Affinage

UNC5B

Netrin receptor UNC5B · UniProt Q8IZJ1

Length
945 aa
Mass
103.6 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2002 Medium

    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

    PMID:12359238

    Open questions at the time
    • Single lab, not independently confirmed
    • Physiological context for Gαi2–UNC5B interaction in vivo undefined
    • Relationship to netrin-dependent signaling not tested
  2. 2003 High

    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

    PMID:12598906

    Open questions at the time
    • Identity of caspase(s) cleaving UNC5B not fully resolved
    • Structural basis for netrin-1-mediated suppression unknown at this point
  3. 2004 High

    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

    PMID:15510105

    Open questions at the time
    • Intracellular signaling pathway linking UNC5B to filopodial retraction not identified
    • Whether endothelial vs. non-endothelial UNC5B drives the phenotype was unresolved
  4. 2005 High

    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

    PMID:15729359

    Open questions at the time
    • How the death domain interaction triggers DAP-kinase dephosphorylation mechanistically was unclear
    • Whether PP2A is involved was not yet known
  5. 2006 Medium

    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

    PMID:17139086

    Open questions at the time
    • Functional significance of dimerization not directly tested
    • Full-length cytoplasmic domain structure not yet available
  6. 2007 High

    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

    PMID:17908930

    Open questions at the time
    • Specific intracellular domains (ZU5, UPA, DD) not individually tested
    • Downstream effectors of repulsive signaling in endothelial cells not identified
  7. 2008 High

    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

    PMID:18223200 PMID:18469807 PMID:18719102

    Open questions at the time
    • Whether PIKE-L functions in endothelial cells (vs. neurons only) was not tested
    • Structural basis of neogenin–UNC5B co-receptor assembly unknown
  8. 2009 High

    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

    PMID:19273616 PMID:19328064 PMID:19492039

    Open questions at the time
    • 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
  9. 2010 High

    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

    PMID:21172653

    Open questions at the time
    • Whether CIP2A competes with PP2A for the same binding site on UNC5B not determined
    • In vivo relevance of CIP2A recruitment not validated genetically
  10. 2011 High

    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

    PMID:21238923 PMID:21656855

    Open questions at the time
    • Intracellular pathway linking Robo4–UNC5B to VEGF signal inhibition not fully resolved
    • How DCC-UNC5B reciprocal regulation occurs in Schwann cells mechanistically unclear
  11. 2016 Medium

    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

    PMID:26840727

    Open questions at the time
    • Stoichiometry of DCC–UNC5B heterooligomers undefined
    • Whether trafficking regulation occurs in endothelial cells (not just neurons) untested
  12. 2017 Medium

    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

    PMID:28576770

    Open questions at the time
    • Whether FLRT2 and netrin-1 compete for UNC5B binding not tested
    • Intracellular signaling downstream of FLRT2–UNC5B in endothelial cells not characterized
  13. 2019 Medium

    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

    PMID:30645777

    Open questions at the time
    • Mechanism by which Myo10 retains UNC5B intracellularly not identified
    • Whether Myo10 regulation of UNC5B occurs in other cell types unknown
  14. 2020 Medium

    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

    PMID:32231305 PMID:32372016 PMID:32929029

    Open questions at the time
    • 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
  15. 2021 Medium

    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

    PMID:34381052

    Open questions at the time
    • How exon-8 loss affects ZU5-UPA-DD supramodule conformation not structurally resolved
    • Whether UNC5B-Δ8 is expressed outside endothelium not surveyed
  16. 2022 High

    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

    PMID:35246514

    Open questions at the time
    • Whether UNC5B directly binds LRP6 or requires an adaptor not resolved
    • Downstream mechanism connecting UNC5B to LRP6 phosphorylation (kinase identity) not identified
  17. 2023 Medium

    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)

    PMID:36670464 PMID:36711611 PMID:37090697

    Open questions at the time
    • 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
  18. 2024 Medium

    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

    PMID:38427724 PMID:39172021

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-5357801 Programmed Cell Death 5 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 2
Partners
CIP2ADAPKFLRT2FLRT3LRP6NEOGENINPIKE-LROBO4

