{"gene":"UNC5B","run_date":"2026-04-28T21:43:01","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 tip cell filopodia extension, excessive vessel branching, and abnormal navigation. Netrin-1 causes endothelial filopodial retraction only when UNC5B is present.","method":"Mouse knockout, zebrafish morpholino knockdown, in vitro filopodial retraction assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function in two species with defined cellular phenotype, replicated across organisms","pmids":["15510105"],"is_preprint":false},{"year":2003,"finding":"UNC5B (p53RDL1) is a direct transcriptional target of p53 and mediates p53-dependent apoptosis through its cytoplasmic death domain. Netrin-1 binding to UNC5B blocks p53-dependent apoptosis, and caspase cleavage of UNC5B is associated with cell death.","method":"Transcriptional reporter assays, overexpression, siRNA knockdown, caspase cleavage assays, co-immunoprecipitation","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in single rigorous paper, foundational discovery","pmids":["12598906"],"is_preprint":false},{"year":2005,"finding":"UNC5B (UNC5H2) physically interacts with the serine/threonine kinase DAP-kinase through their respective death domains. In the absence of netrin-1, UNC5H2 reduces DAP-kinase autophosphorylation on Ser308 and increases its catalytic (pro-apoptotic) activity; netrin-1 binding to UNC5H2 blocks this DAP-kinase activation.","method":"Co-immunoprecipitation in cell culture and embryonic mouse brain, dominant-negative mutants, DAP-kinase knockout MEFs, kinase activity assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP in vivo and in vitro, genetic rescue with knockout MEFs, kinase activity measurement","pmids":["15729359"],"is_preprint":false},{"year":2007,"finding":"UNC5B activation by netrin-1 inhibits sprouting angiogenesis; a truncated UNC5B lacking the intracellular signaling domain fails to induce endothelial cell repulsion, demonstrating that the intracellular domain is required for repulsive signaling.","method":"Loss-of-function (genetic unc5b knockout), truncation mutants, Matrigel/tumor angiogenesis assays, in vitro repulsion assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with defined phenotype plus domain-deletion mechanistic follow-up","pmids":["17908930"],"is_preprint":false},{"year":2008,"finding":"Endothelial-specific deletion of UNC5B causes a specific structural and functional deficiency in arterioles of the placental labyrinth leading to flow reversal in the umbilical artery and embryonic death, demonstrating UNC5B mediates autonomous pro-angiogenic signaling in the fetal-placental vasculature.","method":"Endothelium-specific conditional knockout mouse, zebrafish unc5b morpholino knockdown, physiological blood flow analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific KO with defined vascular phenotype, replicated in zebrafish","pmids":["18223200"],"is_preprint":false},{"year":2008,"finding":"Netrin-1 induces interaction of UNC5B with the brain-specific GTPase PIKE-L, triggering PI3K signaling, preventing UNC5B's pro-apoptotic activity, and enhancing neuronal survival. This interaction requires Fyn-mediated tyrosine phosphorylation of PIKE-L.","method":"Co-immunoprecipitation, Fyn-null mouse embryos, PI3K assay, apoptosis assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, genetic (Fyn-null) validation, PI3K activity measurement","pmids":["18469807"],"is_preprint":false},{"year":2008,"finding":"Netrin-4 binds to neogenin (not directly to UNC5B) and recruits UNC5B via neogenin; co-immunoprecipitation showed Netrin-4 increases association between UNC5B and neogenin on endothelial cells. Silencing either neogenin or UNC5B abolishes Netrin-4 inhibitory effects on endothelial migration.","method":"Co-immunoprecipitation, siRNA knockdown, endothelial migration/tube formation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus siRNA epistasis with defined cellular readout","pmids":["18719102"],"is_preprint":false},{"year":2009,"finding":"Crystal structure of the UNC5B cytoplasmic domain reveals three folded domains (ZU5, UPA, death domain) forming a supramodule in which ZU5 binds both UPA and DD, locking the receptor in a closed autoinhibited conformation. Release of this closed conformation activates apoptotic and vascular patterning functions.","method":"Crystal structure determination, mutagenesis, functional apoptosis and vascular patterning assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional mutagenesis validation in a single rigorous study","pmids":["19328064"],"is_preprint":false},{"year":2009,"finding":"UNC5B interacts with neogenin as a co-receptor for repulsive guidance molecule A (RGMa), and recruits leukemia-associated guanine nucleotide exchange factor (LARG) to transduce RhoA signaling. FAK mediates RGMa-induced tyrosine phosphorylation of LARG and subsequent RhoA activation leading to growth cone collapse.","method":"Co-immunoprecipitation, dominant-negative mutants, RhoA activation assay, growth cone collapse assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple Co-IP, biochemical RhoA assay, functional growth cone readout","pmids":["19273616"],"is_preprint":false},{"year":2009,"finding":"UNC5B (Unc5B) interacts with FLRT3 through high-affinity binding; both proteins synergize to induce cell de-adhesion in Xenopus embryos. The small GTPase Rnd1 physically and functionally interacts with UNC5B and mediates its effect on cell adhesion.","method":"Expression screen, co-immunoprecipitation, morpholino knockdown, overexpression in Xenopus embryos","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — protein-protein interaction with Co-IP, genetic epistasis by morpholino, functional readout in vivo","pmids":["19492039"],"is_preprint":false},{"year":2010,"finding":"UNC5H2/B recruits a protein complex containing the PP2A structural subunit PR65β and DAPk. PP2A dephosphorylates and activates DAPk to promote apoptosis in the absence of netrin-1. Netrin-1 binding recruits the PP2A inhibitor CIP2A to UNC5H2/B, blocking this mechanism.","method":"siRNA screen, co-immunoprecipitation, PP2A activity assay, DAPk phosphorylation assay, angiogenesis assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — siRNA screen followed by biochemical reconstitution of PP2A-DAPk complex on UNC5B, mechanistically rigorous","pmids":["21172653"],"is_preprint":false},{"year":2011,"finding":"Robo4 specifically binds to UNC5B extracellular domain (identified by protein-protein interaction screen). Robo4-UNC5B signaling maintains vascular integrity by inhibiting signaling downstream of VEGF. Function-blocking antibodies against either Robo4 or UNC5B increase angiogenesis and disrupt vessel integrity.","method":"Protein-protein interaction screen, function-blocking monoclonal antibodies, Robo4−/− mouse rescue experiments","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — unbiased interaction screen plus in vivo genetic and antibody rescue experiments with defined vascular phenotype","pmids":["21238923"],"is_preprint":false},{"year":2002,"finding":"The constitutively active Gαi2 (gip2) interacts with the cytoplasmic domain of UNC5B (UNC5H2) specifically when charged with GTP. This interaction sequesters Gαi2 from adenylyl cyclase, relieving inhibition and increasing intracellular cAMP levels.","method":"Co-immunoprecipitation, adenylyl cyclase activity assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical pulldown with adenylyl cyclase functional assay, single lab","pmids":["12359238"],"is_preprint":false},{"year":2011,"finding":"In Schwann cells, DCC promotes SC outgrowth while UNC5B (Unc5H2) inhibits it following nerve injury; local Unc5H2 knockdown at the injury site facilitates axon regrowth. Forced DCC inhibition causes reciprocal upregulation of Unc5H2, placing UNC5B as an intrinsic brake to peripheral nerve regeneration downstream of DCC.","method":"In vivo siRNA knockdown, immunolocalization, axon regeneration quantification","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo siRNA with functional nerve regeneration readout; epistatic relationship inferred but not fully reconstituted","pmids":["21656855"],"is_preprint":false},{"year":2011,"finding":"Akt phosphorylates PIKE-A on Ser-472 and enhances PIKE-A's interaction with UNC5B; overexpression of PIKE-A diminishes UNC5B expression by downregulating p53, while PIKE-A knockout stabilizes p53 and increases UNC5B, thereby escalating UV-triggered apoptosis.","method":"Co-immunoprecipitation, kinase assays, PIKE−/− MEFs, siRNA, overexpression, apoptosis assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical methods, genetic PIKE-KO cells, but single lab","pmids":["21460185"],"is_preprint":false},{"year":2016,"finding":"Netrin-4 binding to the Unc5B receptor and subsequent activation of tyrosine phosphatase SHP2 mediates Netrin-4-induced pain signaling (spinal sensitization) in the dorsal horn. Transient suppression of Netrin-4 or Unc5B prevents allodynia after peripheral nerve injury.","method":"Netrin-4-mutant rats, intrathecal netrin-4 injection, siRNA knockdown, electrophysiology, behavioral pain tests","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 — genetic mutant plus in vivo siRNA and pharmacological approach with defined behavioral and electrophysiological phenotype","pmids":["27856613"],"is_preprint":false},{"year":2016,"finding":"Netrin-1-induced recruitment of DCC and UNC5B to the plasma membrane from preexisting intracellular clusters was observed by live-cell imaging; this requires netrin-1-activated Src family kinase signaling. Netrin-1 also induced co-localization and