Affinage

UNC5D

Netrin receptor UNC5D · UniProt Q6UXZ4

Length
953 aa
Mass
105.9 kDa
Annotated
2026-06-10
17 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UNC5D is a netrin-dependence receptor that couples ligand availability to cell-survival and apoptotic decisions in both neural development and tumor suppression (PMID:21216843, PMID:23778138). As a p53-responsive gene whose induction during DNA-damage-induced apoptosis depends on p53 binding to tandem response elements in intron 1, UNC5D is embedded in the p53 stress-response transcriptional program (PMID:18402767). In the absence of its ligand netrin-1, UNC5D is cleaved by caspases 2/3, releasing an intracellular fragment that translocates to the nucleus and interacts with E2F1 to selectively transactivate proapoptotic genes; netrin-1 blocks this cleavage and apoptosis, and Unc5d-/- neurons resist NGF-deprivation-induced death, defining UNC5D as a death-domain-dependent inducer of apoptosis that feeds back to amplify p53/E2F1 signaling (PMID:23778138, PMID:24519068). In cortical development, netrin-4 binds UNC5D-expressing cells and promotes lamina-specific survival of layer 4 neurons (PMID:21216843), while UNC5D marks and guides multipolar migrating cells of the subventricular zone (PMID:18547816). Across multiple epithelial cancers UNC5D acts as a growth and metastasis suppressor: it restrains proliferation, migration, and invasion and induces apoptosis, in part by recruiting and activating DAPK1 downstream of its receptor function (PMID:23589179, PMID:30632669). Beyond these roles, UNC5D has been linked to cisplatin-induced apoptosis via DAPK (PMID:24518784) and to neurite-outgrowth control downstream of DISC1 in iPSC-derived neurons (PMID:30410030).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2008 High

    Established that UNC5D is wired into the p53 stress-response network as a direct transcriptional target, explaining its induction during DNA-damage apoptosis.

    Evidence Luciferase reporter, ChIP, and p53 siRNA knockdown in p53-proficient vs -deficient cell lines

    PMID:18402767

    Open questions at the time
    • Does not establish the downstream apoptotic mechanism of induced UNC5D
    • p53-binding shown only at intron 1 elements, not other regulatory regions
  2. 2008 Medium

    Localized UNC5D to multipolar migrating cells of the subventricular zone, implicating it in cortical neuronal migration.

    Evidence In situ hybridization, immunofluorescence, and nuclear/cytoplasmic RNA fractionation in embryonic cortex

    PMID:18547816

    Open questions at the time
    • No functional consequence of UNC5D in migration tested
    • Relationship between the intronic Svet1 RNA and UNC5D protein function unresolved
  3. 2011 Medium

    Identified UNC5D as a netrin-4 receptor that mediates lamina-specific survival, linking ligand binding to a developmental cell-survival outcome.

    Evidence Cell-surface binding assay and in vitro cell-death rescue with exogenous netrin-4 on layer 4 cortical cells

    PMID:21216843

    Open questions at the time
    • Intracellular signaling from netrin-4-bound UNC5D not defined
    • In vivo requirement for netrin-4/UNC5D survival not genetically tested here
  4. 2013 High

    Defined the dependence-receptor apoptotic mechanism: ligand-free UNC5D is caspase-cleaved and its fragment drives E2F1-dependent proapoptotic transcription, with genetic validation in vivo.

    Evidence Caspase cleavage assays, nuclear fractionation, UNC5D-E2F1 Co-IP, and Unc5d-/- mouse neuronal phenotyping

    PMID:23778138

    Open questions at the time
    • Identity of the caspase cleavage site(s) not mapped
    • How the released fragment is targeted to E2F1-bound promoters unresolved
  5. 2013 Medium

    Extended UNC5D function to epithelial tumor suppression, showing it restrains growth and invasion and is silenced in renal cancer.

