{"gene":"UNC5B","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2004,"finding":"UNC5B functions as a repulsive netrin receptor in endothelial tip cells; disruption of Unc5b in mice or zebrafish leads to aberrant filopodial extension and excessive vessel branching; netrin-1 causes endothelial filopodial retraction only when UNC5B is present, establishing UNC5B as a repulsive guidance receptor controlling vascular morphogenesis.","method":"Genetic knockout in mice, morpholino knockdown in zebrafish, endothelial cell assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function in two vertebrate species with defined cellular phenotype, replicated across labs","pmids":["15510105"],"is_preprint":false},{"year":2003,"finding":"UNC5B (p53RDL1) is a direct transcriptional target of p53 that mediates p53-dependent apoptosis through its cytoplasmic death domain; when the ligand netrin-1 binds to p53RDL1/UNC5B, p53-dependent apoptosis is blocked, identifying a netrin-p53RDL1 pathway that balances cell survival and death.","method":"Gene cloning, reporter assays, overexpression/knockdown in cell lines, apoptosis assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter, OE, KD, apoptosis readout), replicated in follow-up studies","pmids":["12598906"],"is_preprint":false},{"year":2005,"finding":"UNC5B (UNC5H2) physically interacts with the serine/threonine kinase DAP-kinase (DAPK) through their respective death domains both in cell culture and embryonic mouse brain. In the absence of netrin-1, UNC5B reduces DAP-kinase autophosphorylation on Ser308 and increases DAPK catalytic activity to promote apoptosis; netrin-1 blocks this UNC5B-dependent DAPK activation.","method":"Co-immunoprecipitation, dominant-negative mutants, DAPK-mutant MEFs, kinase activity assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in multiple systems, functional rescue with dominant-negatives, replicated concept in follow-up work","pmids":["15729359"],"is_preprint":false},{"year":2007,"finding":"UNC5B full-length receptor triggers endothelial cell repulsion and inhibits sprouting angiogenesis in response to netrin-1; a truncated UNC5B lacking the intracellular signaling domain fails to induce repulsion, establishing that the intracellular domain is required for repulsive signaling. Genetic loss of unc5b reduces netrin-1-mediated angiogenesis inhibition.","method":"Full-length vs. truncation constructs, loss-of-function genetic model, in vitro repulsion assay, Matrigel/tumor angiogenesis models","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-deletion mutagenesis combined with genetic loss-of-function and cellular phenotype readout","pmids":["17908930"],"is_preprint":false},{"year":2008,"finding":"Netrin-1 induces interaction of UNC5B with the brain-specific GTPase PIKE-L, triggering PI3K signaling that prevents UNC5B's pro-apoptotic activity and enhances neuronal survival. This interaction requires Fyn kinase-mediated tyrosine phosphorylation of PIKE-L and is absent in Fyn-null mice.","method":"Co-immunoprecipitation, PI3K activity assay, Fyn-null mice, overexpression/knockdown","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic validation in Fyn KO mice, PI3K activity assay, multiple orthogonal methods","pmids":["18469807"],"is_preprint":false},{"year":2009,"finding":"Crystal structure of the cytoplasmic portion of UNC5B reveals three domains (ZU5, UPA, death domain) forming a structural supramodule in which ZU5 binds both UPA and DD, locking the complex in a closed/autoinhibited conformation that suppresses apoptotic and vascular patterning activity; release of this closed conformation activates the receptor.","method":"X-ray crystallography of cytoplasmic domain, functional validation of open vs. closed conformations","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, defines autoinhibition mechanism","pmids":["19328064"],"is_preprint":false},{"year":2009,"finding":"UNC5B interacts with neogenin as a co-receptor for the repulsive guidance molecule RGMa; the guanine nucleotide exchange factor LARG associates with UNC5B to transduce RhoA activation; FAK is involved in RGMa-induced tyrosine phosphorylation of LARG and RhoA activation, mediating growth cone collapse.","method":"Co-immunoprecipitation, dominant-negative assays, kinase activity assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional assays in single lab, two orthogonal methods","pmids":["19273616"],"is_preprint":false},{"year":2009,"finding":"UNC5B and FLRT3 interact as high-affinity binding partners; UNC5B and FLRT3 synergize to induce cell deadhesion in Xenopus embryos; the small GTPase Rnd1, which mediates FLRT3 deadhesion activity, physically and functionally interacts with UNC5B to modulate cell adhesion.","method":"Expression screen, overexpression, morpholino knockdown, Co-immunoprecipitation in Xenopus","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and genetic knockdown with phenotypic readout, single system","pmids":["19492039"],"is_preprint":false},{"year":2010,"finding":"UNC5B (UNC5H2/B) recruits a complex containing the PP2A structural subunit PR65β and DAPK; PP2A dephosphorylates and thereby activates DAPK to promote apoptosis. Netrin-1 binding recruits the PP2A inhibitor CIP2A to UNC5B, blocking this mechanism and preventing cell death.","method":"siRNA screen, Co-immunoprecipitation, PP2A activity assays, dominant-negative approaches","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — siRNA screen followed by biochemical reconstitution of PP2A-DAPK-UNC5B complex, phosphatase activity assays, replicated concept","pmids":["21172653"],"is_preprint":false},{"year":2011,"finding":"Robo4 specifically binds to UNC5B via a protein-protein interaction between their extracellular domains; Robo4-UNC5B signaling maintains vascular integrity by inhibiting VEGF downstream signaling; function-blocking antibodies against either Robo4 or UNC5B increase angiogenesis and disrupt vessel integrity; soluble Robo4 rescues barrier defects in Robo4−/− mice via UNC5B.","method":"Protein-protein interaction screen, Co-immunoprecipitation, function-blocking antibodies, Robo4 KO mouse rescue experiments","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased interaction screen confirmed by Co-IP, genetic and antibody-based functional validation, rescue experiment","pmids":["21238923"],"is_preprint":false},{"year":2008,"finding":"Netrin-4 does not bind directly to UNC5B or UNC5C but binds neogenin; Netrin-4 increases association between UNC5B and neogenin (demonstrated by Co-IP); silencing either neogenin or UNC5B abolishes Netrin-4's inhibitory effect on endothelial cell migration, indicating both receptors are required for Netrin-4 anti-angiogenic function.","method":"Binding assays, Co-immunoprecipitation, siRNA knockdown, endothelial migration assays, in vivo angiogenesis models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing netrin-4-induced UNC5B-neogenin complex, siRNA functional validation, single lab","pmids":["18719102"],"is_preprint":false},{"year":2002,"finding":"The cytoplasmic domain of UNC5B (UNC5H2) binds activated GTP-bound Gαi2; this interaction sequesters Gαi2 from inhibiting adenylyl cyclase, thereby increasing intracellular cAMP levels, identifying UNC5B as a novel inhibitor of Gαi2 signaling.","method":"Binding assays with constitutively-activated Gαi2 (gip2), adenylyl cyclase activity assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single binding assay with activity readout, no in vivo validation","pmids":["12359238"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of the UNC5H2 (UNC5B) death domain at 2.1 Å resolution reveals a six-helix bundle fold; the death domain forms a homodimer in crystal and in solution through hydrophobic contacts, which may block caspase access to its cleavage site when netrin-1 is bound.","method":"X-ray crystallography, solution biophysics","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure with clear mechanistic implication but limited functional experimental validation in this paper","pmids":["17139086"],"is_preprint":false},{"year":2011,"finding":"UNC5B (Unc5H2) acts as a repulsive receptor in Schwann cells that functions as an intrinsic brake on peripheral nerve regeneration; local siRNA knockdown of Unc5H2 at the injury site facilitates axon regrowth, and forced DCC inhibition causes reciprocal upregulation of Unc5H2.","method":"In vivo siRNA knockdown at nerve injury site, axon regeneration functional assay","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo siRNA with defined phenotype, reciprocal regulation observed, single lab","pmids":["21656855"],"is_preprint":false},{"year":2009,"finding":"Netrin-1 increases renal