heterooligomerization of co-expressed DCC and UNC5B at the plasma membrane.","method":"Live-cell TIRF microscopy, temporal image cross-correlation spectroscopy (TICCS), pharmacological Src kinase inhibition","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative live-cell imaging with pharmacological validation, single lab but multiple orthogonal imaging methods","pmids":["26840727"],"is_preprint":false},{"year":2006,"finding":"The crystal structure of the UNC5H2 (UNC5B) death domain at 2.1 Å resolution reveals a six-helix bundle fold; the domain forms a homodimer in crystal and solution, which may represent the netrin-1-bound state and could block caspase access to its cleavage site.","method":"X-ray crystallography, solution state analysis","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"Medium","confidence_rationale":"Tier 1 — crystal structure, but functional validation of dimer blocking caspase is inferred not directly tested","pmids":["17139086"],"is_preprint":false},{"year":2017,"finding":"FLRT2 expressed in placental labyrinth endothelial cells binds UNC5B and mediates inter-endothelial repulsion; endothelial-specific FLRT2 deletion causes aberrant endothelial alignment and disrupted feto-maternal circulation, phenocopying UNC5B-mediated repulsion.","method":"Endothelial-specific conditional knockout mouse, in vitro binding assays, histological and physiological vascular analysis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with defined vascular phenotype attributed to UNC5B-FLRT2 binding, single study","pmids":["28576770"],"is_preprint":false},{"year":2020,"finding":"Netrin-1 deficiency in Parkinson's disease activates MST1, which selectively binds and phosphorylates UNC5B on T428, promoting its apoptotic activation and dopaminergic neuronal loss. Knockout of UNC5B abolishes netrin depletion-induced dopaminergic loss; blockade of MST1-phosphorylating UNC5B suppresses neuronal apoptosis.","method":"Co-immunoprecipitation, site-specific phosphorylation assays, UNC5B knockout mice, human PD brain samples","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — specific phosphorylation site identified, genetic KO rescue, human tissue validation; single lab","pmids":["32929029"],"is_preprint":false},{"year":2020,"finding":"Netrin-1 promotes naive pluripotency by inducing FAK kinase to inactivate Gsk3α/β (stabilizing β-catenin) and by activating a Ppp2r2c-containing PP2A complex to reduce Erk1/2 activity, with the balance of Unc5B vs Neo1 receptor expression co-regulating these Wnt and MAPK pathway outputs.","method":"Chemical inhibition, receptor overexpression and knockdown, phospho-protein assays, mESC self-renewal assays","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pathway assays and receptor balancing experiments; complex phenotype but single lab","pmids":["32231305"],"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":"Identification of splicing isoform, NOVA2 knockdown, endothelial-specific isoform expression, apoptosis assays, in vivo vascular development analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — isoform characterization with functional rescue and in vivo validation; single lab","pmids":["34381052"],"is_preprint":false},{"year":2022,"finding":"Endothelial UNC5B controls blood-brain barrier integrity by maintaining Wnt/β-catenin signaling. Netrin-1 enhances UNC5B interaction with the Wnt co-receptor LRP6, induces LRP6 phosphorylation, and activates downstream Wnt/β-catenin signaling, maintaining Claudin-5 expression and repressing PLVAP. Inducible endothelial deletion of Unc5B causes BBB leak.","method":"Inducible endothelial-specific Unc5B knockout, β-catenin gain-of-function rescue, co-immunoprecipitation of UNC5B-LRP6, antibody blocking of Netrin-1 binding, tracer permeability assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — inducible KO with genetic rescue, biochemical UNC5B-LRP6 interaction, antibody blocking, multiple orthogonal methods","pmids":["35246514"],"is_preprint":false},{"year":2024,"finding":"Notch signaling rapidly upregulates UNC5B in endothelial cells; UNC5B mediates specific Notch-regulated phenotypes including inhibition of endothelial migration and proliferation and stabilization of endothelial junctions in response to shear stress. Endothelial-specific loss of UNC5B leads to excessive retinal vascularization.","method":"Unbiased translated mRNA screen, endothelial-specific UNC5B conditional knockout, gain-of-function, junction stability assays under shear stress","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — unbiased screen plus conditional KO with multiple defined endothelial phenotypes; single lab","pmids":["38866944"],"is_preprint":false},{"year":2020,"finding":"UNC5B inhibits bladder cancer cell G2/M phase arrest by binding to CDC14A and p53; UNC5B-CDC14A interaction dephosphorylates p53 at Ser-315, reducing cyclin B1 expression and increasing p-CDK1, thereby causing G2/M arrest. Knockdown of CDC14A suppresses this arrest.","method":"Mass spectrometry, co-immunoprecipitation, site-specific phosphorylation assays, siRNA knockdown, flow cytometry, xenograft tumor implantation","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 — MS-identified interaction, Co-IP, specific phosphorylation site, genetic epistasis with siRNA; single lab","pmids":["32372016"],"is_preprint":false},{"year":2013,"finding":"Netrin-1 mediates its protective effect against renal ischemia-reperfusion injury through UNC5B receptor expressed on leukocytes. Neutralization of UNC5B increases monocyte/neutrophil infiltration, cytokine production, and kidney injury, demonstrating UNC5B as the key receptor for netrin-1's anti-inflammatory signaling in this context.","method":"Neutralizing antibodies against UNC5B, siRNA knockdown, ischemia-reperfusion injury mouse model, cytokine measurements","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — antibody blockade plus siRNA with defined inflammatory phenotype; single lab","pmids":["20693423"],"is_preprint":false},{"year":2023,"finding":"FUT8 (fucosyltransferase 8) fucosylates UNC5B primarily in the endoplasmic reticulum; hypofucosylation of Unc5B by Fut8 reduction is associated with enhanced macrophage migration via inactivation of the p-CDC42/p-PAK pathway. Unc5b overexpression activates the p-CDC42/p-PAK pathway and decreases macrophage migration.","method":"Co-immunoprecipitation, siRNA/overexpression of Unc5b and Fut8, lectin pulldown for fucosylation, migration assays, ApoE−/− mouse model","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 — PTM (fucosylation) identified with writer (Fut8) and downstream signaling pathway; single lab","pmids":["36670464"],"is_preprint":false},{"year":2024,"finding":"FLRT3 expressed on cancer cells inhibits T cell activity through UNC5B, an axon guidance receptor upregulated on activated human T cells. FLRT3-UNC5B interaction functions as a T cell checkpoint; a monoclonal antibody blocking FLRT3-UNC5B interactions reverses immune suppression and inhibits tumor growth.","method":"Gain-of-function genetic screen, co-immunoprecipitation of FLRT3-UNC5B, blocking monoclonal antibody, CAR-T and BiTE + T cell killing assays, humanized cancer models","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 — unbiased genetic screen, Co-IP of interaction, antibody blocking with functional in vivo rescue; single lab","pmids":["38427724"],"is_preprint":false},{"year":2023,"finding":"Netrin-1-Unc5B signaling promotes blood-retina barrier integrity by enhancing phosphorylation of the Norrin receptor LRP5 via the intracellular scaffolding protein Dlg1, activating β-catenin-dependent BRB gene expression. Inducible deletion of Unc5B or Ntn1 reduces LRP5 phosphorylation and converts retinal endothelial cells to a leaky phenotype.","method":"Inducible loss- and gain-of-function alleles, tracer permeability assays, phospho-signaling studies, β-catenin gain-of-function rescue","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple genetic alleles with biochemical signaling readout; preprint, not yet peer reviewed","pmids":["36711611"],"is_preprint":true},{"year":2019,"finding":"Myosin X (Myo10) negatively regulates Unc5B cell-surface targeting in osteoclast-lineage cells; loss of Myo10 increases Unc5B cell-surface levels and enhances RANKL-induced osteoclastogenesis. Suppression of Unc5B in Myo10-mutant bone marrow macrophages impairs osteoclast genesis.","method":"Myo10 conditional knockout mouse, lentiviral Unc5b shRNA, cell-surface biotinylation, RANKL-induced osteoclast differentiation assays","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO and shRNA-mediated rescue with defined cellular phenotype; single lab","pmids":["30645777"],"is_preprint":false},{"year":2023,"finding":"FLRT2 directly interacts with UNC5B via its extracellular domain and activates Akt/mTOR signaling to drive monocyte-to-macrophage differentiation; myeloid-specific FLRT2 deletion impairs macrophage generation and function, and mTOR agonist reverses impaired phenotypes.","method":"Co-immunoprecipitation (FLRT2-UNC5B), gain/loss-of-function in THP-1 and human PBMCs, myeloid-specific conditional KO, mTOR agonist rescue","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding established by Co-IP, genetic KO with pharmacological rescue; single lab","pmids":["37090697"],"is_preprint":false},{"year":2024,"finding":"YAP induces UNC5B expression through TEAD DNA-binding partners (TEAD1/4); CRISPR screens link UNC5B to YAP-induced cytostasis in YAPoff cancers. UNC5B and Netrin-1 cooperate with integrin-αV/β5 to mediate this anti-proliferative effect; a YAP S94A mutation (disrupting TEAD binding) blocks UNC5B induction.","method":"CRISPR screen, TEAD1/4 loss-of-function, YAP S94A mutant, decoy receptor blocking, integrin KO assays","journal":"Cancer research communications","confidence":"Medium","confidence_rationale":"Tier 2 — unbiased CRISPR screen plus multiple genetic validations; single lab","pmids":["39172021"],"is_preprint":false}],"current_model":"UNC5B is a dependence receptor for netrin-1 whose cytoplasmic ZU5-UPA-death domain supramodule is held in an autoinhibited closed conformation; in the absence of netrin-1, this conformation is released, enabling recruitment of PP2A to dephosphorylate and activate DAP-kinase (via its death domain), interaction with CDC14A/p53 to drive G2/M arrest, and MST1-mediated phosphorylation at T428 to promote apoptosis, while netrin-1 binding recruits PIKE-L (activating PI3K-Akt survival signaling) and CIP2A (blocking PP2A), suppresses apoptosis, and in endothelial cells enhances UNC5B interaction with LRP6 to activate Wnt/β-catenin signaling and maintain vascular barrier integrity; additionally, UNC5B acts as a co-receptor with neogenin for RGMa/LARG/RhoA repulsive signaling, is repulsively activated by Robo4 to counteract VEGF signaling, and is functionally regulated by post-translational fucosylation (Fut8), alternative splicing (NOVA2/UNC5B-Δ8), and surface trafficking controlled by Myosin X."