    Evidence Gain/loss-of-function with proliferation, colony, migration/invasion, and cell-cycle assays plus methylation and LOH analysis in RCC

    PMID:23589179

    Open questions at the time
    • Molecular effector of G2-M arrest not identified
    • Causal link between methylation/LOH and tumor progression correlative
  6. 2014 Medium

    Dissected domain requirements for UNC5D apoptosis, confirming caspase cleavage and the death domain are necessary and netrin-1 is inhibitory.

    Evidence Overexpression with netrin-1 rescue, caspase inhibitor, and death-domain mutant experiments in neuroblastoma cells

    PMID:24519068

    Open questions at the time
    • Performed in a single cell line by overexpression
    • Does not address endogenous threshold for ligand-dependence
  7. 2014 Medium

    Placed DAPK downstream of UNC5D in chemotherapy-induced apoptosis, connecting UNC5D to drug sensitivity.

    Evidence Cisplatin treatment with dual UNC5D/DAPK knockdown, TUNEL, and viability assays in bladder cancer cells

    PMID:24518784

    Open questions at the time
    • Mechanism of UNC5D-driven DAPK dephosphorylation not defined
    • Direct UNC5D-DAPK interaction not demonstrated in this study
  8. 2014 Low

    Proposed a feedback arm in which UNC5D promotes p53 Ser15 phosphorylation to amplify p53-dependent apoptosis.

    Evidence Western blot of phospho-p53 Ser15 in UNC5D-overexpressing H1299 cells co-expressing p53

    PMID:24691657

    Open questions at the time
    • Single method (Western blot) with no mechanistic intermediary identified
    • Kinase mediating Ser15 phosphorylation downstream of UNC5D unknown
  9. 2018 Medium

    Positioned UNC5D downstream of DISC1 in neurite outgrowth, linking it to a neurodevelopmental signaling axis.

    Evidence siRNA knockdown and endogenous upregulation/rescue with longitudinal neurite analysis in iPSC-derived NGN2 neurons

    PMID:30410030

    Open questions at the time
    • Direct molecular connection between DISC1 and UNC5D not established
    • Receptor signaling driving neurite growth not defined
  10. 2019 Medium

    Identified DAPK1 as a direct UNC5D partner required for its metastasis-suppressor activity, providing a physical effector for migration control.

    Evidence UNC5D-DAPK1 Co-IP with knockdown/overexpression migration and invasion assays in vitro and in xenografts

    PMID:30632669

    Open questions at the time
    • Mechanism of DAPK1 activation by UNC5D not detailed
    • Reciprocal interaction validation not reported
  11. 2024 Low

    Linked UNC5D to immune-evasion signaling via control of STAT1/STAT3 phosphorylation and IFN-induced PD-L1.

    Evidence Overexpression with IFN stimulation and Western blot of phospho-STAT1/STAT3 and PD-L1 in colorectal cells

    PMID:38235871

    Open questions at the time
    • How UNC5D regulates STAT phosphorylation mechanistically unknown
    • No upstream or receptor-level connection established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The biochemical link between ligand-free UNC5D at the membrane and its nuclear/transcriptional and STAT-regulatory outputs remains incompletely defined.
  • Caspase cleavage site and fragment-targeting mechanism unmapped
  • How UNC5D selects between survival, apoptotic, and migratory outputs in different tissues unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-5357801 Programmed Cell Death 2
Partners
DAPK1E2F1NTN1NTN4TP53