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 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. Mouse knockout, zebrafish morpholino knockdown, in vitro filopodial retraction assay Nature High 15510105
2003 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. Transcriptional reporter assays, overexpression, siRNA knockdown, caspase cleavage assays, co-immunoprecipitation Nature cell biology High 12598906
2005 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. Co-immunoprecipitation in cell culture and embryonic mouse brain, dominant-negative mutants, DAP-kinase knockout MEFs, kinase activity assays The EMBO journal High 15729359
2007 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. Loss-of-function (genetic unc5b knockout), truncation mutants, Matrigel/tumor angiogenesis assays, in vitro repulsion assay Genes & development High 17908930
2008 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. Endothelium-specific conditional knockout mouse, zebrafish unc5b morpholino knockdown, physiological blood flow analysis Development (Cambridge, England) High 18223200
2008 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. Co-immunoprecipitation, Fyn-null mouse embryos, PI3K assay, apoptosis assays Nature cell biology High 18469807
2008 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. Co-immunoprecipitation, siRNA knockdown, endothelial migration/tube formation assays Proceedings of the National Academy of Sciences of the United States of America High 18719102
2009 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. Crystal structure determination, mutagenesis, functional apoptosis and vascular patterning assays Molecular cell High 19328064
2009 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. Co-immunoprecipitation, dominant-negative mutants, RhoA activation assay, growth cone collapse assay The Journal of cell biology High 19273616
2009 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. Expression screen, co-immunoprecipitation, morpholino knockdown, overexpression in Xenopus embryos PloS one High 19492039
2010 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. siRNA screen, co-immunoprecipitation, PP2A activity assay, DAPk phosphorylation assay, angiogenesis assay Molecular cell High 21172653
2011 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. Protein-protein interaction screen, function-blocking monoclonal antibodies, Robo4−/− mouse rescue experiments Developmental cell High 21238923
2002 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. Co-immunoprecipitation, adenylyl cyclase activity assay Biochemical and biophysical research communications Medium 12359238
2011 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. In vivo siRNA knockdown, immunolocalization, axon regeneration quantification Glia Medium 21656855
2011 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. Co-immunoprecipitation, kinase assays, PIKE−/− MEFs, siRNA, overexpression, apoptosis assays Molecular biology of the cell Medium 21460185
2016 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. Netrin-4-mutant rats, intrathecal netrin-4 injection, siRNA knockdown, electrophysiology, behavioral pain tests The Journal of experimental medicine Medium 27856613
2016 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. Live-cell TIRF microscopy, temporal image cross-correlation spectroscopy (TICCS), pharmacological Src kinase inhibition Biophysical journal Medium 26840727
2006 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. X-ray crystallography, solution state analysis Acta crystallographica. Section D, Biological crystallography Medium 17139086
2017 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. Endothelial-specific conditional knockout mouse, in vitro binding assays, histological and physiological vascular analysis Development (Cambridge, England) Medium 28576770
2020 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. Co-immunoprecipitation, site-specific phosphorylation assays, UNC5B knockout mice, human PD brain samples Proceedings of the National Academy of Sciences of the United States of America Medium 32929029
2020 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. Chemical inhibition, receptor overexpression and knockdown, phospho-protein assays, mESC self-renewal assays Nature cell biology Medium 32231305
2021 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. Identification of splicing isoform, NOVA2 knockdown, endothelial-specific isoform expression, apoptosis assays, in vivo vascular development analysis Nature communications Medium 34381052
2022 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. 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 Nature communications High 35246514
2024 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. Unbiased translated mRNA screen, endothelial-specific UNC5B conditional knockout, gain-of-function, junction stability assays under shear stress Scientific reports Medium 38866944
2020 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. Mass spectrometry, co-immunoprecipitation, site-specific phosphorylation assays, siRNA knockdown, flow cytometry, xenograft tumor implantation Cancer gene therapy Medium 32372016
2013 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. Neutralizing antibodies against UNC5B, siRNA knockdown, ischemia-reperfusion injury mouse model, cytokine measurements Journal of immunology Medium 20693423
2023 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. Co-immunoprecipitation, siRNA/overexpression of Unc5b and Fut8, lectin pulldown for fucosylation, migration assays, ApoE−/− mouse model Cell & bioscience Medium 36670464
2024 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. Gain-of-function genetic screen, co-immunoprecipitation of FLRT3-UNC5B, blocking monoclonal antibody, CAR-T and BiTE + T cell killing assays, humanized cancer models Science advances Medium 38427724
2023 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. Inducible loss- and gain-of-function alleles, tracer permeability assays, phospho-signaling studies, β-catenin gain-of-function rescue bioRxivpreprint Medium 36711611
2019 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. Myo10 conditional knockout mouse, lentiviral Unc5b shRNA, cell-surface biotinylation, RANKL-induced osteoclast differentiation assays Journal of bone and mineral research Medium 30645777
2023 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. Co-immunoprecipitation (FLRT2-UNC5B), gain/loss-of-function in THP-1 and human PBMCs, myeloid-specific conditional KO, mTOR agonist rescue Frontiers in immunology Medium 37090697
2024 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. CRISPR screen, TEAD1/4 loss-of-function, YAP S94A mutant, decoy receptor blocking, integrin KO assays Cancer research communications Medium 39172021

