is allosterically regulated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length receptor structure spanning ectodomain to death domain\", \"Quantitative model of effector competition kinetics in intact cells lacking\", \"Systematic identification of context-dependent co-receptor complexes not achieved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5, 6, 14, 32]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 15, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 16, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 14, 19]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [26, 28]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 6, 9, 18, 20, 25, 32]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 4, 7, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [17, 30]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [22, 23]}\n    ],\n    \"complexes\": [\n      \"p75NTR-TrkA co-receptor complex\",\n      \"p75NTR-NgR-Lingo-1 MAG receptor complex\",\n      \"p75NTR-PIR-B signaling complex\"\n    ],\n    \"partners\": [\n      \"NTRK1\",\n      \"NGFR\",\n      \"TRAF6\",\n      \"TRAF2\",\n      \"NRIF\",\n      \"PDLIM1\",\n      \"RHOGDI\",\n      \"RIPK2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"TNFRSF1B (TNFR2/p75) is a TNF receptor superfamily member that transduces TNF-α signals to regulate NF-κB activation, JNK signaling, cell survival, and programmed cell death in immune and epithelial cells. The receptor forms pre-ligand trimers via an extracellular PLAD domain, binds TNF-α with lower affinity than TNFR1 (Kd ~4.2 × 10⁻¹⁰ M), and signals by recruiting TRAF2 directly through a cytoplasmic SXXE motif, with TRAF1 and c-IAP1/c-IAP2 assembling indirectly via TRAF2 [PMID:8069916, PMID:8548810, PMID:10206649, PMID:10875917, PMID:9435233]. TNFRSF1B potentiates TNFR1-mediated apoptosis and programmed necrosis by triggering c-IAP1-dependent ubiquitination and proteasomal degradation of TRAF2, thereby depleting antiapoptotic signaling capacity [PMID:11907583, PMID:14532286, PMID:9743381]. Recurrent gain-of-function mutations in TNFRSF1B, notably Thr377Ile, drive non-canonical NF-κB activation and are found in ~18% of cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome) cases [PMID:26258847].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Molecular cloning of TNFRSF1B established it as a second, distinct TNF receptor with cysteine-rich extracellular repeats that binds both TNF-α and TNF-β, resolving the question of whether multiple TNF receptor species exist.\",\n      \"evidence\": \"cDNA expression cloning from human fibroblast and serum-derived sequences, radiolabeled ligand binding in transfected cells, and biochemical purification of soluble ectodomains from urine\",\n      \"pmids\": [\"2160731\", \"2158863\", \"2153136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No intracellular signaling mechanism identified\",\n        \"Relative contributions of TNFR1 vs TNFR2 to TNF responses unknown\",\n        \"Ectodomain shedding mechanism and regulation uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Demonstration that TNFRSF1B sheds a soluble ectodomain capable of inhibiting TNF revealed a built-in negative regulatory mechanism for the TNF pathway.\",\n      \"evidence\": \"cDNA expression in COS-7 cells with soluble receptor fragment isolation and TNF-binding assay\",\n      \"pmids\": [\"2172983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of the sheddase protease unknown\",\n        \"Physiological significance of constitutive shedding not established\"\n      ]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Identification of TRAF1 and TRAF2 as the first signal transducers recruited to the TNFRSF1B cytoplasmic domain answered how a death-domain-lacking receptor signals, establishing that a C-terminal 78-residue region mediates adaptor recruitment.\",\n      \"evidence\": \"Yeast two-hybrid, biochemical purification, co-immunoprecipitation, and deletion mutagenesis\",\n      \"pmids\": [\"8069916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream effectors of TRAF2 at TNFR2 unknown\",\n        \"Structural basis of the TRAF2–receptor interaction unresolved\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"TRAF2 was established as the direct mediator of NF-κB activation downstream of TNFRSF1B, and c-IAP1/c-IAP2 were identified as TRAF1/TRAF2-dependent components of the receptor signaling complex, defining the core adaptor architecture.\",\n      \"evidence\": \"Dominant-negative TRAF2 blocking NF-κB reporter activation; biochemical purification and domain mapping of c-IAP1/c-IAP2 interaction with TRAF1/TRAF2\",\n      \"pmids\": [\"7544915\", \"8548810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Enzymatic activity of c-IAPs in TNFR2 signaling not known\",\n        \"Mechanism of JNK activation via TRAF2 at TNFR2 not dissected\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"The discovery that TNFRSF1B co-stimulation depletes TRAF2 and thereby potentiates TNFR1-induced apoptosis resolved the paradox of how a receptor lacking a death domain enhances cell death, and quantitative binding kinetics explained why TNFR2 preferentially responds to membrane-bound rather than soluble TNF.