},"narrative":{"teleology":[{"year":2002,"claim":"Establishing that UNC5B has a signaling-competent cytoplasmic domain that directly engages heterotrimeric G proteins: the GTP-charged Gαi2 interacts with UNC5B's intracellular domain, sequestering it from adenylyl cyclase and modulating cAMP levels, revealing a first intracellular signaling partner.","evidence":"Co-immunoprecipitation and adenylyl cyclase activity assays in transfected cells","pmids":["12359238"],"confidence":"Medium","gaps":["Single lab, not independently confirmed","Physiological context for Gαi2–UNC5B interaction in vivo undefined","Relationship to netrin-dependent signaling not tested"]},{"year":2003,"claim":"Identifying UNC5B as a p53 transcriptional target and dependence receptor: UNC5B mediates p53-dependent apoptosis through its death domain, while netrin-1 binding suppresses this apoptosis, establishing the dependence receptor paradigm for UNC5B.","evidence":"Transcriptional reporter assays, siRNA knockdown, caspase cleavage assays, overexpression","pmids":["12598906"],"confidence":"High","gaps":["Identity of caspase(s) cleaving UNC5B not fully resolved","Structural basis for netrin-1-mediated suppression unknown at this point"]},{"year":2004,"claim":"Demonstrating that UNC5B is a repulsive netrin receptor required for vascular patterning: genetic disruption in mice and zebrafish showed aberrant tip cell navigation and vessel branching, establishing UNC5B as an endothelial guidance receptor.","evidence":"Mouse knockout and zebrafish morpholino knockdown with filopodial retraction assays","pmids":["15510105"],"confidence":"High","gaps":["Intracellular signaling pathway linking UNC5B to filopodial retraction not identified","Whether endothelial vs. non-endothelial UNC5B drives the phenotype was unresolved"]},{"year":2005,"claim":"Revealing the death-domain-mediated mechanism of pro-apoptotic signaling: UNC5B physically recruits DAP-kinase via death domain interaction and activates it by reducing Ser308 autophosphorylation in the absence of netrin-1, providing the first enzymatic effector of UNC5B-induced apoptosis.","evidence":"Reciprocal Co-IP in cell culture and embryonic mouse brain, DAP-kinase knockout MEFs, kinase assays","pmids":["15729359"],"confidence":"High","gaps":["How the death domain interaction triggers DAP-kinase dephosphorylation mechanistically was unclear","Whether PP2A is involved was not yet known"]},{"year":2006,"claim":"Structural characterization of the UNC5B death domain revealed a six-helix bundle that homodimerizes, suggesting a conformational switch model for ligand-dependent regulation of caspase access.","evidence":"X-ray crystallography at 2.1 Å with solution-state oligomerization analysis","pmids":["17139086"],"confidence":"Medium","gaps":["Functional significance of dimerization not directly tested","Full-length cytoplasmic domain structure not yet available"]},{"year":2007,"claim":"Establishing that the UNC5B intracellular domain is required for repulsive signaling: a truncated UNC5B lacking the cytoplasmic domain fails to induce endothelial repulsion, confirming signal transduction rather than passive ligand sequestration.","evidence":"Truncation mutants, genetic UNC5B knockout, Matrigel and tumor angiogenesis assays","pmids":["17908930"],"confidence":"High","gaps":["Specific intracellular domains (ZU5, UPA, DD) not individually tested","Downstream effectors of repulsive signaling in endothelial cells not identified"]},{"year":2008,"claim":"Three parallel advances defined UNC5B's vascular, survival, and co-receptor functions: endothelial-specific deletion proved autonomous vascular roles in placental labyrinth; netrin-1 was shown to recruit PIKE-L via Fyn to activate PI3K survival signaling; and netrin-4 was found to recruit UNC5B through neogenin as a co-receptor complex on endothelial cells.","evidence":"Endothelium-specific conditional KO mice; Fyn-null embryos with Co-IP and PI3K assays; neogenin–UNC5B Co-IP with siRNA epistasis","pmids":["18223200","18469807","18719102"],"confidence":"High","gaps":["Whether PIKE-L functions in endothelial cells (vs. neurons only) was not tested","Structural basis of neogenin–UNC5B co-receptor assembly unknown"]},{"year":2009,"claim":"A structural and mechanistic watershed: the crystal structure of the ZU5-UPA-death domain supramodule revealed an autoinhibited closed conformation, while parallel work showed UNC5B acts as a neogenin co-receptor for RGMa via LARG/RhoA in growth cone collapse, and FLRT3 was identified as a UNC5B ligand mediating cell de-adhesion via Rnd1.","evidence":"Crystal structure with mutagenesis and functional assays; Co-IP of neogenin-UNC5B-LARG with RhoA activation and growth cone collapse; FLRT3-UNC5B Co-IP with Rnd1 epistasis in Xenopus","pmids":["19328064","19273616","19492039"],"confidence":"High","gaps":["How netrin-1 binding triggers conformational change from closed to open state not structurally resolved","Relative contributions of FLRT3 vs. netrin-1 to UNC5B activation in vivo unclear"]},{"year":2010,"claim":"Completing the apoptotic signaling circuit: an siRNA screen identified PP2A (PR65β) as the phosphatase recruited by UNC5B to dephosphorylate and activate DAP-kinase, while netrin-1 binding recruits the PP2A inhibitor CIP2A, providing a full ligand-dependent switch mechanism.","evidence":"siRNA screen, PP2A activity assays, DAPk phosphorylation, UNC5B Co-IP with PP2A and CIP2A","pmids":["21172653"],"confidence":"High","gaps":["Whether CIP2A competes with PP2A for the same binding site on UNC5B not determined","In vivo relevance of CIP2A recruitment not validated genetically"]},{"year":2011,"claim":"Robo4 was identified as a UNC5B-binding partner that maintains vascular integrity by counteracting VEGF signaling, expanding UNC5B's ligand repertoire beyond netrins and FLRTs; separately, UNC5B was shown to act as a brake on peripheral nerve regeneration in Schwann cells.","evidence":"Protein-protein interaction screen, function-blocking antibodies, Robo4−/− rescue; in vivo siRNA with nerve regeneration quantification","pmids":["21238923","21656855"],"confidence":"High","gaps":["Intracellular pathway linking Robo4–UNC5B to VEGF signal inhibition not fully resolved","How DCC-UNC5B reciprocal regulation occurs in Schwann cells mechanistically unclear"]},{"year":2016,"claim":"UNC5B's dynamic membrane trafficking was visualized: netrin-1 induces Src-dependent recruitment of UNC5B from intracellular clusters to the plasma membrane, where it heterooligomerizes with DCC, revealing surface delivery as a regulated step.","evidence":"Live-cell TIRF microscopy and temporal image cross-correlation spectroscopy with Src kinase inhibitors","pmids":["26840727"],"confidence":"Medium","gaps":["Stoichiometry of DCC–UNC5B heterooligomers undefined","Whether trafficking regulation occurs in endothelial cells (not just neurons) untested"]},{"year":2017,"claim":"FLRT2 was established as a physiological UNC5B ligand in placental endothelium: endothelial-specific FLRT2 deletion phenocopied UNC5B vascular defects, confirming FLRT-UNC5B repulsion shapes feto-maternal circulation.","evidence":"Endothelial-specific FLRT2 conditional knockout with histological and physiological vascular analysis","pmids":["28576770"],"confidence":"Medium","gaps":["Whether FLRT2 and netrin-1 compete for UNC5B binding not tested","Intracellular signaling downstream of FLRT2–UNC5B in endothelial cells not characterized"]},{"year":2019,"claim":"Myosin X was identified as a negative regulator of UNC5B surface expression in osteoclast-lineage cells, linking UNC5B trafficking to osteoclastogenesis via RANKL signaling.","evidence":"Myo10 conditional knockout, cell-surface biotinylation, Unc5b shRNA rescue, osteoclast differentiation assays","pmids":["30645777"],"confidence":"Medium","gaps":["Mechanism by which Myo10 retains UNC5B intracellularly not identified","Whether Myo10 regulation of UNC5B occurs in other cell types unknown"]},{"year":2020,"claim":"Three studies expanded UNC5B functions: MST1 was shown to phosphorylate UNC5B-T428 to activate apoptosis in dopaminergic neurons under netrin-1 deficiency; UNC5B-CDC14A interaction was found to dephosphorylate p53-Ser315 causing G2/M arrest in bladder