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 450 15510105
2007 Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis. Genes & development 198 17908930
2011 Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B. Developmental cell 174 21238923
2003 p53RDL1 regulates p53-dependent apoptosis. Nature cell biology 147 12598906
2005 The dependence receptor UNC5H2 mediates apoptosis through DAP-kinase. The EMBO journal 143 15729359
2008 Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B. Proceedings of the National Academy of Sciences of the United States of America 130 18719102
2010 Netrin-1 regulates Th1/Th2/Th17 cytokine production and inflammation through UNC5B receptor and protects kidney against ischemia-reperfusion injury. Journal of immunology (Baltimore, Md. : 1950) 115 20693423
2010 The dependence receptor UNC5H2/B triggers apoptosis via PP2A-mediated dephosphorylation of DAP kinase. Molecular cell 110 21172653
2008 The netrin receptor UNC5B promotes angiogenesis in specific vascular beds. Development (Cambridge, England) 107 18223200
2022 Endothelial Unc5B controls blood-brain barrier integrity. Nature communications 94 35246514
2008 Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B. Nature cell biology 92 18469807
2013 Hypoxia induces netrin-1 and Unc5b in atherosclerotic plaques: mechanism for macrophage retention and survival. Arteriosclerosis, thrombosis, and vascular biology 88 23599441
2011 Schwann cells direct peripheral nerve regeneration through the Netrin-1 receptors, DCC and Unc5H2. Glia 78 21656855
2009 Autoinhibition of UNC5b revealed by the cytoplasmic domain structure of the receptor. Molecular cell 75 19328064
2009 Unc5B associates with LARG to mediate the action of repulsive guidance molecule. The Journal of cell biology 72 19273616
2017 Recombinant Netrin-1 binding UNC5B receptor attenuates neuroinflammation and brain injury via PPARγ/NFκB signaling pathway after subarachnoid hemorrhage in rats. Brain, behavior, and immunity 69 29162556
2011 Clinical significance of UNC5B expression in colorectal cancer. International journal of oncology 54 21922135
2001 Expression of netrin-1 and its receptors DCC and UNC-5H2 after axotomy and during regeneration of adult rat retinal ganglion cells. Experimental neurology 53 11170725
2009 Netrin-1 increases proliferation and migration of renal proximal tubular epithelial cells via the UNC5B receptor. American journal of physiology. Renal physiology 50 19211685
2015 Netrin-1 induces the migration of Schwann cells via p38 MAPK and PI3K-Akt signaling pathway mediated by the UNC5B receptor. Biochemical and biophysical research communications 48 26116534
2009 Unc5B interacts with FLRT3 and Rnd1 to modulate cell adhesion in Xenopus embryos. PloS one 47 19492039
2020 Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling. Nature cell biology 41 32231305
2020 Netrin1 deficiency activates MST1 via UNC5B receptor, promoting dopaminergic apoptosis in Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America 39 32929029
2011 Akt-phosphorylated PIKE-A inhibits UNC5B-induced apoptosis in cancer cell lines in a p53-dependent manner. Molecular biology of the cell 38 21460185
2003 Expression of Netrin-1 and its two receptors DCC and UNC5H2 in the developing mouse lung. Gene expression patterns : GEP 38 12799072
2007 Netrin-1 induces proliferation of Schwann cells through Unc5b receptor. Biochemical and biophysical research communications 37 17825258
2013 Association of neuroimmune guidance cue netrin-1 and its chemorepulsive receptor UNC5B with atherosclerotic plaque expression signatures and stability in human(s): Tampere Vascular Study (TVS). Circulation. Cardiovascular genetics 36 24122613