proximal tubular epithelial cell proliferation and migration through the UNC5B receptor; siRNA inhibition of UNC5B (but not UNC5C) completely blocks netrin-1-induced proliferation and migration; downstream signaling involves phosphorylation of Akt and ERK, with PI3K and MEK1/2 inhibition blocking proliferation but not migration.","method":"siRNA knockdown, proliferation assays, PI3K/MEK inhibitors, Western blot phosphorylation assays","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-selective siRNA, pharmacological pathway dissection, single lab","pmids":["19211685"],"is_preprint":false},{"year":2022,"finding":"Endothelial UNC5B controls blood-brain barrier integrity by maintaining Wnt/β-catenin signaling; inducible endothelial-specific UNC5B deletion reduces Claudin-5 and increases PLVAP, causing BBB leak. Mechanistically, netrin-1 enhances UNC5B interaction with the Wnt co-receptor LRP6, induces LRP6 phosphorylation, and activates Wnt/β-catenin signaling; β-catenin overexpression rescues UNC5B mutant BBB defects.","method":"Inducible endothelial-specific knockout, Co-immunoprecipitation (UNC5B-LRP6), Western blot for LRP6 phosphorylation, β-catenin rescue, function-blocking antibodies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, molecular mechanism (LRP6 phosphorylation), Co-IP, genetic rescue, multiple orthogonal methods","pmids":["35246514"],"is_preprint":false},{"year":2020,"finding":"Netrin-1 reduction in Parkinson's disease activates MST1, which binds and phosphorylates UNC5B at T428, promoting its apoptotic activation and dopaminergic neuronal loss; knockout of UNC5B abolishes netrin depletion-induced dopaminergic loss; blockade of MST1 phosphorylation of UNC5B suppresses neuronal apoptosis.","method":"Co-immunoprecipitation, phosphorylation site mapping (T428), UNC5B knockout, MST1 blockade","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphorylation site identified, genetic KO with defined phenotype, interaction confirmed by Co-IP, multiple orthogonal methods","pmids":["32929029"],"is_preprint":false},{"year":2011,"finding":"Akt phosphorylates PIKE-A on Ser-472, enhancing PIKE-A interaction with UNC5B and inhibiting UNC5B-provoked apoptosis in a p53-dependent manner; overexpression of PIKE-A diminishes UNC5B expression through downregulation of p53; PIKE-A directly interacts with UNC5B regulated by netrin-1-activated Akt.","method":"Co-immunoprecipitation, phosphorylation-site mutagenesis, PIKE knockout MEFs, apoptosis assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-site mutagenesis, Co-IP, genetic KO cells, single lab","pmids":["21460185"],"is_preprint":false},{"year":2016,"finding":"Netrin-4 acts through its receptor neogenin and recruits UNC5B; activation of UNC5B by Netrin-4/neogenin signaling leads to RhoA activation via SHP2 phosphatase in dorsal horn neurons; transient suppression of Netrin-4 or Unc5B after injury prevents allodynia, and intrathecal Netrin-4 protein enhances excitatory synaptic transmission and induces allodynia in naive rats.","method":"Netrin-4 mutant rats, in vivo siRNA, intrathecal protein administration, electrophysiology","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mutant rats, in vivo siRNA, electrophysiology, single lab","pmids":["27856613"],"is_preprint":false},{"year":2017,"finding":"FLRT2 binds to UNC5B via its extracellular domain and activates Akt/mTOR signaling to drive monocyte-to-macrophage differentiation; endothelial repulsion in the placental labyrinth is mediated through FLRT2 binding to UNC5B; endothelial-specific FLRT2 deletion causes embryonic lethality with aberrant endothelial alignment in the placenta.","method":"Endothelial-specific knockout, binding assays, Co-immunoprecipitation, mTOR agonist rescue","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with phenotype, binding assay, single lab","pmids":["28576770"],"is_preprint":false},{"year":2023,"finding":"FLRT2 directly interacts with UNC5B via its extracellular domain and activates Akt/mTOR signaling to promote monocyte-to-macrophage differentiation; myeloid-specific Flrt2 deletion impairs macrophage generation; in vivo administration of mTOR agonist reverses impaired phenotypes in Flrt2 mutant mice.","method":"Myeloid-specific conditional knockout, Co-immunoprecipitation, mTOR agonist rescue in vivo","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, Co-IP, genetic rescue, single lab","pmids":["37090697"],"is_preprint":false},{"year":2021,"finding":"An endothelial cell-specific UNC5B splicing isoform (UNC5B-Δ8), generated through exon-8 skipping by the alternative splicing factor NOVA2, is constitutively pro-apoptotic and insensitive to netrin-1; this isoform is required for specific blood vessel development in an apoptosis-dependent manner.","method":"Isoform cloning, NOVA2 knockdown/overexpression, apoptosis assays, zebrafish and mouse vascular development models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — splice isoform characterized, splicing factor identified, functional validation in multiple models","pmids":["34381052"],"is_preprint":false},{"year":2016,"finding":"Netrin-1 regulates UNC5B distribution at the plasma membrane: UNC5B expressed alone is recruited by netrin-1 to the plasma membrane; coexpressed DCC and UNC5B undergo netrin-1-induced colocalization and heterooligomerization via vesicular recruitment to the plasma membrane; this plasma membrane recruitment requires netrin-1-activated Src family kinase signaling.","method":"TIRF microscopy, temporal image cross-correlation spectroscopy (TICCS), fluorescently-tagged receptors in HEK293T cells, pharmacological Src inhibition","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative live-cell imaging with receptor interaction measurements, pharmacological validation, single lab","pmids":["26840727"],"is_preprint":false},{"year":2024,"finding":"Notch signaling in endothelial cells rapidly upregulates UNC5B expression; loss or gain of UNC5B recapitulates Notch-regulated phenotypes including inhibition of endothelial migration and proliferation; UNC5B is required for stabilization of endothelial junctions in response to shear stress; endothelial-specific loss of UNC5B leads to excessive vascularization and increased branchpoints in developing mouse retina.","method":"Translated mRNA screen, endothelial-specific UNC5B loss/gain-of-function, shear stress experiments, neonatal mouse retinal vascular analysis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased screen, genetic gain- and loss-of-function, in vivo retinal phenotype, multiple cellular readouts","pmids":["38866944"],"is_preprint":false},{"year":2020,"finding":"UNC5B mediates G2/M phase cell cycle arrest in bladder cancer cells by forming a complex with CDC14A phosphatase and P53; this complex dephosphorylates P53 at Ser-315, reducing cyclin B1 expression and increasing p-CDK1, thereby inhibiting tumor proliferation; CDC14A knockdown suppresses UNC5B-induced G2/M arrest.","method":"Mass spectrometry, Co-immunoprecipitation, site-specific phosphorylation analysis, CDC14A knockdown, xenograft tumor model","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified complex, Co-IP, phospho-site analysis, genetic knockdown validation in vitro and in vivo, single lab","pmids":["32372016"],"is_preprint":false},{"year":2020,"finding":"Netrin-1 promotes naive pluripotency in mESCs through a balance of Neo1 and Unc5B receptors that co-regulate Wnt and MAPK pathways; Netrin-1 induces FAK kinase to inactivate Gsk3α/β and stabilize β-catenin while increasing activity of a Ppp2r2c-containing PP2A complex to reduce Erk1/2 activity.","method":"Chemical inhibitor substitution assays, Western blot, phosphorylation analysis, PP2A activity assay, receptor knockdown in mESCs","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection with multiple pathway readouts, genetic receptor manipulation, PP2A activity assay, FAK-GSK3 phosphorylation","pmids":["32231305"],"is_preprint":false},{"year":2022,"finding":"UNC5B overexpression in Schwann cells facilitates autophagic flux via phosphorylation of AMPK and ULK1 in a netrin-1-dependent manner; UNC5B helps recruit netrin-1 to the cell membrane; overexpression of UNC5B alleviates neuropathic pain and rescues myelin degeneration in a rat CCI model, and autophagy inhibitor reverses the analgesic effect.","method":"AAV-mediated UNC5B overexpression, autophagy flux assays, AMPK/ULK1 phosphorylation Western blot, autophagy inhibitor, CCI rat model","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo OE with defined behavioral phenotype, pathway phosphorylation assays, pharmacological inhibitor confirmation, single lab","pmids":["35668343"],"is_preprint":false},{"year":2023,"finding":"Netrin-1 