cancer; and UNC5B was placed as a receptor balancing Wnt and MAPK signaling in naive pluripotency.","evidence":"MST1–UNC5B Co-IP with phospho-site mapping and UNC5B KO rescue in PD model; mass spectrometry-identified CDC14A–UNC5B interaction with cell cycle analysis; receptor overexpression/knockdown with phospho-protein assays in mESCs","pmids":["32929029","32372016","32231305"],"confidence":"Medium","gaps":["Whether T428 phosphorylation disrupts the ZU5-UPA-DD closed conformation not tested structurally","CDC14A–UNC5B interaction validated only in bladder cancer cells","In vivo relevance of UNC5B in pluripotency maintenance not demonstrated"]},{"year":2021,"claim":"An endothelial-specific splice variant UNC5B-Δ8, generated by NOVA2-mediated exon-8 skipping, was shown to be constitutively pro-apoptotic and netrin-1-insensitive, revealing that alternative splicing provides a ligand-independent activation mechanism for vessel remodeling.","evidence":"Isoform identification, NOVA2 knockdown, endothelial-specific expression, apoptosis and vascular development assays","pmids":["34381052"],"confidence":"Medium","gaps":["How exon-8 loss affects ZU5-UPA-DD supramodule conformation not structurally resolved","Whether UNC5B-Δ8 is expressed outside endothelium not surveyed"]},{"year":2022,"claim":"UNC5B was established as a critical maintainer of blood-brain barrier integrity via Wnt/β-catenin signaling: netrin-1 enhances UNC5B–LRP6 interaction, phosphorylates LRP6, activates β-catenin, and maintains Claudin-5 expression, with inducible UNC5B deletion causing BBB leak.","evidence":"Inducible endothelial-specific Unc5B knockout, β-catenin gain-of-function rescue, UNC5B–LRP6 Co-IP, antibody blocking, tracer permeability","pmids":["35246514"],"confidence":"High","gaps":["Whether UNC5B directly binds LRP6 or requires an adaptor not resolved","Downstream mechanism connecting UNC5B to LRP6 phosphorylation (kinase identity) not identified"]},{"year":2023,"claim":"Three studies expanded UNC5B's roles in immune and metabolic regulation: FUT8-mediated fucosylation of UNC5B in the ER was shown to regulate macrophage migration via CDC42/PAK; FLRT2–UNC5B interaction was found to drive monocyte-to-macrophage differentiation via Akt/mTOR; and netrin-1–UNC5B was shown to promote blood-retina barrier integrity through LRP5/Dlg1/β-catenin signaling.","evidence":"FUT8–UNC5B Co-IP with lectin pulldown and ApoE−/− mouse model; FLRT2–UNC5B Co-IP with myeloid-specific KO and mTOR agonist rescue; inducible genetic alleles with phospho-signaling and tracer permeability (preprint)","pmids":["36670464","37090697","36711611"],"confidence":"Medium","gaps":["Specific fucosylation sites on UNC5B not mapped","Whether FLRT2–UNC5B and netrin-1–UNC5B signaling converge on shared Akt/mTOR intermediates unknown","Blood-retina barrier study is a preprint awaiting peer review"]},{"year":2024,"claim":"UNC5B was identified as an immune checkpoint receptor on T cells and a YAP-TEAD effector in cancer: FLRT3 on tumor cells engages UNC5B on activated T cells to suppress anti-tumor immunity, while YAP-TEAD transcriptionally induces UNC5B to mediate cytostasis cooperatively with netrin-1 and integrin-αV/β5.","evidence":"Genetic screens (gain-of-function for FLRT3–UNC5B; CRISPR for YAP–UNC5B), blocking antibodies, CAR-T killing assays, TEAD-binding mutants","pmids":["38427724","39172021"],"confidence":"Medium","gaps":["UNC5B intracellular signaling in T cells upon FLRT3 engagement not characterized","Whether YAP–UNC5B cytostasis operates through the canonical death-domain apoptotic pathway unknown","In vivo validation of FLRT3–UNC5B checkpoint blockade in immunocompetent tumor models limited"]},{"year":null,"claim":"Key unresolved questions include: how netrin-1 binding triggers the ZU5-UPA-DD conformational transition at atomic resolution; whether the multiple UNC5B ligands (netrin-1, Robo4, FLRT2/3, RGMa/neogenin) engage distinct or overlapping intracellular effector complexes; the physiological significance of UNC5B's immune checkpoint function in human cancer; and whether therapeutic targeting of UNC5B can selectively modulate barrier integrity without compromising its apoptotic tumor-suppressive role.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length ectodomain–ligand co-crystal structure available","Ligand competition and hierarchy at UNC5B not systematically tested","No clinical data on anti-UNC5B or anti-FLRT3 checkpoint therapy"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3,11,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,10,24]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,10,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,11,16,29]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[26]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,2,5,10,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,11,20,22,31]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,4,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[25,27]}],"complexes":[],"partners":["DAPK","LRP6","PIKE-L","NEOGENIN","ROBO4","FLRT3","FLRT2","CIP2A"],"other_free_text":[]},"mechanistic_narrative":"UNC5B is a transmembrane dependence receptor for netrin-1 that functions as a central integrator of apoptotic, repulsive, and vascular integrity signaling in endothelial cells, neurons, and immune cells. In the absence of netrin-1, its cytoplasmic ZU5-UPA-death domain supramodule adopts an open conformation that recruits PP2A to dephosphorylate and activate DAP-kinase, and permits MST1-mediated phosphorylation at T428, both driving apoptosis; netrin-1 binding closes this supramodule, recruits PIKE-L to activate PI3K-Akt survival signaling, and recruits the PP2A inhibitor CIP2A to block DAP-kinase activation [PMID:19328064, PMID:21172653, PMID:15729359, PMID:18469807, PMID:32929029]. UNC5B also serves as an endothelial guidance receptor that mediates repulsive signaling downstream of netrin-1, Robo4, and FLRT2/3, controls sprouting angiogenesis, and maintains blood-brain and blood-retina barrier integrity by enhancing Wnt/β-catenin signaling through interaction with the co-receptor LRP6 [PMID:15510105, PMID:21238923, PMID:35246514, PMID:28576770]. Beyond vascular biology, UNC5B acts as a co-receptor with neogenin for RGMa/LARG/RhoA repulsive signaling in growth cone collapse, mediates anti-inflammatory netrin-1 signaling on leukocytes, functions as an immune checkpoint receptor for FLRT3 on T cells, and drives CDC14A/p53-dependent G2/M arrest in cancer cells [PMID:19273616, PMID:20693423, PMID:38427724, PMID:32372016]."},"prefetch_data":{"uniprot":{"accession":"Q8IZJ1","full_name":"Netrin receptor UNC5B","aliases":["Protein unc-5 homolog 2","Protein unc-5 homolog B","p53-regulated receptor for death and life protein 1","p53RDL1"],"length_aa":945,"mass_kda":103.6,"function":"Receptor for netrin required for axon guidance. Mediates axon repulsion of neuronal growth cones in the developing nervous system upon ligand binding. Axon repulsion in growth cones may be caused by its association with DCC that may trigger signaling for repulsion (By similarity). Functions as a netrin receptor that negatively regulates vascular branching during angiogenesis. Mediates retraction of tip cell filopodia on endothelial growth cones in response to netrin (By similarity). It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand (PubMed:12598906). Mediates apoptosis by activating DAPK1. In the absence of NTN1, activates DAPK1 by reducing its autoinhibitory phosphorylation at Ser-308 thereby increasing its catalytic activity (By similarity)","subcellular_location":"Cell membrane; Membrane raft","url":"https://www.uniprot.org/uniprotkb/Q8IZJ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UNC5B","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UNC5B","total_profiled":1310},"omim":[{"mim_id":"610643","title":"CELL PROLIFERATION-REGULATING INHIBITOR OF PROTEIN PHOSPHATASE 2A; CIP2A","url":"https://www.omim.org/entry/610643"},{"mim_id":"607870","title":"UNC5 NETRIN RECEPTOR B; UNC5B","url":"https://www.omim.org/entry/607870"},{"mim_id":"607869","title":"UNC5 NETRIN RECEPTOR A; UNC5A","url":"https://www.omim.org/entry/607869"},{"mim_id":"603610","title":"UNC5 NETRIN RECEPTOR C; UNC5C","url":"https://www.omim.org/entry/603610"},{"mim_id":"602782","title":"HISTIOCYTOSIS-LYMPHADENOPATHY PLUS SYNDROME","url":"https://www.omim.org/entry/602782"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UNC5B"},"hgnc":{"alias_symbol":["UNC5H2","p53RDL1"],"prev_symbol":[]},"alphafold":{"accession":"Q8IZJ1","domains":[{"cath_id":"2.60.40.10","chopping":"50-149","consensus_level":"high","plddt":89.5223,"start":50,"end":149},{"cath_id":"2.60.40.10","chopping":"151-245","consensus_level":"medium","plddt":93.0039,"start":151,"end":245},{"cath_id":"-","chopping":"249-287","consensus_level":"medium","plddt":91.0197,"start":249,"end":287},{"cath_id":"2.60.220.30","chopping":"545-689","consensus_level":"medium","plddt":90.3388,"start":545,"end":689},{"cath_id":"2.60.40.10","chopping":"693-828","consensus_level":"high","plddt":92.5668,"start":693,"end":828},{"cath_id":"1.10.533.10","chopping":"857-945","consensus_level":"medium","plddt":84.0454,"start":857,"end":945}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZJ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZJ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZJ1-F1-predicted_aligned_error_v6.png","plddt_mean":76.