2022 PTBP1 knockdown promotes neural differentiation of glioblastoma cells through UNC5B receptor. Theranostics 31 35664063
2020 HIF-1α-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4. Journal of experimental & clinical cancer research : CR 31 32522234
2018 LncRNA TNRC6C-AS1 regulates UNC5B in thyroid cancer to influence cell proliferation, migration, and invasion as a competing endogenous RNA of miR-129-5p. Journal of cellular biochemistry 30 29893424
2021 A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis. Nature communications 29 34381052
2019 The lncRNA UNC5B-AS1 promotes proliferation, migration, and invasion in papillary thyroid cancer cell lines. Human cell 29 30805847
2016 Netrin-1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 29 27502509
2022 Netrin-1 upregulates GPX4 and prevents ferroptosis after traumatic brain injury via the UNC5B/Nrf2 signaling pathway. CNS neuroscience & therapeutics 28 36468399
2017 Placental labyrinth formation in mice requires endothelial FLRT2/UNC5B signaling. Development (Cambridge, England) 27 28576770
2021 UNC5B Promotes Vascular Endothelial Cell Senescence via the ROS-Mediated P53 Pathway. Oxidative medicine and cellular longevity 25 34239689
2020 UNC5B-AS1 promoted ovarian cancer progression by regulating the H3K27me on NDRG2 via EZH2. Cell biology international 24 31903696
2014 PKC α regulates netrin-1/UNC5B-mediated survival pathway in bladder cancer. BMC cancer 23 24528886
2009 Characterization and expression of netrin-1 and its receptors UNC5B and DCC in human placenta. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 23 19826074
2019 Netrin-1 works with UNC5B to regulate angiogenesis in diabetic kidney disease. Frontiers of medicine 22 31884526
2013 UNC5B receptor deletion exacerbates tissue injury in response to AKI. Journal of the American Society of Nephrology : JASN 22 24115477
2021 UNC5B-AS1 promotes the proliferation, migration and EMT of hepatocellular carcinoma cells via regulating miR-4306/KDM2A axis. Cell cycle (Georgetown, Tex.) 20 34612138
2016 Overexpression of UNC5B in bladder cancer cells inhibits proliferation and reduces the volume of transplantation tumors in nude mice. BMC cancer 20 27846823
2018 The role of UNC5b in ox-LDL inhibiting migration of RAW264.7 macrophages and the involvement of CCR7. Biochemical and biophysical research communications 18 30286954
2016 Netrin-1-Regulated Distribution of UNC5B and DCC in Live Cells Revealed by TICCS. Biophysical journal 18 26840727
2002 Modulation of G(ialpha(2)) signaling by the axonal guidance molecule UNC5H2. Biochemical and biophysical research communications 17 12359238
2022 UNC5B Overexpression Alleviates Peripheral Neuropathic Pain by Stimulating Netrin-1-Dependent Autophagic Flux in Schwann Cells. Molecular neurobiology 16 35668343
2022 Netrin-1 induces the anti-apoptotic and pro-survival effects of B-ALL cells through the Unc5b-MAPK axis. Cell communication and signaling : CCS 15 35974411
2012 Clinical significance of UNC5B expression in bladder cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 15 23055195
2021 Δ40p53 isoform up-regulates netrin-1/UNC5B expression and potentiates netrin-1 pro-oncogenic activity. Proceedings of the National Academy of Sciences of the United States of America 14 34470826
2022 Oleanolic Acid (OA) Targeting UNC5B Inhibits Proliferation and EMT of Ovarian Cancer Cell and Increases Chemotherapy Sensitivity of Niraparib. Journal of oncology 13 35035481
2020 LncRNA UNC5B-AS1 promotes malignant progression of prostate cancer by competitive binding to caspase-9. European review for medical and pharmacological sciences 13 32196578
2020 UNC5B mediates G2/M phase arrest of bladder cancer cells by binding to CDC14A and P53. Cancer gene therapy 13 32372016