and UNC5B form heterocomplexes; biophysical analysis shows NET-1 exists in a monomer-dimer equilibrium (pH-sensitive antiparallel dimer) and UNC5B forms equimolar heterocomplexes with both monomeric and dimeric NET-1.","method":"Multi-wavelength analytical ultracentrifugation (AUC), sedimentation velocity experiments","journal":"European biophysics journal : EBJ","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous biophysical characterization of complex stoichiometry, single lab, no functional validation in same study","pmids":["36939874"],"is_preprint":false},{"year":2023,"finding":"Netrin-1 binding to endothelial Unc5B controls blood-retina barrier (BRB) integrity via the Norrin receptor LRP5; Unc5B deletion or Ntn1 deletion reduces LRP5 phosphorylation and β-catenin/LEF1 expression, converting retinal endothelium to a leaky phenotype; Unc5B in pericytes contributes to BRB permeability via regulation of endothelial Unc5B; mechanistically, Netrin-1-Unc5B signaling promotes LRP5 phosphorylation via the Dlg1 intracellular scaffolding protein.","method":"Inducible conditional knockout of Unc5B and Ntn1, tracer injection, phosphorylation/signaling analysis, β-catenin gain-of-function rescue, Ntn1 overexpression","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO in two genes, molecular mechanism (LRP5 phosphorylation via Dlg1), genetic rescue, preprint not yet peer-reviewed","pmids":["36711611"],"is_preprint":true},{"year":2024,"finding":"FLRT3 expressed on cancer cells inhibits T cell activity through UNC5B, which is upregulated on activated human T cells; FLRT3-UNC5B interaction suppresses CAR-T and BiTE+T cell killing; a monoclonal antibody blocking FLRT3-UNC5B interactions reverses T cell inhibition, identifying UNC5B as a T cell checkpoint receptor.","method":"Gain-of-function genetic screen, T cell functional assays, humanized cancer models, monoclonal antibody blockade","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen, functional T cell assays, antibody blockade with immune-dependent phenotype, single lab","pmids":["38427724"],"is_preprint":false},{"year":2024,"finding":"YAP induces UNC5B expression through TEAD transcription factors (blocked by TEAD1/4 loss, S94A YAP mutation, or netrin-1 VI-V peptide); UNC5B and netrin-1 cooperate with integrin-αV/β5 to mediate YAP-induced cytostasis in YAPoff cancers; CRISPR screens linked UNC5B to this anticancer pathway.","method":"CRISPR screens, TEAD mutant analysis, UNC5B knockout, integrin blocking assays, receptor decoy experiments","journal":"Cancer research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen, mutant validation, multiple genetic tools, single lab","pmids":["39172021"],"is_preprint":false},{"year":2023,"finding":"Fucosyltransferase 8 (Fut8) regulates α-1,6-fucosylation of Unc5b predominantly in the ER; hypofucosylation of Unc5b (by Fut8 silencing or deletion of fucosylation sites) restores macrophage migration capacity; Unc5b-mediated inhibition of macrophage migration depends on activation of the p-CDC42/p-PAK pathway.","method":"Co-immunoprecipitation (Fut8-Unc5b), site-directed deletion of fucosylation sites, wound healing assay, in vivo ApoE-/- atherosclerosis model","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM identified (fucosylation), Co-IP, site-deletion mutagenesis, in vitro and in vivo functional validation, single lab","pmids":["36670464"],"is_preprint":false},{"year":2025,"finding":"Netrin-1 binding to UNC5B activates AMPK, which phosphorylates and inactivates the ferroptosis facilitator BACH1; co-immunoprecipitation confirms AMPK physically binds BACH1; UNC5B knockdown prevents netrin-1-mediated AMPK activation and BACH1 suppression; netrin-1/UNC5B/AMPK-BACH1 signaling protects neurons against ferroptosis after ischemic stroke.","method":"siRNA knockdown, AMPK inhibitor, BACH1 activator, Co-immunoprecipitation (AMPK-BACH1), photo-thrombosis stroke model","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, pharmacological and genetic dissection, in vivo stroke model, single lab","pmids":["40086580"],"is_preprint":false}],"current_model":"UNC5B is a dependence receptor for netrin-1 that, in the absence of ligand, adopts an active closed autoinhibitory conformation (ZU5-UPA-DD supramodule) and drives apoptosis by recruiting a PP2A/PR65β-DAPK complex that dephosphorylates and activates DAPK; MST1 kinase further amplifies apoptotic signaling by phosphorylating UNC5B at T428; netrin-1 binding recruits CIP2A (a PP2A inhibitor) and PIKE-L (via Fyn-mediated phosphorylation) to UNC5B, suppressing DAPK activity and activating PI3K/Akt survival signaling; in endothelial cells, UNC5B acts as a repulsive guidance receptor that inhibits angiogenic sprouting, and netrin-1-bound UNC5B interacts with LRP6 to activate Wnt/β-catenin signaling maintaining blood-brain and blood-retina barrier integrity; UNC5B also serves as a co-receptor for RGMa (with neogenin) activating RhoA via LARG/FAK, interacts with FLRT2/FLRT3 via extracellular domain interactions to modulate cell adhesion and macrophage differentiation, and functions as a T cell checkpoint receptor through FLRT3 binding; its apoptotic activity is regulated post-translationally by Fut8-mediated fucosylation and by an EC-specific NOVA2-driven exon-skipping isoform (UNC5B-Δ8) that is constitutively pro-apoptotic and netrin-1-insensitive."},"narrative":{"mechanistic_narrative":"UNC5B is a single-pass dependence receptor for netrin-1 that switches between pro-apoptotic/repulsive and pro-survival outputs depending on ligand occupancy, governing vascular morphogenesis, neuronal survival, and immune regulation [PMID:15510105, PMID:12598906]. Its cytoplasmic ZU5-UPA-death-domain supramodule adopts a closed, autoinhibited conformation whose release activates apoptotic and vascular-patterning signaling [PMID:19328064]. In the unliganded state, UNC5B drives apoptosis by engaging DAP-kinase (DAPK) through reciprocal death-domain contacts and by recruiting a PP2A/PR65β complex that dephosphorylates and activates DAPK [PMID:15729359, PMID:21172653]; this apoptotic activity is a direct downstream effector of p53, which transcriptionally induces UNC5B [PMID:12598906], and is amplified by MST1-mediated phosphorylation of UNC5B at Thr428 during dopaminergic neuronal loss [PMID:32929029]. Netrin-1 binding reverses this program: it recruits the PP2A inhibitor CIP2A to block DAPK activation [PMID:21172653] and engages PIKE-L/PIKE-A through Fyn- and Akt-dependent phosphorylation to drive PI3K/Akt survival signaling [PMID:18469807, PMID:21460185]. As a repulsive guidance receptor in endothelial tip cells, UNC5B restrains filopodial extension and sprouting angiogenesis through its intracellular domain [PMID:15510105, PMID:17908930], is induced by Notch and required for shear-stress junctional stability [PMID:38866944], and partners with the netrin-1 co-receptor LRP6/LRP5 to sustain Wnt/β-catenin signaling that maintains blood-brain and blood-retina barrier integrity [PMID:35246514, PMID:36711611]. UNC5B further interacts through its extracellular domain with Robo4 to preserve vascular integrity by suppressing VEGF signaling [PMID:21238923], with neogenin as an RGMa co-receptor that activates RhoA via LARG/FAK [PMID:19273616], and with FLRT2/FLRT3 to control cell adhesion, macrophage differentiation, and T-cell checkpoint function [PMID:19492039, PMID:28576770, PMID:38427724]. An endothelial NOVA2-driven exon-8-skipping isoform (UNC5B-Δ8) is constitutively pro-apoptotic and netrin-1-insensitive [PMID:34381052], and full-length UNC5B apoptotic signaling is additionally tuned by Fut8-mediated fucosylation [PMID:36670464].","teleology":[{"year":2003,"claim":"Established UNC5B as a p53-inducible dependence receptor whose cytoplasmic death domain executes apoptosis unless netrin-1 is bound, defining the survival/death switch at its core.","evidence":"Gene cloning, reporter assays, overexpression/knockdown and apoptosis assays in cell lines","pmids":["12598906"],"confidence":"High","gaps":["Did not identify the death-domain effectors","Did not resolve how ligand binding mechanically blocks the apoptotic output"]},{"year":2004,"claim":"Identified UNC5B's physiological role as a repulsive netrin receptor in endothelial tip cells, linking the receptor to vascular morphogenesis beyond apoptosis.","evidence":"Genetic knockout in mice and morpholino knockdown in zebrafish with endothelial filopodial assays","pmids":["15510105"],"confidence":"High","gaps":["Did not define the intracellular signaling required for repulsion","Did not connect repulsion to the apoptotic machinery"]},{"year":2005,"claim":"Resolved the proximal