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 UNC5D (UNC5H4) is a direct transcriptional target of p53: p53-responsive elements within intron 1 of UNC5D were identified, and luciferase reporter assay and ChIP analysis demonstrated that two tandem elements respond to exogenous p53 which is recruited onto them. UNC5D induction during adriamycin-mediated apoptosis is p53-dependent (induced in p53-proficient U2OS cells but not p53-deficient H1299 cells), and siRNA knockdown of p53 attenuates this induction. Luciferase reporter assay, ChIP analysis, siRNA knockdown, Western blot, RT-PCR Biochemical and biophysical research communications High 18402767
2008 UNC5D (UNC5H4) protein localizes to multipolar migrating cells in the subventricular zone (SVZ) of the embryonic cerebral cortex. The Svet1 RNA, a widely used SVZ marker, was found to map within the first intron of Unc5d and is present only in the nucleus (not cytoplasm), representing a spliced-out intronic sequence of the Unc5d primary transcript. In situ hybridization, immunofluorescence, subcellular fractionation, nuclear/cytoplasmic RNA detection Molecular and cellular neurosciences Medium 18547816
2011 Netrin-4 binds directly to UNC5D-expressing cells (cell surface binding assay), and exogenous netrin-4 reduces cell death of unc5d-expressing layer 4 cortical cells in vitro, indicating UNC5D acts as a netrin-4 receptor mediating cell survival in a lamina-specific manner in primary sensory cortex. Cell surface binding assay, in vitro cell death assay with exogenous netrin-4 protein Cerebral cortex Medium 21216843
2013 During NGF withdrawal in neuroblastoma, UNC5D is cleaved by caspases 2/3, and the released intracellular fragment translocates into the nucleus where it interacts with E2F1 to selectively transactivate proapoptotic target genes. Netrin-1 strongly inhibits UNC5D cleavage and apoptosis induction. Unc5d-/- mice show increased dorsal root ganglia neurons and resistance to NGF depletion-induced apoptosis in sympathetic neurons, placing UNC5D in a positive feedback loop with p53 and E2F1. Caspase cleavage assays, nuclear fractionation, co-immunoprecipitation (UNC5D with E2F1), genetic knockout (Unc5d-/- mice), in vivo neuronal counting The Journal of clinical investigation High 23778138
2013 Restoration of UNC5D expression in renal cancer cells with silenced UNC5D inhibits cell proliferation, anchorage-dependent and -independent growth, migration and invasion, and induces G2-M cell-cycle arrest. Knockdown of UNC5D promotes cell growth. UNC5D promoter is hypermethylated in 40.9% of primary RCC tumors, and LOH at the UNC5D locus is observed in 29.5% of RCC patients. Ectopic expression/knockdown (MTT, colony formation, Transwell), flow cytometry (cell cycle), methylation-specific PCR, LOH analysis Clinical cancer research Medium 23589179
2014 UNC5D overexpression in neuroblastoma SH-SY5Y cells inhibits growth, migration, and invasion, and triggers apoptosis. Apoptosis induction by UNC5D is abolished in the presence of its ligand netrin-1. Caspase cleavage and the presence of the death domain are required for UNC5D-induced apoptosis. Overexpression, colony formation assay, migration/invasion assay, apoptosis assay, netrin-1 rescue, caspase inhibitor and death domain mutant experiments Tumour biology Medium 24519068
2014 Cisplatin treatment induces UNC5D expression and DAPK dephosphorylation in bladder cancer cells. UNC5D knockdown decreases cell sensitivity to cisplatin. DAPK silencing significantly inhibits the apoptotic effect of UNC5D, placing DAPK downstream of UNC5D in cisplatin-induced apoptosis. Western blot, siRNA knockdown (UNC5D and DAPK), MTT assay, TUNEL staining, colony formation assay The Journal of urology Medium 24518784
2014 UNC5D overexpression induces phosphorylation of p53 at serine-15, suggesting UNC5D can act upstream of p53 to amplify p53-dependent apoptosis via this phosphorylation event. Western blot (phospho-p53 Ser15), stable transfection, co-expression with p53 in H1299 cells Molecular medicine reports Low 24691657
2018 UNC5D knockdown in human iPSC-derived excitatory neurons (via NGN2 differentiation) reduces neurite outgrowth, mimicking the phenotype of DISC1 mutant neurons. Transient upregulation of endogenous UNC5D rescues the decreased neurite outgrowth caused by DISC1 mutations, placing UNC5D downstream of DISC1 in the regulation of neurite growth. iPSC differentiation, siRNA knockdown, endogenous gene upregulation (CRISPRa or equivalent), longitudinal neurite outgrowth analysis, RNA sequencing, qPCR Translational psychiatry Medium 30410030
2019 UNC5D recruits and activates death-associated protein kinase 1 (DAPK1), which is essential for UNC5D's metastatic suppressor function in prostate cancer cells. Ectopic UNC5D expression reduces migration and invasion in vitro and in vivo, and siRNA-mediated knockdown yields consistent results. Co-immunoprecipitation (UNC5D-DAPK1 interaction), siRNA knockdown, migration/invasion assays (Transwell, in vivo xenograft) Cancer science Medium 30632669
2024 UNC5D overexpression in colorectal tumor cells controls STAT1/STAT3 phosphorylation, thereby regulating IFN-induced PD-L1 expression. UNC5D overexpression reduces proliferation, motility, and invasion of colorectal tumor cells. Overexpression, Western blot (phospho-STAT1/STAT3, PD-L1), IFN stimulation, proliferation/migration/invasion assays European review for medical and pharmacological sciences Low 38235871