2019 Downregulation of the Netrin-1 Receptor UNC5b Underlies Increased Placental Angiogenesis in Human Gestational Diabetes Mellitus. International journal of molecular sciences 13 30897795
2022 Isoflurane and Netrin-1 combination therapy enhances angiogenesis and neurological recovery by improving the expression of HIF-1α-Netrin-1-UNC5B/VEGF cascade to attenuate cerebral ischemia injury. Experimental neurology 12 35247371
2018 A network map of netrin receptor UNC5B-mediated signaling. Journal of cell communication and signaling 12 30084000
2013 PKCα is involved in the progression of kidney carcinoma through regulating netrin-1/UNC5B signaling pathway. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 12 23526078
2013 CoCl2 induces PC12 cells apoptosis through p53 stability and regulating UNC5B. Brain research bulletin 12 23651544
2012 Expression patterns and functional evaluation of the UNC5b receptor during the early phase of peripheral nerve regeneration using the mouse median nerve model. Microsurgery 12 23180484
2024 Notch signaling regulates UNC5B to suppress endothelial proliferation, migration, junction activity, and retinal plexus branching. Scientific reports 11 38866944
2022 Netrin-1 attenuates hepatic steatosis via UNC5b/PPARγ-mediated suppression of inflammation and ER stress. Life sciences 11 36400204
2020 Silencing UNC5B antisense lncRNA 1 represses growth and metastasis of human Colon cancer cells via raising miR-622. Artificial cells, nanomedicine, and biotechnology 11 31852293
2016 Dorsal horn interneuron-derived Netrin-4 contributes to spinal sensitization in chronic pain via Unc5B. The Journal of experimental medicine 11 27856613
2013 Interactional expression of netrin-1 and its dependence receptor UNC5B in prostate carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 11 23666553
2013 The uncoordinated-5 homolog B (UNC5B) receptor increases myocardial ischemia-reperfusion injury. PloS one 11 23936025
2021 Inhibition of the long non-coding RNA UNC5B-AS1/miR-4455/RSPO4 axis reduces cervical cancer growth in vitro and in vivo. The journal of gene medicine 9 34350661
2020 Polyomavirus Small T Antigen Induces Apoptosis in Mammalian Cells through the UNC5B Pathway in a PP2A-Dependent Manner. Journal of virology 9 32404521
2019 Lack of Myosin X Enhances Osteoclastogenesis and Increases Cell Surface Unc5b in Osteoclast-Lineage Cells. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 9 30645777
2016 Unc-5 homolog B (UNC5B) is one of the key downstream targets of N-α-Acetyltransferase 10 (Naa10). Scientific reports 9 27910960
2015 Deletion of UNC5B in Kidney Epithelium Exacerbates Diabetic Nephropathy in Mice. American journal of nephrology 9 25896231
2023 Hypofucosylation of Unc5b regulated by Fut8 enhances macrophage emigration and prevents atherosclerosis. Cell & bioscience 8 36670464
2020 PKCα and Netrin-1/UNC5B positive feedback control in relation with chemical therapy in bladder cancer. European review for medical and pharmacological sciences 8 32141538
2008 Molecular cloning of a porcine (Sus scrofa) apoptosis inhibitory ligand, netrin-1, and its receptor, p53RDL1. The Journal of reproduction and development 8 18497489
2023 Fibronectin leucine-rich transmembrane protein 2 drives monocyte differentiation into macrophages via the UNC5B-Akt/mTOR axis. Frontiers in immunology 7 37090697
2014 UNC5B receptor deletion exacerbates DSS-induced colitis in mice by increasing epithelial cell apoptosis. Journal of cellular and molecular medicine 7 24720832
2007 Expression pattern for unc5b, an axon guidance gene in embryonic zebrafish development. Gene expression 7 17708418