apoptotic effector by showing UNC5B binds and activates DAPK via death-domain interactions in a netrin-1-inhibitable manner.","evidence":"Reciprocal Co-IP in cells and mouse brain, dominant-negative mutants, DAPK-mutant MEFs, kinase activity assays","pmids":["15729359"],"confidence":"High","gaps":["Mechanism by which UNC5B reduces DAPK autophosphorylation not yet defined","Did not identify the phosphatase involved"]},{"year":2007,"claim":"Mapped repulsive and anti-angiogenic signaling to the UNC5B intracellular domain, demonstrating it is required for endothelial repulsion and angiogenesis inhibition.","evidence":"Full-length vs. truncation constructs, genetic loss-of-function, in vitro repulsion and tumor angiogenesis models","pmids":["17908930"],"confidence":"High","gaps":["Did not identify intracellular signaling partners mediating repulsion","Did not separate apoptotic from repulsive outputs of the intracellular domain"]},{"year":2009,"claim":"Defined the structural basis of receptor autoinhibition, showing the ZU5-UPA-DD supramodule locks UNC5B in a closed conformation that suppresses apoptotic and patterning activity.","evidence":"X-ray crystallography of the cytoplasmic domain with functional validation of open vs. closed states","pmids":["19328064"],"confidence":"High","gaps":["How netrin-1 binding triggers conformational release not structurally resolved","Full-length receptor structure not determined"]},{"year":2009,"claim":"Broadened UNC5B's receptor repertoire beyond netrin by establishing it as a neogenin co-receptor for RGMa that activates RhoA through LARG and FAK.","evidence":"Co-IP, dominant-negative assays, kinase activity assays","pmids":["19273616"],"confidence":"Medium","gaps":["Single-lab evidence","Stoichiometry of the UNC5B-neogenin co-receptor complex unresolved"]},{"year":2008,"claim":"Identified the netrin-1-induced survival arm, showing Fyn-dependent PIKE-L recruitment to UNC5B triggers PI3K signaling that suppresses apoptosis.","evidence":"Co-IP, PI3K activity assays, Fyn-null mice, overexpression/knockdown","pmids":["18469807"],"confidence":"High","gaps":["Brain-specific PIKE-L limits generality to other tissues","Coupling between PIKE-L binding and conformational opening not defined"]},{"year":2010,"claim":"Reconstituted the apoptotic switch biochemically, showing UNC5B recruits PP2A/PR65β to activate DAPK and that netrin-1 recruits the PP2A inhibitor CIP2A to abort death.","evidence":"siRNA screen, Co-IP, PP2A activity assays, dominant-negative approaches","pmids":["21172653"],"confidence":"High","gaps":["Spatial/temporal regulation of CIP2A recruitment not defined","Does not address vascular repulsion mechanism"]},{"year":2011,"claim":"Extended UNC5B into vascular barrier maintenance by identifying the extracellular Robo4-UNC5B interaction that preserves vessel integrity through VEGF suppression.","evidence":"Interaction screen, Co-IP, function-blocking antibodies, Robo4 KO mouse rescue","pmids":["21238923"],"confidence":"High","gaps":["Intracellular signaling downstream of Robo4-UNC5B not defined","Relationship to netrin-1 signaling unclear"]},{"year":2020,"claim":"Identified MST1 as an apoptotic amplifier, mapping phosphorylation of UNC5B at Thr428 as a driver of dopaminergic neuron loss upon netrin-1 depletion.","evidence":"Co-IP, phospho-site mapping, UNC5B knockout, MST1 blockade in a Parkinson's model","pmids":["32929029"],"confidence":"High","gaps":["How T428 phosphorylation alters the autoinhibited conformation unresolved","Whether MST1 acts upstream or parallel to PP2A/DAPK not defined"]},{"year":2022,"claim":"Established a non-apoptotic vascular barrier function in which netrin-1-bound UNC5B engages LRP6 to sustain Wnt/β-catenin signaling and blood-brain barrier integrity.","evidence":"Inducible endothelial KO, UNC5B-LRP6 Co-IP, LRP6 phosphorylation, β-catenin rescue, blocking antibodies","pmids":["35246514"],"confidence":"High","gaps":["Mechanism coupling UNC5B to LRP6 phosphorylation not detailed","Whether barrier and repulsion functions share signaling unresolved"]},{"year":2021,"claim":"Revealed isoform-level control of apoptosis through a NOVA2-driven exon-8-skipping isoform (UNC5B-Δ8) that is constitutively pro-apoptotic and netrin-1-insensitive during vascular development.","evidence":"Isoform cloning, NOVA2 knockdown/overexpression, apoptosis assays, zebrafish and mouse vascular models","pmids":["34381052"],"confidence":"High","gaps":["Structural basis of netrin-1 insensitivity not defined","Tissue distribution of the isoform beyond endothelium unclear"]},{"year":2024,"claim":"Connected UNC5B to upstream Notch transcriptional control and shear-stress junctional stabilization, integrating it into endothelial flow responses.","evidence":"Translated mRNA screen, endothelial loss/gain-of-function, shear stress, neonatal retinal vascular analysis","pmids":["38866944"],"confidence":"High","gaps":["Notch-to-UNC5B transcriptional intermediates not defined","Junctional effectors downstream of UNC5B under shear unresolved"]},{"year":2024,"claim":"Defined UNC5B as an inducible T-cell checkpoint receptor engaged by tumor FLRT3, opening an immunotherapeutic axis.","evidence":"Gain-of-function genetic screen, T cell functional assays, humanized cancer models, antibody blockade","pmids":["38427724"],"confidence":"Medium","gaps":["Single-lab evidence","Intracellular signaling driving T-cell suppression not defined"]},{"year":2023,"claim":"Identified post-translational fucosylation as a tuning mechanism for UNC5B, with Fut8-mediated α-1,6-fucosylation controlling macrophage migration via CDC42/PAK.","evidence":"Co-IP, 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/36711611","citation_count":5,"is_preprint":false},{"pmid":"33706585","id":"PMC_33706585","title":"Long non-coding RNA PITPNA-AS1 regulates UNC5B expression in papillary thyroid cancer via sponging miR-129-5p.","date":"2021","source":"The International journal of biological markers","url":"https://pubmed.ncbi.nlm.nih.gov/33706585","citation_count":5,"is_preprint":false},{"pmid":"40086580","id":"PMC_40086580","title":"Netrin-1 binding to UNC5b improves post-stroke neuronal ferroptosis via AMPK-BACH1 pathway.","date":"2025","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40086580","citation_count":5,"is_preprint":false},{"pmid":"17139086","id":"PMC_17139086","title":"Structure of the UNC5H2 death domain.","date":"2006","source":"Acta crystallographica. 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research","url":"https://pubmed.ncbi.nlm.nih.gov/31769036","citation_count":2,"is_preprint":false},{"pmid":"39381040","id":"PMC_39381040","title":"Acute myeloid leukemia cells adhere to bone marrow and acquire chemoresistance by downregulating UNC5B expression.","date":"2024","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39381040","citation_count":2,"is_preprint":false},{"pmid":"41072782","id":"PMC_41072782","title":"Jiawei Qingxin Zishen Decoction mitigates granulosa cell apoptosis and enhances ovarian reserve through Netrin/UNC5B signaling pathway.","date":"2025","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41072782","citation_count":2,"is_preprint":false},{"pmid":"24432616","id":"PMC_24432616","title":"[Expressions of netrin-1 and UNC5B in prostate cancer and their clinical significance].","date":"2013","source":"Zhonghua nan ke xue = National journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/24432616","citation_count":2,"is_preprint":false},{"pmid":"40796890","id":"PMC_40796890","title":"Direction and modality of transcription changes caused by TAD boundary disruption in Slc29a3/Unc5b locus depends on tissue-specific epigenetic context.","date":"2025","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/40796890","citation_count":2,"is_preprint":false},{"pmid":"40728980","id":"PMC_40728980","title":"Characterization of Netrin-1 and Its Receptors UNC5B and Neogenin-1 in a Rat Rotator Cuff Tear Model: Associations with Inflammatory Mediators and Neurite Extension.","date":"2025","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40728980","citation_count":1,"is_preprint":false},{"pmid":"36110982","id":"PMC_36110982","title":"Expression and Relationship of Netrin-1, DCC, UNC5B, and VEGF in Villous Tissues of Patients with Delayed Abortion.","date":"2022","source":"Contrast media & molecular imaging","url":"https://pubmed.ncbi.nlm.nih.gov/36110982","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53153,"output_tokens":8312,"usd":0.142069,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18001,"output_tokens":4919,"usd":0.10649,"stage2_stop_reason":"end_turn"},"total_usd":0.248559,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"UNC5B functions as a repulsive netrin receptor in endothelial tip cells; disruption of Unc5b in mice or zebrafish leads to aberrant filopodial extension and excessive vessel branching; netrin-1 causes endothelial filopodial retraction only when UNC5B is present, establishing UNC5B as a repulsive guidance receptor controlling vascular morphogenesis.