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UNC5B","jax_strain_url":"https://www.jax.org/strain/search?query=UNC5B"},"sequence":{"accession":"Q8IZJ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IZJ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IZJ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZJ1"}},"corpus_meta":[{"pmid":"15510105","id":"PMC_15510105","title":"The 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surgery]","url":"https://pubmed.ncbi.nlm.nih.gov/20092749","citation_count":4,"is_preprint":false},{"pmid":"36939874","id":"PMC_36939874","title":"Investigation of dynamic solution interactions between NET-1 and UNC-5B by multi-wavelength analytical ultracentrifugation.","date":"2023","source":"European biophysics journal : EBJ","url":"https://pubmed.ncbi.nlm.nih.gov/36939874","citation_count":3,"is_preprint":false},{"pmid":"39722317","id":"PMC_39722317","title":"Unc5b prevents macrophage-derived foam cell migration and promotes atherosclerotic development via the P53-cuproptosis signaling pathway.","date":"2024","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39722317","citation_count":3,"is_preprint":false},{"pmid":"39172021","id":"PMC_39172021","title":"Netrin-1 and UNC5B Cooperate with Integrins to Mediate YAP-Driven Cytostasis.","date":"2024","source":"Cancer research 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ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41072782","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52018,"output_tokens":7547,"usd":0.13463},"stage2":{"model":"claude-opus-4-6","input_tokens":11330,"output_tokens":5073,"usd":0.275213},"total_usd":0.409843,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","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 tip cell filopodia extension, excessive vessel branching, and abnormal navigation. Netrin-1 causes endothelial filopodial retraction only when UNC5B is present.\",\n      \"method\": \"Mouse knockout, zebrafish morpholino knockdown, in vitro filopodial retraction assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function in two species with defined cellular phenotype, replicated across organisms\",\n      \"pmids\": [\"15510105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"UNC5B (p53RDL1) is a direct transcriptional target of p53 and mediates p53-dependent apoptosis through its cytoplasmic death domain. Netrin-1 binding to UNC5B blocks p53-dependent apoptosis, and caspase cleavage of UNC5B is associated with cell death.\",\n      \"method\": \"Transcriptional reporter assays, overexpression, siRNA knockdown, caspase cleavage assays, co-immunoprecipitation\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in single rigorous paper, foundational discovery\",\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 through their respective death domains. In the absence of netrin-1, UNC5H2 reduces DAP-kinase autophosphorylation on Ser308 and increases its catalytic (pro-apoptotic) activity; netrin-1 binding to UNC5H2 blocks this DAP-kinase activation.\",\n      \"method\": \"Co-immunoprecipitation in cell culture and embryonic mouse brain, dominant-negative mutants, DAP-kinase knockout MEFs, kinase activity assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP in vivo and in vitro, genetic rescue with knockout MEFs, kinase activity measurement\",\n      \"pmids\": [\"15729359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"UNC5B activation by netrin-1 inhibits sprouting angiogenesis; a truncated UNC5B lacking the intracellular signaling domain fails to induce endothelial cell repulsion, demonstrating that the intracellular domain is required for repulsive signaling.\",\n      \"method\": \"Loss-of-function (genetic unc5b knockout), truncation mutants, Matrigel/tumor angiogenesis assays, in vitro repulsion assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with defined phenotype plus domain-deletion mechanistic follow-up\",\n      \"pmids\": [\"17908930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Endothelial-specific deletion of UNC5B causes a specific structural and functional deficiency in arterioles of the placental labyrinth leading to flow reversal in the umbilical artery and embryonic death, demonstrating UNC5B mediates autonomous pro-angiogenic signaling in the fetal-placental vasculature.\",\n      \"method\": \"Endothelium-specific conditional knockout mouse, zebrafish unc5b morpholino knockdown, physiological blood flow analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with defined vascular phenotype, replicated in zebrafish\",\n      \"pmids\": [\"18223200\"],\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, preventing UNC5B's pro-apoptotic activity, and enhancing neuronal survival. This interaction requires Fyn-mediated tyrosine phosphorylation of PIKE-L.\",\n      \"method\": \"Co-immunoprecipitation, Fyn-null mouse embryos, PI3K assay, apoptosis assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genetic (Fyn-null) validation, PI3K activity measurement\",\n      \"pmids\": [\"18469807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Netrin-4 binds to neogenin (not directly to UNC5B) and recruits UNC5B via neogenin; co-immunoprecipitation showed Netrin-4 increases association between UNC5B and neogenin on endothelial cells. Silencing either neogenin or UNC5B abolishes Netrin-4 inhibitory effects on endothelial migration.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, endothelial migration/tube formation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus siRNA epistasis with defined cellular readout\",\n      \"pmids\": [\"18719102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structure of the UNC5B cytoplasmic domain reveals three folded domains (ZU5, UPA, death domain) forming a supramodule in which ZU5 binds both UPA and DD, locking the receptor in a closed autoinhibited conformation. Release of this closed conformation activates apoptotic and vascular patterning functions.\",\n      \"method\": \"Crystal structure determination, mutagenesis, functional apoptosis and vascular patterning assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional mutagenesis validation in a single rigorous study\",\n      \"pmids\": [\"19328064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"UNC5B interacts with neogenin as a co-receptor for repulsive guidance molecule A (RGMa), and recruits leukemia-associated guanine nucleotide exchange factor (LARG) to transduce RhoA signaling. FAK mediates RGMa-induced tyrosine phosphorylation of LARG and subsequent RhoA activation leading to growth cone collapse.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative mutants, RhoA activation assay, growth cone collapse assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple Co-IP, biochemical RhoA assay, functional growth cone readout\",\n      \"pmids\": [\"19273616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"UNC5B (Unc5B) interacts with FLRT3 through high-affinity binding; both proteins synergize to induce cell de-adhesion in Xenopus embryos. The small GTPase Rnd1 physically and functionally interacts with UNC5B and mediates its effect on cell adhesion.\",\n      \"method\": \"Expression screen, co-immunoprecipitation, morpholino knockdown, overexpression in Xenopus embryos\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — protein-protein interaction with Co-IP, genetic epistasis by morpholino, functional readout in vivo\",\n      \"pmids\": [\"19492039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UNC5H2/B recruits a protein complex containing the PP2A structural subunit PR65β and DAPk. PP2A dephosphorylates and activates DAPk to promote apoptosis in the absence of netrin-1. Netrin-1 binding recruits the PP2A inhibitor CIP2A to UNC5H2/B, blocking this mechanism.\",\n      \"method\": \"siRNA screen, co-immunoprecipitation, PP2A activity assay, DAPk phosphorylation assay, angiogenesis assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — siRNA screen followed by biochemical reconstitution of PP2A-DAPk complex on UNC5B, mechanistically rigorous\",\n      \"pmids\": [\"21172653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Robo4 specifically binds to UNC5B extracellular domain (identified by protein-protein interaction screen). Robo4-UNC5B signaling maintains vascular integrity by inhibiting signaling downstream of VEGF. Function-blocking antibodies against either Robo4 or UNC5B increase angiogenesis and disrupt vessel integrity.\",\n      \"method\": \"Protein-protein interaction screen, function-blocking monoclonal antibodies, Robo4−/− mouse rescue experiments\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased interaction screen plus in vivo genetic and antibody rescue experiments with defined vascular phenotype\",\n      \"pmids\": [\"21238923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The constitutively active Gαi2 (gip2) interacts with the cytoplasmic domain of UNC5B (UNC5H2) specifically when charged with GTP. This interaction sequesters Gαi2 from adenylyl cyclase, relieving inhibition and increasing intracellular cAMP levels.\",\n      \"method\": \"Co-immunoprecipitation, adenylyl cyclase activity assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical pulldown with adenylyl cyclase functional assay, single lab\",\n      \"pmids\": [\"12359238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In Schwann cells, DCC promotes SC outgrowth while UNC5B (Unc5H2) inhibits it following nerve injury; local Unc5H2 knockdown at the injury site facilitates axon regrowth. Forced DCC inhibition causes reciprocal upregulation of Unc5H2, placing UNC5B as an intrinsic brake to peripheral nerve regeneration downstream of DCC.