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression. The Journal of clinical investigation 49 23778138
2008 A newly identified dependence receptor UNC5H4 is induced during DNA damage-mediated apoptosis and transcriptional target of tumor suppressor p53. Biochemical and biophysical research communications 37 18402767
2011 Laminar and areal expression of unc5d and its role in cortical cell survival. Cerebral cortex (New York, N.Y. : 1991) 36 21216843
2008 The cortical subventricular zone-specific molecule Svet1 is part of the nuclear RNA coded by the putative netrin receptor gene Unc5d and is expressed in multipolar migrating cells. Molecular and cellular neurosciences 35 18547816
2017 Genome-wide gene by lead exposure interaction analysis identifies UNC5D as a candidate gene for neurodevelopment. Environmental health : a global access science source 24 28754176
2018 Convergence of independent DISC1 mutations on impaired neurite growth via decreased UNC5D expression. Translational psychiatry 22 30410030
2013 The tumor-suppressive function of UNC5D and its repressed expression in renal cell carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 19 23589179
2021 Identification of tumors with NRG1 rearrangement, including a novel putative pathogenic UNC5D-NRG1 gene fusion in prostate cancer by data-drilling a de-identified tumor database. Genes, chromosomes & cancer 15 33583086
2020 Hypermethylated promoters of genes UNC5D and KCNA1 as potential novel diagnostic biomarkers in colorectal cancer. Epigenomics 15 33078631
2014 Down-regulation of UNC5D in bladder cancer: UNC5D as a possible mediator of cisplatin induced apoptosis in bladder cancer cells. The Journal of urology 14 24518784
2014 Unc5D regulates p53-dependent apoptosis in neuroblastoma cells. Molecular medicine reports 13 24691657
2019 UNC5D, suppressed by promoter hypermethylation, inhibits cell metastasis by activating death-associated protein kinase 1 in prostate cancer. Cancer science 12 30632669
2017 Tumor-suppressive function of UNC5D in papillary thyroid cancer. Oncotarget 8 29221192
2014 Overexpression of the dependence receptor UNC5H4 inhibits cell migration and invasion, and triggers apoptosis in neuroblastoma cell. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 6 24519068
2017 Exome sequencing identifies a novel UNC5D mutation in a severe myopic anisometropia family: A case report. Medicine 5 28614238
2013 UNC5H4-induced apoptosis in non-small cell lung cancer is not dependent on p53 status only. Oncology letters 3 24179525
2024 The expression of UNC5D is abnormal in the early stage of colorectal tumors associated with its proliferation and migration. European review for medical and pharmacological sciences 2 38235871

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