\",\n      \"method\": \"Genetic knockout in mice, morpholino knockdown in zebrafish, endothelial cell assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function in two vertebrate species with defined cellular phenotype, replicated across labs\",\n      \"pmids\": [\"15510105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"UNC5B (p53RDL1) is a direct transcriptional target of p53 that mediates p53-dependent apoptosis through its cytoplasmic death domain; when the ligand netrin-1 binds to p53RDL1/UNC5B, p53-dependent apoptosis is blocked, identifying a netrin-p53RDL1 pathway that balances cell survival and death.\",\n      \"method\": \"Gene cloning, reporter assays, overexpression/knockdown in cell lines, apoptosis assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter, OE, KD, apoptosis readout), replicated in follow-up studies\",\n      \"pmids\": [\"12598906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"UNC5B (UNC5H2) physically interacts with the serine/threonine kinase DAP-kinase (DAPK) through their respective death domains both in cell culture and embryonic mouse brain. In the absence of netrin-1, UNC5B reduces DAP-kinase autophosphorylation on Ser308 and increases DAPK catalytic activity to promote apoptosis; netrin-1 blocks this UNC5B-dependent DAPK activation.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative mutants, DAPK-mutant MEFs, kinase activity assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in multiple systems, functional rescue with dominant-negatives, replicated concept in follow-up work\",\n      \"pmids\": [\"15729359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UNC5B full-length receptor triggers endothelial cell repulsion and inhibits sprouting angiogenesis in response to netrin-1; a truncated UNC5B lacking the intracellular signaling domain fails to induce repulsion, establishing that the intracellular domain is required for repulsive signaling. Genetic loss of unc5b reduces netrin-1-mediated angiogenesis inhibition.\",\n      \"method\": \"Full-length vs. truncation constructs, loss-of-function genetic model, in vitro repulsion assay, Matrigel/tumor angiogenesis models\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-deletion mutagenesis combined with genetic loss-of-function and cellular phenotype readout\",\n      \"pmids\": [\"17908930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Netrin-1 induces interaction of UNC5B with the brain-specific GTPase PIKE-L, triggering PI3K signaling that prevents UNC5B's pro-apoptotic activity and enhances neuronal survival. This interaction requires Fyn kinase-mediated tyrosine phosphorylation of PIKE-L and is absent in Fyn-null mice.\",\n      \"method\": \"Co-immunoprecipitation, PI3K activity assay, Fyn-null mice, overexpression/knockdown\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic validation in Fyn KO mice, PI3K activity assay, multiple orthogonal methods\",\n      \"pmids\": [\"18469807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structure of the cytoplasmic portion of UNC5B reveals three domains (ZU5, UPA, death domain) forming a structural supramodule in which ZU5 binds both UPA and DD, locking the complex in a closed/autoinhibited conformation that suppresses apoptotic and vascular patterning activity; release of this closed conformation activates the receptor.\",\n      \"method\": \"X-ray crystallography of cytoplasmic domain, functional validation of open vs. closed conformations\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, defines autoinhibition mechanism\",\n      \"pmids\": [\"19328064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"UNC5B interacts with neogenin as a co-receptor for the repulsive guidance molecule RGMa; the guanine nucleotide exchange factor LARG associates with UNC5B to transduce RhoA activation; FAK is involved in RGMa-induced tyrosine phosphorylation of LARG and RhoA activation, mediating growth cone collapse.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative assays, kinase activity assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional assays in single lab, two orthogonal methods\",\n      \"pmids\": [\"19273616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"UNC5B and FLRT3 interact as high-affinity binding partners; UNC5B and FLRT3 synergize to induce cell deadhesion in Xenopus embryos; the small GTPase Rnd1, which mediates FLRT3 deadhesion activity, physically and functionally interacts with UNC5B to modulate cell adhesion.\",\n      \"method\": \"Expression screen, overexpression, morpholino knockdown, Co-immunoprecipitation in Xenopus\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and genetic knockdown with phenotypic readout, single system\",\n      \"pmids\": [\"19492039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UNC5B (UNC5H2/B) recruits a complex containing the PP2A structural subunit PR65β and DAPK; PP2A dephosphorylates and thereby activates DAPK to promote apoptosis. Netrin-1 binding recruits the PP2A inhibitor CIP2A to UNC5B, blocking this mechanism and preventing cell death.\",\n      \"method\": \"siRNA screen, Co-immunoprecipitation, PP2A activity assays, dominant-negative approaches\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — siRNA screen followed by biochemical reconstitution of PP2A-DAPK-UNC5B complex, phosphatase activity assays, replicated concept\",\n      \"pmids\": [\"21172653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Robo4 specifically binds to UNC5B via a protein-protein interaction between their extracellular domains; Robo4-UNC5B signaling maintains vascular integrity by inhibiting VEGF downstream signaling; function-blocking antibodies against either Robo4 or UNC5B increase angiogenesis and disrupt vessel integrity; soluble Robo4 rescues barrier defects in Robo4−/− mice via UNC5B.\",\n      \"method\": \"Protein-protein interaction screen, Co-immunoprecipitation, function-blocking antibodies, Robo4 KO mouse rescue experiments\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased interaction screen confirmed by Co-IP, genetic and antibody-based functional validation, rescue experiment\",\n      \"pmids\": [\"21238923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Netrin-4 does not bind directly to UNC5B or UNC5C but binds neogenin; Netrin-4 increases association between UNC5B and neogenin (demonstrated by Co-IP); silencing either neogenin or UNC5B abolishes Netrin-4's inhibitory effect on endothelial cell migration, indicating both receptors are required for Netrin-4 anti-angiogenic function.\",\n      \"method\": \"Binding assays, Co-immunoprecipitation, siRNA knockdown, endothelial migration assays, in vivo angiogenesis models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing netrin-4-induced UNC5B-neogenin complex, siRNA functional validation, single lab\",\n      \"pmids\": [\"18719102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The cytoplasmic domain of UNC5B (UNC5H2) binds activated GTP-bound Gαi2; this interaction sequesters Gαi2 from inhibiting adenylyl cyclase, thereby increasing intracellular cAMP levels, identifying UNC5B as a novel inhibitor of Gαi2 signaling.\",\n      \"method\": \"Binding assays with constitutively-activated Gαi2 (gip2), adenylyl cyclase activity assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single binding assay with activity readout, no in vivo validation\",\n      \"pmids\": [\"12359238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of the UNC5H2 (UNC5B) death domain at 2.1 Å resolution reveals a six-helix bundle fold; the death domain forms a homodimer in crystal and in solution through hydrophobic contacts, which may block caspase access to its cleavage site when netrin-1 is bound.\",\n      \"method\": \"X-ray crystallography, solution biophysics\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure with clear mechanistic implication but limited functional experimental validation in this paper\",\n      \"pmids\": [\"17139086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UNC5B (Unc5H2) acts as a repulsive receptor in Schwann cells that functions as an intrinsic brake on peripheral nerve regeneration; local siRNA knockdown of Unc5H2 at the injury site facilitates axon regrowth, and forced DCC inhibition causes reciprocal upregulation of Unc5H2.