\",\n      \"method\": \"In vivo siRNA knockdown, immunolocalization, axon regeneration quantification\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo siRNA with functional nerve regeneration readout; epistatic relationship inferred but not fully reconstituted\",\n      \"pmids\": [\"21656855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Akt phosphorylates PIKE-A on Ser-472 and enhances PIKE-A's interaction with UNC5B; overexpression of PIKE-A diminishes UNC5B expression by downregulating p53, while PIKE-A knockout stabilizes p53 and increases UNC5B, thereby escalating UV-triggered apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, kinase assays, PIKE−/− MEFs, siRNA, overexpression, apoptosis assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods, genetic PIKE-KO cells, but single lab\",\n      \"pmids\": [\"21460185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Netrin-4 binding to the Unc5B receptor and subsequent activation of tyrosine phosphatase SHP2 mediates Netrin-4-induced pain signaling (spinal sensitization) in the dorsal horn. Transient suppression of Netrin-4 or Unc5B prevents allodynia after peripheral nerve injury.\",\n      \"method\": \"Netrin-4-mutant rats, intrathecal netrin-4 injection, siRNA knockdown, electrophysiology, behavioral pain tests\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic mutant plus in vivo siRNA and pharmacological approach with defined behavioral and electrophysiological phenotype\",\n      \"pmids\": [\"27856613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Netrin-1-induced recruitment of DCC and UNC5B to the plasma membrane from preexisting intracellular clusters was observed by live-cell imaging; this requires netrin-1-activated Src family kinase signaling. Netrin-1 also induced co-localization and heterooligomerization of co-expressed DCC and UNC5B at the plasma membrane.\",\n      \"method\": \"Live-cell TIRF microscopy, temporal image cross-correlation spectroscopy (TICCS), pharmacological Src kinase inhibition\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative live-cell imaging with pharmacological validation, single lab but multiple orthogonal imaging methods\",\n      \"pmids\": [\"26840727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The crystal structure of the UNC5H2 (UNC5B) death domain at 2.1 Å resolution reveals a six-helix bundle fold; the domain forms a homodimer in crystal and solution, which may represent the netrin-1-bound state and could block caspase access to its cleavage site.\",\n      \"method\": \"X-ray crystallography, solution state analysis\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure, but functional validation of dimer blocking caspase is inferred not directly tested\",\n      \"pmids\": [\"17139086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FLRT2 expressed in placental labyrinth endothelial cells binds UNC5B and mediates inter-endothelial repulsion; endothelial-specific FLRT2 deletion causes aberrant endothelial alignment and disrupted feto-maternal circulation, phenocopying UNC5B-mediated repulsion.\",\n      \"method\": \"Endothelial-specific conditional knockout mouse, in vitro binding assays, histological and physiological vascular analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined vascular phenotype attributed to UNC5B-FLRT2 binding, single study\",\n      \"pmids\": [\"28576770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Netrin-1 deficiency in Parkinson's disease activates MST1, which selectively binds and phosphorylates UNC5B on T428, promoting its apoptotic activation and dopaminergic neuronal loss. Knockout of UNC5B abolishes netrin depletion-induced dopaminergic loss; blockade of MST1-phosphorylating UNC5B suppresses neuronal apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, site-specific phosphorylation assays, UNC5B knockout mice, human PD brain samples\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — specific phosphorylation site identified, genetic KO rescue, human tissue validation; single lab\",\n      \"pmids\": [\"32929029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Netrin-1 promotes naive pluripotency by inducing FAK kinase to inactivate Gsk3α/β (stabilizing β-catenin) and by activating a Ppp2r2c-containing PP2A complex to reduce Erk1/2 activity, with the balance of Unc5B vs Neo1 receptor expression co-regulating these Wnt and MAPK pathway outputs.\",\n      \"method\": \"Chemical inhibition, receptor overexpression and knockdown, phospho-protein assays, mESC self-renewal assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pathway assays and receptor balancing experiments; complex phenotype but single lab\",\n      \"pmids\": [\"32231305\"],\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\": \"Identification of splicing isoform, NOVA2 knockdown, endothelial-specific isoform expression, apoptosis assays, in vivo vascular development analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isoform characterization with functional rescue and in vivo validation; single lab\",\n      \"pmids\": [\"34381052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Endothelial UNC5B controls blood-brain barrier integrity by maintaining Wnt/β-catenin signaling. Netrin-1 enhances UNC5B interaction with the Wnt co-receptor LRP6, induces LRP6 phosphorylation, and activates downstream Wnt/β-catenin signaling, maintaining Claudin-5 expression and repressing PLVAP. Inducible endothelial deletion of Unc5B causes BBB leak.\",\n      \"method\": \"Inducible endothelial-specific Unc5B knockout, β-catenin gain-of-function rescue, co-immunoprecipitation of UNC5B-LRP6, antibody blocking of Netrin-1 binding, tracer permeability assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — inducible KO with genetic rescue, biochemical UNC5B-LRP6 interaction, antibody blocking, multiple orthogonal methods\",\n      \"pmids\": [\"35246514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Notch signaling rapidly upregulates UNC5B in endothelial cells; UNC5B mediates specific Notch-regulated phenotypes including inhibition of endothelial migration and proliferation and stabilization of endothelial junctions in response to shear stress. Endothelial-specific loss of UNC5B leads to excessive retinal vascularization.\",\n      \"method\": \"Unbiased translated mRNA screen, endothelial-specific UNC5B conditional knockout, gain-of-function, junction stability assays under shear stress\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — unbiased screen plus conditional KO with multiple defined endothelial phenotypes; single lab\",\n      \"pmids\": [\"38866944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UNC5B inhibits bladder cancer cell G2/M phase arrest by binding to CDC14A and p53; UNC5B-CDC14A interaction dephosphorylates p53 at Ser-315, reducing cyclin B1 expression and increasing p-CDK1, thereby causing G2/M arrest. Knockdown of CDC14A suppresses this arrest.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, site-specific phosphorylation assays, siRNA knockdown, flow cytometry, xenograft tumor implantation\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS-identified interaction, Co-IP, specific phosphorylation site, genetic epistasis with siRNA; single lab\",\n      \"pmids\": [\"32372016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Netrin-1 mediates its protective effect against renal ischemia-reperfusion injury through UNC5B receptor expressed on leukocytes. Neutralization of UNC5B increases monocyte/neutrophil infiltration, cytokine production, and kidney injury, demonstrating UNC5B as the key receptor for netrin-1's anti-inflammatory signaling in this context.\",\n      \"method\": \"Neutralizing antibodies against UNC5B, siRNA knockdown, ischemia-reperfusion injury mouse model, cytokine measurements\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — antibody blockade plus siRNA with defined inflammatory phenotype; single lab\",\n      \"pmids\": [\"20693423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FUT8 (fucosyltransferase 8) fucosylates UNC5B primarily in the endoplasmic reticulum; hypofucosylation of Unc5B by Fut8 reduction is associated with enhanced macrophage migration via inactivation of the p-CDC42/p-PAK pathway. Unc5b overexpression activates the p-CDC42/p-PAK pathway and decreases macrophage migration.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/overexpression of Unc5b and Fut8, lectin pulldown for fucosylation, migration assays, ApoE−/− mouse model\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — PTM (fucosylation) identified with writer (Fut8) and downstream signaling pathway; single lab\",\n      \"pmids\": [\"36670464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FLRT3 expressed on cancer cells inhibits T cell activity through UNC5B, an axon guidance receptor upregulated on activated human T cells. FLRT3-UNC5B interaction functions as a T cell checkpoint; a monoclonal antibody blocking FLRT3-UNC5B interactions reverses immune suppression and inhibits tumor growth.\",\n      \"method\": \"Gain-of-function genetic screen, co-immunoprecipitation of FLRT3-UNC5B, blocking monoclonal antibody, CAR-T and BiTE + T cell killing assays, humanized cancer models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — unbiased genetic screen, Co-IP of interaction, antibody blocking with functional in vivo rescue; single lab\",\n      \"pmids\": [\"38427724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Netrin-1-Unc5B signaling promotes blood-retina barrier integrity by enhancing phosphorylation of the Norrin receptor LRP5 via the intracellular scaffolding protein Dlg1, activating β-catenin-dependent BRB gene expression. Inducible deletion of Unc5B or Ntn1 reduces LRP5 phosphorylation and converts retinal endothelial cells to a leaky phenotype.