\",\n      \"evidence\": \"Dominant-negative and overexpression studies with JNK and cell death readouts; kinetic binding measurements at 37°C showing transient TNFR2–TNF complexes (Kd ~4.2 × 10⁻¹⁰ M)\",\n      \"pmids\": [\"9743381\", \"9435233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism of TRAF2 depletion (ubiquitination) not yet identified\",\n        \"Role of membrane-TNF versus soluble-TNF in vivo not fully delineated\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"The crystal structure of the TRAF2 TRAF domain in complex with a TNFR2 peptide revealed the SXXE motif as the TRAF2-binding consensus and showed receptor binding to a shallow surface depression on a trimeric TRAF scaffold, providing the first atomic-level view of TNFRSF1B signal transduction.\",\n      \"evidence\": \"X-ray crystallography of TRAF2 TRAF-domain/TNFR2-peptide co-crystal\",\n      \"pmids\": [\"10206649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full-length receptor–TRAF2 complex structure lacking\",\n        \"Structural basis for selectivity among different TRAF-recruiting receptors not resolved\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of the pre-ligand assembly domain (PLAD) showed that TNFRSF1B forms trimers before ligand binding, revealing that receptor pre-assembly is a prerequisite for TNF-α binding and signaling.\",\n      \"evidence\": \"Domain mutagenesis, FRET, co-immunoprecipitation, and functional signaling assays\",\n      \"pmids\": [\"10875917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure of PLAD-mediated trimer interface not determined\",\n        \"How ligand binding transitions pre-assembled trimers to active signaling complexes unknown\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The mechanism by which TNFRSF1B potentiates apoptosis was resolved: c-IAP1 functions as an E3 ubiquitin ligase that ubiquitinates TRAF2 for proteasomal degradation upon TNFR2 activation, depleting antiapoptotic signals.\",\n      \"evidence\": \"In vitro ubiquitination reconstitution, E3-defective c-IAP1 mutant blocking TRAF2 degradation, proteasome inhibitor rescue\",\n      \"pmids\": [\"11907583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Ubiquitin chain type on TRAF2 not characterized\",\n        \"Whether c-IAP2 has redundant E3 activity in this context not tested\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"TNFRSF1B was shown to potentiate TNFR1-dependent programmed necrosis by enhancing RIP kinase recruitment to TNFR1, and TNFR2-deficient mice showed defective antiviral inflammatory responses, linking receptor crosstalk to innate immunity.\",\n      \"evidence\": \"TNFR2 knockout mice with vaccinia infection, co-immunoprecipitation of RIP with TNFR1 after TNFR2 pre-stimulation\",\n      \"pmids\": [\"14532286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TNFR2 directly modulates RIP phosphorylation status unknown\",\n        \"Necroptotic pathway components downstream of RIP in this context not mapped\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Progranulin was identified as an alternative endogenous ligand that competes with TNF-α for binding to TNFRSF1B, expanding the receptor's ligand repertoire and establishing a new anti-inflammatory axis.\",\n      \"evidence\": \"Direct binding assays, competitive displacement of TNF-α, progranulin-deficient mice with inflammatory arthritis, therapeutic rescue with engineered Atsttrin fragment\",\n      \"pmids\": [\"21393509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Binding site overlap between progranulin and TNF-α on TNFR2 not structurally resolved\",\n        \"Whether progranulin activates or only blocks TNFR2 signaling remains debated\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Recurrent somatic TNFRSF1B mutations, especially Thr377Ile, were identified as oncogenic drivers in cutaneous T-cell lymphoma, demonstrating that gain-of-function TNFR2 signaling activates non-canonical NF-κB and is targetable with proteasome inhibition.\",\n      \"evidence\": \"Whole-genome sequencing of mycosis fungoides/Sézary syndrome, functional expression of Thr377Ile mutant in T cells, NF-κB signaling and bortezomib sensitivity assays\",\n      \"pmids\": [\"26258847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural mechanism by which Thr377Ile activates non-canonical NF-κB not determined\",\n        \"Whether wild-type TNFR2 also engages non-canonical NF-κB under physiological conditions unclear\",\n        \"Clinical efficacy of proteasome inhibitors in TNFRSF1B-mutant lymphoma not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full-length structure of the TNFR2 signaling complex, the precise mechanism of PLAD-mediated pre-assembly transition to active signaling, whether TNFR2-selective agonism versus antagonism can be therapeutically harnessed, and the contribution of non-canonical NF-κB signaling through wild-type TNFR2 in normal immune homeostasis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No full-length TNFR2 signaling complex structure available\",\n        \"Therapeutic TNFR2-selective agents not clinically validated\",\n        \"Physiological role of non-canonical NF-κB through wild-type TNFR2 not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 5, 13, 15]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 6, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3, 15]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 3, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 6, 9, 14, 15, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 12, 18, 20]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11, 17, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"complexes\": [\n      \"TNFR2–TRAF1–TRAF2–cIAP1/2 signaling complex\"\n    ],\n    \"partners\": [\n      \"TRAF2\",\n      \"TRAF1\",\n      \"BIRC2\",\n      \"BIRC3\",\n      \"GRN\",\n      \"KRT8\",\n      \"KRT18\",\n      \"RIPK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}