\",\n      \"method\": \"In vivo siRNA knockdown at nerve injury site, axon regeneration functional assay\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo siRNA with defined phenotype, reciprocal regulation observed, single lab\",\n      \"pmids\": [\"21656855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Netrin-1 increases renal proximal tubular epithelial cell proliferation and migration through the UNC5B receptor; siRNA inhibition of UNC5B (but not UNC5C) completely blocks netrin-1-induced proliferation and migration; downstream signaling involves phosphorylation of Akt and ERK, with PI3K and MEK1/2 inhibition blocking proliferation but not migration.\",\n      \"method\": \"siRNA knockdown, proliferation assays, PI3K/MEK inhibitors, Western blot phosphorylation assays\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-selective siRNA, pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"19211685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Endothelial UNC5B controls blood-brain barrier integrity by maintaining Wnt/β-catenin signaling; inducible endothelial-specific UNC5B deletion reduces Claudin-5 and increases PLVAP, causing BBB leak. Mechanistically, netrin-1 enhances UNC5B interaction with the Wnt co-receptor LRP6, induces LRP6 phosphorylation, and activates Wnt/β-catenin signaling; β-catenin overexpression rescues UNC5B mutant BBB defects.\",\n      \"method\": \"Inducible endothelial-specific knockout, Co-immunoprecipitation (UNC5B-LRP6), Western blot for LRP6 phosphorylation, β-catenin rescue, function-blocking antibodies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, molecular mechanism (LRP6 phosphorylation), Co-IP, genetic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"35246514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Netrin-1 reduction in Parkinson's disease activates MST1, which binds and phosphorylates UNC5B at T428, promoting its apoptotic activation and dopaminergic neuronal loss; knockout of UNC5B abolishes netrin depletion-induced dopaminergic loss; blockade of MST1 phosphorylation of UNC5B suppresses neuronal apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation site mapping (T428), UNC5B knockout, MST1 blockade\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphorylation site identified, genetic KO with defined phenotype, interaction confirmed by Co-IP, multiple orthogonal methods\",\n      \"pmids\": [\"32929029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Akt phosphorylates PIKE-A on Ser-472, enhancing PIKE-A interaction with UNC5B and inhibiting UNC5B-provoked apoptosis in a p53-dependent manner; overexpression of PIKE-A diminishes UNC5B expression through downregulation of p53; PIKE-A directly interacts with UNC5B regulated by netrin-1-activated Akt.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation-site mutagenesis, PIKE knockout MEFs, apoptosis assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-site mutagenesis, Co-IP, genetic KO cells, single lab\",\n      \"pmids\": [\"21460185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Netrin-4 acts through its receptor neogenin and recruits UNC5B; activation of UNC5B by Netrin-4/neogenin signaling leads to RhoA activation via SHP2 phosphatase in dorsal horn neurons; transient suppression of Netrin-4 or Unc5B after injury prevents allodynia, and intrathecal Netrin-4 protein enhances excitatory synaptic transmission and induces allodynia in naive rats.\",\n      \"method\": \"Netrin-4 mutant rats, in vivo siRNA, intrathecal protein administration, electrophysiology\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mutant rats, in vivo siRNA, electrophysiology, single lab\",\n      \"pmids\": [\"27856613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FLRT2 binds to UNC5B via its extracellular domain and activates Akt/mTOR signaling to drive monocyte-to-macrophage differentiation; endothelial repulsion in the placental labyrinth is mediated through FLRT2 binding to UNC5B; endothelial-specific FLRT2 deletion causes embryonic lethality with aberrant endothelial alignment in the placenta.\",\n      \"method\": \"Endothelial-specific knockout, binding assays, Co-immunoprecipitation, mTOR agonist rescue\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with phenotype, binding assay, single lab\",\n      \"pmids\": [\"28576770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FLRT2 directly interacts with UNC5B via its extracellular domain and activates Akt/mTOR signaling to promote monocyte-to-macrophage differentiation; myeloid-specific Flrt2 deletion impairs macrophage generation; in vivo administration of mTOR agonist reverses impaired phenotypes in Flrt2 mutant mice.\",\n      \"method\": \"Myeloid-specific conditional knockout, Co-immunoprecipitation, mTOR agonist rescue in vivo\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, Co-IP, genetic rescue, single lab\",\n      \"pmids\": [\"37090697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"An endothelial cell-specific UNC5B splicing isoform (UNC5B-Δ8), generated through exon-8 skipping by the alternative splicing factor NOVA2, is constitutively pro-apoptotic and insensitive to netrin-1; this isoform is required for specific blood vessel development in an apoptosis-dependent manner.\",\n      \"method\": \"Isoform cloning, NOVA2 knockdown/overexpression, apoptosis assays, zebrafish and mouse vascular development models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — splice isoform characterized, splicing factor identified, functional validation in multiple models\",\n      \"pmids\": [\"34381052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Netrin-1 regulates UNC5B distribution at the plasma membrane: UNC5B expressed alone is recruited by netrin-1 to the plasma membrane; coexpressed DCC and UNC5B undergo netrin-1-induced colocalization and heterooligomerization via vesicular recruitment to the plasma membrane; this plasma membrane recruitment requires netrin-1-activated Src family kinase signaling.\",\n      \"method\": \"TIRF microscopy, temporal image cross-correlation spectroscopy (TICCS), fluorescently-tagged receptors in HEK293T cells, pharmacological Src inhibition\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative live-cell imaging with receptor interaction measurements, pharmacological validation, single lab\",\n      \"pmids\": [\"26840727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Notch signaling in endothelial cells rapidly upregulates UNC5B expression; loss or gain of UNC5B recapitulates Notch-regulated phenotypes including inhibition of endothelial migration and proliferation; UNC5B is required for stabilization of endothelial junctions in response to shear stress; endothelial-specific loss of UNC5B leads to excessive vascularization and increased branchpoints in developing mouse retina.\",\n      \"method\": \"Translated mRNA screen, endothelial-specific UNC5B loss/gain-of-function, shear stress experiments, neonatal mouse retinal vascular analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased screen, genetic gain- and loss-of-function, in vivo retinal phenotype, multiple cellular readouts\",\n      \"pmids\": [\"38866944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UNC5B mediates G2/M phase cell cycle arrest in bladder cancer cells by forming a complex with CDC14A phosphatase and P53; this complex dephosphorylates P53 at Ser-315, reducing cyclin B1 expression and increasing p-CDK1, thereby inhibiting tumor proliferation; CDC14A knockdown suppresses UNC5B-induced G2/M arrest.\",\n      \"method\": \"Mass spectrometry, Co-immunoprecipitation, site-specific phosphorylation analysis, CDC14A knockdown, xenograft tumor model\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified complex, Co-IP, phospho-site analysis, genetic knockdown validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"32372016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Netrin-1 promotes naive pluripotency in mESCs through a balance of Neo1 and Unc5B receptors that co-regulate Wnt and MAPK pathways; Netrin-1 induces FAK kinase to inactivate Gsk3α/β and stabilize β-catenin while increasing activity of a Ppp2r2c-containing PP2A complex to reduce Erk1/2 activity.\",\n      \"method\": \"Chemical inhibitor substitution assays, Western blot, phosphorylation analysis, PP2A activity assay, receptor knockdown in mESCs\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection with multiple pathway readouts, genetic receptor manipulation, PP2A activity assay, FAK-GSK3 phosphorylation\",\n      \"pmids\": [\"32231305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UNC5B overexpression in Schwann cells facilitates autophagic flux via phosphorylation of AMPK and ULK1 in a netrin-1-dependent manner; UNC5B helps recruit netrin-1 to the cell membrane; overexpression of UNC5B alleviates neuropathic pain and rescues myelin degeneration in a rat CCI model, and autophagy inhibitor reverses the analgesic effect.