\",\n      \"method\": \"Inducible loss- and gain-of-function alleles, tracer permeability assays, phospho-signaling studies, β-catenin gain-of-function rescue\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic alleles with biochemical signaling readout; preprint, not yet peer reviewed\",\n      \"pmids\": [\"36711611\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Myosin X (Myo10) negatively regulates Unc5B cell-surface targeting in osteoclast-lineage cells; loss of Myo10 increases Unc5B cell-surface levels and enhances RANKL-induced osteoclastogenesis. Suppression of Unc5B in Myo10-mutant bone marrow macrophages impairs osteoclast genesis.\",\n      \"method\": \"Myo10 conditional knockout mouse, lentiviral Unc5b shRNA, cell-surface biotinylation, RANKL-induced osteoclast differentiation assays\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO and shRNA-mediated rescue with defined cellular phenotype; single lab\",\n      \"pmids\": [\"30645777\"],\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 drive monocyte-to-macrophage differentiation; myeloid-specific FLRT2 deletion impairs macrophage generation and function, and mTOR agonist reverses impaired phenotypes.\",\n      \"method\": \"Co-immunoprecipitation (FLRT2-UNC5B), gain/loss-of-function in THP-1 and human PBMCs, myeloid-specific conditional KO, mTOR agonist rescue\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding established by Co-IP, genetic KO with pharmacological rescue; single lab\",\n      \"pmids\": [\"37090697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YAP induces UNC5B expression through TEAD DNA-binding partners (TEAD1/4); CRISPR screens link UNC5B to YAP-induced cytostasis in YAPoff cancers. UNC5B and Netrin-1 cooperate with integrin-αV/β5 to mediate this anti-proliferative effect; a YAP S94A mutation (disrupting TEAD binding) blocks UNC5B induction.\",\n      \"method\": \"CRISPR screen, TEAD1/4 loss-of-function, YAP S94A mutant, decoy receptor blocking, integrin KO assays\",\n      \"journal\": \"Cancer research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — unbiased CRISPR screen plus multiple genetic validations; single lab\",\n      \"pmids\": [\"39172021\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UNC5B is a dependence receptor for netrin-1 whose cytoplasmic ZU5-UPA-death domain supramodule is held in an autoinhibited closed conformation; in the absence of netrin-1, this conformation is released, enabling recruitment of PP2A to dephosphorylate and activate DAP-kinase (via its death domain), interaction with CDC14A/p53 to drive G2/M arrest, and MST1-mediated phosphorylation at T428 to promote apoptosis, while netrin-1 binding recruits PIKE-L (activating PI3K-Akt survival signaling) and CIP2A (blocking PP2A), suppresses apoptosis, and in endothelial cells enhances UNC5B interaction with LRP6 to activate Wnt/β-catenin signaling and maintain vascular barrier integrity; additionally, UNC5B acts as a co-receptor with neogenin for RGMa/LARG/RhoA repulsive signaling, is repulsively activated by Robo4 to counteract VEGF signaling, and is functionally regulated by post-translational fucosylation (Fut8), alternative splicing (NOVA2/UNC5B-Δ8), and surface trafficking controlled by Myosin X.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"UNC5B is a transmembrane dependence receptor for netrin-1 that functions as a central integrator of apoptotic, repulsive, and vascular integrity signaling in endothelial cells, neurons, and immune cells. In the absence of netrin-1, its cytoplasmic ZU5-UPA-death domain supramodule adopts an open conformation that recruits PP2A to dephosphorylate and activate DAP-kinase, and permits MST1-mediated phosphorylation at T428, both driving apoptosis; netrin-1 binding closes this supramodule, recruits PIKE-L to activate PI3K-Akt survival signaling, and recruits the PP2A inhibitor CIP2A to block DAP-kinase activation [PMID:19328064, PMID:21172653, PMID:15729359, PMID:18469807, PMID:32929029]. UNC5B also serves as an endothelial guidance receptor that mediates repulsive signaling downstream of netrin-1, Robo4, and FLRT2/3, controls sprouting angiogenesis, and maintains blood-brain and blood-retina barrier integrity by enhancing Wnt/β-catenin signaling through interaction with the co-receptor LRP6 [PMID:15510105, PMID:21238923, PMID:35246514, PMID:28576770]. Beyond vascular biology, UNC5B acts as a co-receptor with neogenin for RGMa/LARG/RhoA repulsive signaling in growth cone collapse, mediates anti-inflammatory netrin-1 signaling on leukocytes, functions as an immune checkpoint receptor for FLRT3 on T cells, and drives CDC14A/p53-dependent G2/M arrest in cancer cells [PMID:19273616, PMID:20693423, PMID:38427724, PMID:32372016].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that UNC5B has a signaling-competent cytoplasmic domain that directly engages heterotrimeric G proteins: the GTP-charged Gαi2 interacts with UNC5B's intracellular domain, sequestering it from adenylyl cyclase and modulating cAMP levels, revealing a first intracellular signaling partner.\",\n      \"evidence\": \"Co-immunoprecipitation and adenylyl cyclase activity assays in transfected cells\",\n      \"pmids\": [\"12359238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not independently confirmed\", \"Physiological context for Gαi2–UNC5B interaction in vivo undefined\", \"Relationship to netrin-dependent signaling not tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying UNC5B as a p53 transcriptional target and dependence receptor: UNC5B mediates p53-dependent apoptosis through its death domain, while netrin-1 binding suppresses this apoptosis, establishing the dependence receptor paradigm for UNC5B.\",\n      \"evidence\": \"Transcriptional reporter assays, siRNA knockdown, caspase cleavage assays, overexpression\",\n      \"pmids\": [\"12598906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of caspase(s) cleaving UNC5B not fully resolved\", \"Structural basis for netrin-1-mediated suppression unknown at this point\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that UNC5B is a repulsive netrin receptor required for vascular patterning: genetic disruption in mice and zebrafish showed aberrant tip cell navigation and vessel branching, establishing UNC5B as an endothelial guidance receptor.\",\n      \"evidence\": \"Mouse knockout and zebrafish morpholino knockdown with filopodial retraction assays\",\n      \"pmids\": [\"15510105\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling pathway linking UNC5B to filopodial retraction not identified\", \"Whether endothelial vs. non-endothelial UNC5B drives the phenotype was unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealing the death-domain-mediated mechanism of pro-apoptotic signaling: UNC5B physically recruits DAP-kinase via death domain interaction and activates it by reducing Ser308 autophosphorylation in the absence of netrin-1, providing the first enzymatic effector of UNC5B-induced apoptosis.\",\n      \"evidence\": \"Reciprocal Co-IP in cell culture and embryonic mouse brain, DAP-kinase knockout MEFs, kinase assays\",\n      \"pmids\": [\"15729359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the death domain interaction triggers DAP-kinase dephosphorylation mechanistically was unclear\", \"Whether PP2A is involved was not yet known\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Structural characterization of the UNC5B death domain revealed a six-helix bundle that homodimerizes, suggesting a conformational switch model for ligand-dependent regulation of caspase access.\",\n      \"evidence\": \"X-ray crystallography at 2.1 Å with solution-state oligomerization analysis\",\n      \"pmids\": [\"17139086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of dimerization not directly tested\", \"Full-length cytoplasmic domain structure not yet available\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that the UNC5B intracellular domain is required for repulsive signaling: a truncated UNC5B lacking the cytoplasmic domain fails to induce endothelial repulsion, confirming signal transduction rather than passive ligand sequestration.\",\n      \"evidence\": \"Truncation mutants, genetic UNC5B knockout, Matrigel and tumor angiogenesis assays\",\n      \"pmids\": [\"17908930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific intracellular domains (ZU5, UPA, DD) not individually tested\", \"Downstream effectors of repulsive signaling in endothelial cells not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Three parallel advances defined UNC5B's vascular, survival, and co-receptor functions: endothelial-specific deletion proved autonomous vascular roles in placental labyrinth; netrin-1 was shown to recruit PIKE-L via Fyn to activate PI3K survival signaling; and netrin-4 was found to recruit UNC5B through neogenin as a co-receptor complex on endothelial cells.\",\n      \"evidence\": \"Endothelium-specific conditional KO mice; Fyn-null embryos with Co-IP and PI3K assays; neogenin–UNC5B Co-IP with siRNA epistasis\",\n      \"pmids\": [\"18223200\", \"18469807\", \"18719102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PIKE-L functions in endothelial cells (vs. neurons only) was not tested\", \"Structural basis of neogenin–UNC5B co-receptor assembly unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"A structural and mechanistic watershed: the crystal structure of the ZU5-UPA-death domain supramodule revealed an autoinhibited closed conformation, while parallel work showed UNC5B acts as a neogenin co-receptor for RGMa via LARG/RhoA in growth cone collapse, and FLRT3 was identified as a UNC5B ligand mediating cell de-adhesion via Rnd1.