2024 Targeting Unc5b in macrophages drives atherosclerosis regression and pro-resolving immune cell function. Proceedings of the National Academy of Sciences of the United States of America 6 39436659
2020 The intracellular domain of UNC5B facilities proliferation and metastasis of bladder cancer cells. Journal of cellular and molecular medicine 6 33345442
2020 [Effects of LncRNA UNC5B-AS1 on adhesion, invasion and migration of lung cancer cells and its mechanism]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 6 33719270
2025 Super-Enhancer-Driven LncRNA UNC5B-AS1 Inhibits Inflammatory Phenotypic Transition in Pulmonary Artery Smooth Muscle Cells via Lactylation. Arteriosclerosis, thrombosis, and vascular biology 5 40336475
2023 Netrin-1 binding to Unc5B regulates Blood-Retina Barrier integrity. bioRxiv : the preprint server for biology 5 36711611
2021 Long non-coding RNA PITPNA-AS1 regulates UNC5B expression in papillary thyroid cancer via sponging miR-129-5p. The International journal of biological markers 5 33706585
2006 Structure of the UNC5H2 death domain. Acta crystallographica. Section D, Biological crystallography 5 17139086
2025 Netrin-1 binding to UNC5b improves post-stroke neuronal ferroptosis via AMPK-BACH1 pathway. European journal of pharmacology 4 40086580
2024 Identification of UNC5B as a novel aggressive biomarker for osteosarcoma based on basement membrane genes. Gene 4 39154972
2009 [Down-regulated expression of UNC5b related to hepatocellular carcinoma angiogenesis]. Zhonghua wai ke za zhi [Chinese journal of surgery] 4 20092749
2024 Unc5b prevents macrophage-derived foam cell migration and promotes atherosclerotic development via the P53-cuproptosis signaling pathway. Life sciences 3 39722317
2023 Investigation of dynamic solution interactions between NET-1 and UNC-5B by multi-wavelength analytical ultracentrifugation. European biophysics journal : EBJ 3 36939874
2025 Fut8 regulated Unc5b hyperfucosylation reduces macrophage emigration and accelerates atherosclerosis development via the ferroptosis pathway. Free radical biology & medicine 2 40262667
2024 The FLRT3-UNC5B checkpoint pathway inhibits T cell-based cancer immunotherapies. Science advances 2 38427724
2024 Cinnamaldehyde attenuates streptozocin-induced diabetic osteoporosis in a rat model by modulating netrin-1/DCC-UNC5B signal transduction. Frontiers in pharmacology 2 38628640
2024 Netrin-1 and UNC5B Cooperate with Integrins to Mediate YAP-Driven Cytostasis. Cancer research communications 2 39172021
2024 Acute myeloid leukemia cells adhere to bone marrow and acquire chemoresistance by downregulating UNC5B expression. Frontiers in oncology 2 39381040
2019 Netrin-1 and its receptor Unc5b as markers of periodontal disease. Journal of periodontal research 2 31769036
2013 [Expressions of netrin-1 and UNC5B in prostate cancer and their clinical significance]. Zhonghua nan ke xue = National journal of andrology 2 24432616
2025 Direction and modality of transcription changes caused by TAD boundary disruption in Slc29a3/Unc5b locus depends on tissue-specific epigenetic context. Epigenetics & chromatin 1 40796890
2025 Jiawei Qingxin Zishen Decoction mitigates granulosa cell apoptosis and enhances ovarian reserve through Netrin/UNC5B signaling pathway. Journal of ethnopharmacology 1 41072782
2024 Long noncoding RNA UNC5B-AS1 suppresses cell proliferation by sponging miR-24-3p in glioblastoma multiforme. BMC medical genomics 1 38594690
2022 Expression and Relationship of Netrin-1, DCC, UNC5B, and VEGF in Villous Tissues of Patients with Delayed Abortion. Contrast media & molecular imaging 1 36110982
2011 Role of unc5b in retinal neovascularization in mice with oxygen-induced retinopathy. International journal of ophthalmology 1 22553628