\",\n      \"method\": \"AAV-mediated UNC5B overexpression, autophagy flux assays, AMPK/ULK1 phosphorylation Western blot, autophagy inhibitor, CCI rat model\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo OE with defined behavioral phenotype, pathway phosphorylation assays, pharmacological inhibitor confirmation, single lab\",\n      \"pmids\": [\"35668343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Netrin-1 and UNC5B form heterocomplexes; biophysical analysis shows NET-1 exists in a monomer-dimer equilibrium (pH-sensitive antiparallel dimer) and UNC5B forms equimolar heterocomplexes with both monomeric and dimeric NET-1.\",\n      \"method\": \"Multi-wavelength analytical ultracentrifugation (AUC), sedimentation velocity experiments\",\n      \"journal\": \"European biophysics journal : EBJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous biophysical characterization of complex stoichiometry, single lab, no functional validation in same study\",\n      \"pmids\": [\"36939874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Netrin-1 binding to endothelial Unc5B controls blood-retina barrier (BRB) integrity via the Norrin receptor LRP5; Unc5B deletion or Ntn1 deletion reduces LRP5 phosphorylation and β-catenin/LEF1 expression, converting retinal endothelium to a leaky phenotype; Unc5B in pericytes contributes to BRB permeability via regulation of endothelial Unc5B; mechanistically, Netrin-1-Unc5B signaling promotes LRP5 phosphorylation via the Dlg1 intracellular scaffolding protein.\",\n      \"method\": \"Inducible conditional knockout of Unc5B and Ntn1, tracer injection, phosphorylation/signaling analysis, β-catenin gain-of-function rescue, Ntn1 overexpression\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO in two genes, molecular mechanism (LRP5 phosphorylation via Dlg1), genetic rescue, preprint not yet peer-reviewed\",\n      \"pmids\": [\"36711611\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FLRT3 expressed on cancer cells inhibits T cell activity through UNC5B, which is upregulated on activated human T cells; FLRT3-UNC5B interaction suppresses CAR-T and BiTE+T cell killing; a monoclonal antibody blocking FLRT3-UNC5B interactions reverses T cell inhibition, identifying UNC5B as a T cell checkpoint receptor.\",\n      \"method\": \"Gain-of-function genetic screen, T cell functional assays, humanized cancer models, monoclonal antibody blockade\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen, functional T cell assays, antibody blockade with immune-dependent phenotype, single lab\",\n      \"pmids\": [\"38427724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YAP induces UNC5B expression through TEAD transcription factors (blocked by TEAD1/4 loss, S94A YAP mutation, or netrin-1 VI-V peptide); UNC5B and netrin-1 cooperate with integrin-αV/β5 to mediate YAP-induced cytostasis in YAPoff cancers; CRISPR screens linked UNC5B to this anticancer pathway.\",\n      \"method\": \"CRISPR screens, TEAD mutant analysis, UNC5B knockout, integrin blocking assays, receptor decoy experiments\",\n      \"journal\": \"Cancer research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen, mutant validation, multiple genetic tools, single lab\",\n      \"pmids\": [\"39172021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Fucosyltransferase 8 (Fut8) regulates α-1,6-fucosylation of Unc5b predominantly in the ER; hypofucosylation of Unc5b (by Fut8 silencing or deletion of fucosylation sites) restores macrophage migration capacity; Unc5b-mediated inhibition of macrophage migration depends on activation of the p-CDC42/p-PAK pathway.\",\n      \"method\": \"Co-immunoprecipitation (Fut8-Unc5b), site-directed deletion of fucosylation sites, wound healing assay, in vivo ApoE-/- atherosclerosis model\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM identified (fucosylation), Co-IP, site-deletion mutagenesis, in vitro and in vivo functional validation, single lab\",\n      \"pmids\": [\"36670464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Netrin-1 binding to UNC5B activates AMPK, which phosphorylates and inactivates the ferroptosis facilitator BACH1; co-immunoprecipitation confirms AMPK physically binds BACH1; UNC5B knockdown prevents netrin-1-mediated AMPK activation and BACH1 suppression; netrin-1/UNC5B/AMPK-BACH1 signaling protects neurons against ferroptosis after ischemic stroke.\",\n      \"method\": \"siRNA knockdown, AMPK inhibitor, BACH1 activator, Co-immunoprecipitation (AMPK-BACH1), photo-thrombosis stroke model\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, pharmacological and genetic dissection, in vivo stroke model, single lab\",\n      \"pmids\": [\"40086580\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UNC5B is a dependence receptor for netrin-1 that, in the absence of ligand, adopts an active closed autoinhibitory conformation (ZU5-UPA-DD supramodule) and drives apoptosis by recruiting a PP2A/PR65β-DAPK complex that dephosphorylates and activates DAPK; MST1 kinase further amplifies apoptotic signaling by phosphorylating UNC5B at T428; netrin-1 binding recruits CIP2A (a PP2A inhibitor) and PIKE-L (via Fyn-mediated phosphorylation) to UNC5B, suppressing DAPK activity and activating PI3K/Akt survival signaling; in endothelial cells, UNC5B acts as a repulsive guidance receptor that inhibits angiogenic sprouting, and netrin-1-bound UNC5B interacts with LRP6 to activate Wnt/β-catenin signaling maintaining blood-brain and blood-retina barrier integrity; UNC5B also serves as a co-receptor for RGMa (with neogenin) activating RhoA via LARG/FAK, interacts with FLRT2/FLRT3 via extracellular domain interactions to modulate cell adhesion and macrophage differentiation, and functions as a T cell checkpoint receptor through FLRT3 binding; its apoptotic activity is regulated post-translationally by Fut8-mediated fucosylation and by an EC-specific NOVA2-driven exon-skipping isoform (UNC5B-Δ8) that is constitutively pro-apoptotic and netrin-1-insensitive.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UNC5B is a single-pass dependence receptor for netrin-1 that switches between pro-apoptotic/repulsive and pro-survival outputs depending on ligand occupancy, governing vascular morphogenesis, neuronal survival, and immune regulation [#0, #1]. Its cytoplasmic ZU5-UPA-death-domain supramodule adopts a closed, autoinhibited conformation whose release activates apoptotic and vascular-patterning signaling [#5]. In the unliganded state, UNC5B drives apoptosis by engaging DAP-kinase (DAPK) through reciprocal death-domain contacts and by recruiting a PP2A/PR65\\u03b2 complex that dephosphorylates and activates DAPK [#2, #8]; this apoptotic activity is a direct downstream effector of p53, which transcriptionally induces UNC5B [#1], and is amplified by MST1-mediated phosphorylation of UNC5B at Thr428 during dopaminergic neuronal loss [#16]. Netrin-1 binding reverses this program: it recruits the PP2A inhibitor CIP2A to block DAPK activation [#8] and engages PIKE-L/PIKE-A through Fyn- and Akt-dependent phosphorylation to drive PI3K/Akt survival signaling [#4, #17]. As a repulsive guidance receptor in endothelial tip cells, UNC5B restrains filopodial extension and sprouting angiogenesis through its intracellular domain [#0, #3], is induced by Notch and required for shear-stress junctional stability [#23], and partners with the netrin-1 co-receptor LRP6/LRP5 to sustain Wnt/\\u03b2-catenin signaling that maintains blood-brain and blood-retina barrier integrity [#15, #28]. UNC5B further interacts through its extracellular domain with Robo4 to preserve vascular integrity by suppressing VEGF signaling [#9], with neogenin as an RGMa co-receptor that activates RhoA via LARG/FAK [#6], and with FLRT2/FLRT3 to control cell adhesion, macrophage differentiation, and T-cell checkpoint function [#7, #19, #29]. An endothelial NOVA2-driven exon-8-skipping isoform (UNC5B-\\u03948) is constitutively pro-apoptotic and netrin-1-insensitive [#21], and full-length UNC5B apoptotic signaling is additionally tuned by Fut8-mediated fucosylation [#31].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established UNC5B as a p53-inducible dependence receptor whose cytoplasmic death domain executes apoptosis unless netrin-1 is bound, defining the survival/death switch at its core.