\",\n      \"evidence\": \"Crystal structure with mutagenesis and functional assays; Co-IP of neogenin-UNC5B-LARG with RhoA activation and growth cone collapse; FLRT3-UNC5B Co-IP with Rnd1 epistasis in Xenopus\",\n      \"pmids\": [\"19328064\", \"19273616\", \"19492039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How netrin-1 binding triggers conformational change from closed to open state not structurally resolved\", \"Relative contributions of FLRT3 vs. netrin-1 to UNC5B activation in vivo unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Completing the apoptotic signaling circuit: an siRNA screen identified PP2A (PR65β) as the phosphatase recruited by UNC5B to dephosphorylate and activate DAP-kinase, while netrin-1 binding recruits the PP2A inhibitor CIP2A, providing a full ligand-dependent switch mechanism.\",\n      \"evidence\": \"siRNA screen, PP2A activity assays, DAPk phosphorylation, UNC5B Co-IP with PP2A and CIP2A\",\n      \"pmids\": [\"21172653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CIP2A competes with PP2A for the same binding site on UNC5B not determined\", \"In vivo relevance of CIP2A recruitment not validated genetically\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Robo4 was identified as a UNC5B-binding partner that maintains vascular integrity by counteracting VEGF signaling, expanding UNC5B's ligand repertoire beyond netrins and FLRTs; separately, UNC5B was shown to act as a brake on peripheral nerve regeneration in Schwann cells.\",\n      \"evidence\": \"Protein-protein interaction screen, function-blocking antibodies, Robo4−/− rescue; in vivo siRNA with nerve regeneration quantification\",\n      \"pmids\": [\"21238923\", \"21656855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular pathway linking Robo4–UNC5B to VEGF signal inhibition not fully resolved\", \"How DCC-UNC5B reciprocal regulation occurs in Schwann cells mechanistically unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"UNC5B's dynamic membrane trafficking was visualized: netrin-1 induces Src-dependent recruitment of UNC5B from intracellular clusters to the plasma membrane, where it heterooligomerizes with DCC, revealing surface delivery as a regulated step.\",\n      \"evidence\": \"Live-cell TIRF microscopy and temporal image cross-correlation spectroscopy with Src kinase inhibitors\",\n      \"pmids\": [\"26840727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of DCC–UNC5B heterooligomers undefined\", \"Whether trafficking regulation occurs in endothelial cells (not just neurons) untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"FLRT2 was established as a physiological UNC5B ligand in placental endothelium: endothelial-specific FLRT2 deletion phenocopied UNC5B vascular defects, confirming FLRT-UNC5B repulsion shapes feto-maternal circulation.\",\n      \"evidence\": \"Endothelial-specific FLRT2 conditional knockout with histological and physiological vascular analysis\",\n      \"pmids\": [\"28576770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FLRT2 and netrin-1 compete for UNC5B binding not tested\", \"Intracellular signaling downstream of FLRT2–UNC5B in endothelial cells not characterized\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Myosin X was identified as a negative regulator of UNC5B surface expression in osteoclast-lineage cells, linking UNC5B trafficking to osteoclastogenesis via RANKL signaling.\",\n      \"evidence\": \"Myo10 conditional knockout, cell-surface biotinylation, Unc5b shRNA rescue, osteoclast differentiation assays\",\n      \"pmids\": [\"30645777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Myo10 retains UNC5B intracellularly not identified\", \"Whether Myo10 regulation of UNC5B occurs in other cell types unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Three studies expanded UNC5B functions: MST1 was shown to phosphorylate UNC5B-T428 to activate apoptosis in dopaminergic neurons under netrin-1 deficiency; UNC5B-CDC14A interaction was found to dephosphorylate p53-Ser315 causing G2/M arrest in bladder cancer; and UNC5B was placed as a receptor balancing Wnt and MAPK signaling in naive pluripotency.\",\n      \"evidence\": \"MST1–UNC5B Co-IP with phospho-site mapping and UNC5B KO rescue in PD model; mass spectrometry-identified CDC14A–UNC5B interaction with cell cycle analysis; receptor overexpression/knockdown with phospho-protein assays in mESCs\",\n      \"pmids\": [\"32929029\", \"32372016\", \"32231305\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether T428 phosphorylation disrupts the ZU5-UPA-DD closed conformation not tested structurally\", \"CDC14A–UNC5B interaction validated only in bladder cancer cells\", \"In vivo relevance of UNC5B in pluripotency maintenance not demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"An endothelial-specific splice variant UNC5B-Δ8, generated by NOVA2-mediated exon-8 skipping, was shown to be constitutively pro-apoptotic and netrin-1-insensitive, revealing that alternative splicing provides a ligand-independent activation mechanism for vessel remodeling.\",\n      \"evidence\": \"Isoform identification, NOVA2 knockdown, endothelial-specific expression, apoptosis and vascular development assays\",\n      \"pmids\": [\"34381052\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How exon-8 loss affects ZU5-UPA-DD supramodule conformation not structurally resolved\", \"Whether UNC5B-Δ8 is expressed outside endothelium not surveyed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"UNC5B was established as a critical maintainer of blood-brain barrier integrity via Wnt/β-catenin signaling: netrin-1 enhances UNC5B–LRP6 interaction, phosphorylates LRP6, activates β-catenin, and maintains Claudin-5 expression, with inducible UNC5B deletion causing BBB leak.\",\n      \"evidence\": \"Inducible endothelial-specific Unc5B knockout, β-catenin gain-of-function rescue, UNC5B–LRP6 Co-IP, antibody blocking, tracer permeability\",\n      \"pmids\": [\"35246514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether UNC5B directly binds LRP6 or requires an adaptor not resolved\", \"Downstream mechanism connecting UNC5B to LRP6 phosphorylation (kinase identity) not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Three studies expanded UNC5B's roles in immune and metabolic regulation: FUT8-mediated fucosylation of UNC5B in the ER was shown to regulate macrophage migration via CDC42/PAK; FLRT2–UNC5B interaction was found to drive monocyte-to-macrophage differentiation via Akt/mTOR; and netrin-1–UNC5B was shown to promote blood-retina barrier integrity through LRP5/Dlg1/β-catenin signaling.\",\n      \"evidence\": \"FUT8–UNC5B Co-IP with lectin pulldown and ApoE−/− mouse model; FLRT2–UNC5B Co-IP with myeloid-specific KO and mTOR agonist rescue; inducible genetic alleles with phospho-signaling and tracer permeability (preprint)\",\n      \"pmids\": [\"36670464\", \"37090697\", \"36711611\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific fucosylation sites on UNC5B not mapped\", \"Whether FLRT2–UNC5B and netrin-1–UNC5B signaling converge on shared Akt/mTOR intermediates unknown\", \"Blood-retina barrier study is a preprint awaiting peer review\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"UNC5B was identified as an immune checkpoint receptor on T cells and a YAP-TEAD effector in cancer: FLRT3 on tumor cells engages UNC5B on activated T cells to suppress anti-tumor immunity, while YAP-TEAD transcriptionally induces UNC5B to mediate cytostasis cooperatively with netrin-1 and integrin-αV/β5.\",\n      \"evidence\": \"Genetic screens (gain-of-function for FLRT3–UNC5B; CRISPR for YAP–UNC5B), blocking antibodies, CAR-T killing assays, TEAD-binding mutants\",\n      \"pmids\": [\"38427724\", \"39172021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"UNC5B intracellular signaling in T cells upon FLRT3 engagement not characterized\", \"Whether YAP–UNC5B cytostasis operates through the canonical death-domain apoptotic pathway unknown\", \"In vivo validation of FLRT3–UNC5B checkpoint blockade in immunocompetent tumor models limited\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how netrin-1 binding triggers the ZU5-UPA-DD conformational transition at atomic resolution; whether the multiple UNC5B ligands (netrin-1, Robo4, FLRT2/3, RGMa/neogenin) engage distinct or overlapping intracellular effector complexes; the physiological significance of UNC5B's immune checkpoint function in human cancer; and whether therapeutic targeting of UNC5B can selectively modulate barrier integrity without compromising its apoptotic tumor-suppressive role.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length ectodomain–ligand co-crystal structure available\", \"Ligand competition and hierarchy at UNC5B not systematically tested\", \"No clinical data on anti-UNC5B or anti-FLRT3 checkpoint therapy\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3, 11, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 10, 24]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 10, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 11, 16, 29]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 2, 5, 10, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 11, 20, 22, 31]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [25, 27]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DAPk\", \"LRP6\", \"PIKE-L\", \"neogenin\", \"Robo4\", \"FLRT3\", \"FLRT2\", \"CIP2A\"],\n    \"other_free_text\": []\n  }\n}\n```"}