\",\n      \"evidence\": \"Gene cloning, reporter assays, overexpression/knockdown and apoptosis assays in cell lines\",\n      \"pmids\": [\"12598906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the death-domain effectors\", \"Did not resolve how ligand binding mechanically blocks the apoptotic output\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified UNC5B's physiological role as a repulsive netrin receptor in endothelial tip cells, linking the receptor to vascular morphogenesis beyond apoptosis.\",\n      \"evidence\": \"Genetic knockout in mice and morpholino knockdown in zebrafish with endothelial filopodial assays\",\n      \"pmids\": [\"15510105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the intracellular signaling required for repulsion\", \"Did not connect repulsion to the apoptotic machinery\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the proximal apoptotic effector by showing UNC5B binds and activates DAPK via death-domain interactions in a netrin-1-inhibitable manner.\",\n      \"evidence\": \"Reciprocal Co-IP in cells and mouse brain, dominant-negative mutants, DAPK-mutant MEFs, kinase activity assays\",\n      \"pmids\": [\"15729359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which UNC5B reduces DAPK autophosphorylation not yet defined\", \"Did not identify the phosphatase involved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped repulsive and anti-angiogenic signaling to the UNC5B intracellular domain, demonstrating it is required for endothelial repulsion and angiogenesis inhibition.\",\n      \"evidence\": \"Full-length vs. truncation constructs, genetic loss-of-function, in vitro repulsion and tumor angiogenesis models\",\n      \"pmids\": [\"17908930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify intracellular signaling partners mediating repulsion\", \"Did not separate apoptotic from repulsive outputs of the intracellular domain\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the structural basis of receptor autoinhibition, showing the ZU5-UPA-DD supramodule locks UNC5B in a closed conformation that suppresses apoptotic and patterning activity.\",\n      \"evidence\": \"X-ray crystallography of the cytoplasmic domain with functional validation of open vs. closed states\",\n      \"pmids\": [\"19328064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How netrin-1 binding triggers conformational release not structurally resolved\", \"Full-length receptor structure not determined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Broadened UNC5B's receptor repertoire beyond netrin by establishing it as a neogenin co-receptor for RGMa that activates RhoA through LARG and FAK.\",\n      \"evidence\": \"Co-IP, dominant-negative assays, kinase activity assays\",\n      \"pmids\": [\"19273616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence\", \"Stoichiometry of the UNC5B-neogenin co-receptor complex unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the netrin-1-induced survival arm, showing Fyn-dependent PIKE-L recruitment to UNC5B triggers PI3K signaling that suppresses apoptosis.\",\n      \"evidence\": \"Co-IP, PI3K activity assays, Fyn-null mice, overexpression/knockdown\",\n      \"pmids\": [\"18469807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Brain-specific PIKE-L limits generality to other tissues\", \"Coupling between PIKE-L binding and conformational opening not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Reconstituted the apoptotic switch biochemically, showing UNC5B recruits PP2A/PR65\\u03b2 to activate DAPK and that netrin-1 recruits the PP2A inhibitor CIP2A to abort death.\",\n      \"evidence\": \"siRNA screen, Co-IP, PP2A activity assays, dominant-negative approaches\",\n      \"pmids\": [\"21172653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial/temporal regulation of CIP2A recruitment not defined\", \"Does not address vascular repulsion mechanism\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended UNC5B into vascular barrier maintenance by identifying the extracellular Robo4-UNC5B interaction that preserves vessel integrity through VEGF suppression.\",\n      \"evidence\": \"Interaction screen, Co-IP, function-blocking antibodies, Robo4 KO mouse rescue\",\n      \"pmids\": [\"21238923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling downstream of Robo4-UNC5B not defined\", \"Relationship to netrin-1 signaling unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified MST1 as an apoptotic amplifier, mapping phosphorylation of UNC5B at Thr428 as a driver of dopaminergic neuron loss upon netrin-1 depletion.\",\n      \"evidence\": \"Co-IP, phospho-site mapping, UNC5B knockout, MST1 blockade in a Parkinson's model\",\n      \"pmids\": [\"32929029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How T428 phosphorylation alters the autoinhibited conformation unresolved\", \"Whether MST1 acts upstream or parallel to PP2A/DAPK not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a non-apoptotic vascular barrier function in which netrin-1-bound UNC5B engages LRP6 to sustain Wnt/\\u03b2-catenin signaling and blood-brain barrier integrity.\",\n      \"evidence\": \"Inducible endothelial KO, UNC5B-LRP6 Co-IP, LRP6 phosphorylation, \\u03b2-catenin rescue, blocking antibodies\",\n      \"pmids\": [\"35246514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling UNC5B to LRP6 phosphorylation not detailed\", \"Whether barrier and repulsion functions share signaling unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed isoform-level control of apoptosis through a NOVA2-driven exon-8-skipping isoform (UNC5B-\\u03948) that is constitutively pro-apoptotic and netrin-1-insensitive during vascular development.\",\n      \"evidence\": \"Isoform cloning, NOVA2 knockdown/overexpression, apoptosis assays, zebrafish and mouse vascular models\",\n      \"pmids\": [\"34381052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of netrin-1 insensitivity not defined\", \"Tissue distribution of the isoform beyond endothelium unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected UNC5B to upstream Notch transcriptional control and shear-stress junctional stabilization, integrating it into endothelial flow responses.\",\n      \"evidence\": \"Translated mRNA screen, endothelial loss/gain-of-function, shear stress, neonatal retinal vascular analysis\",\n      \"pmids\": [\"38866944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Notch-to-UNC5B transcriptional intermediates not defined\", \"Junctional effectors downstream of UNC5B under shear unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined UNC5B as an inducible T-cell checkpoint receptor engaged by tumor FLRT3, opening an immunotherapeutic axis.\",\n      \"evidence\": \"Gain-of-function genetic screen, T cell functional assays, humanized cancer models, antibody blockade\",\n      \"pmids\": [\"38427724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence\", \"Intracellular signaling driving T-cell suppression not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified post-translational fucosylation as a tuning mechanism for UNC5B, with Fut8-mediated \\u03b1-1,6-fucosylation controlling macrophage migration via CDC42/PAK.\",\n      \"evidence\": \"Co-IP, fucosylation-site deletion, wound healing assay, ApoE-/- atherosclerosis model\",\n      \"pmids\": [\"36670464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab evidence\", \"How fucosylation alters receptor signaling conformation unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single receptor partitions its multiple, sometimes opposing outputs (apoptosis, endothelial repulsion, Wnt-dependent barrier maintenance, RhoA-mediated guidance, immune checkpoint signaling) into distinct ligand-, isoform-, PTM-, and tissue-dependent programs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking conformational state to choice of downstream effector\", \"Combinatorial logic of co-receptors (neogenin, Robo4, LRP6/LRP5, FLRT2/3, integrin) not integrated\", \"Structure of full-length ligand-engaged receptor unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 9, 29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [22, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 2, 8, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 15, 25]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 3, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [29, 31]}\n    ],\n    \"complexes\": [\n      \"UNC5B-PP2A(PR65\\u03b2)-DAPK apoptotic complex\",\n      \"UNC5B-neogenin RGMa co-receptor complex\",\n      \"UNC5B-CDC14A-p53 complex\"\n    ],\n    \"partners\": [\n      \"DAPK1\",\n      \"PIKE-L/AGAP2\",\n      \"CIP2A\",\n      \"NEO1\",\n      \"ROBO4\",\n      \"LRP6\",\n      \"FLRT2\",\n      \"FLRT3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}