Affinage

VHL

von Hippel-Lindau disease tumor suppressor · UniProt P40337

Round 2 corrected
Length
213 aa
Mass
24.2 kDa
Annotated
2026-04-28
130 papers in source corpus 45 papers cited in narrative 45 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VHL encodes the substrate-recognition subunit of a Cullin 2–Elongin B/C–Rbx1 E3 ubiquitin ligase that serves as the principal effector of the cellular oxygen-sensing pathway by targeting prolyl-hydroxylated HIF-α subunits for polyubiquitination and proteasomal degradation (PMID:10353251, PMID:11292862, PMID:10973499). The β-domain of pVHL directly engages the hydroxyproline residue of HIF-α in a stereospecific pocket, while the α-domain recruits ElonginC to assemble the E3 complex; tumor-associated mutations cluster at both interfaces and abolish HIF-α ubiquitylation, driving constitutive activation of hypoxia-inducible genes including VEGF, EPO, and CXCR4 that underlie von Hippel–Lindau disease, Chuvash polycythemia, and clear-cell renal cell carcinoma (PMID:12004076, PMID:12050673, PMID:11987242, PMID:12086860). Beyond HIF, pVHL stabilizes astral microtubules to ensure correct mitotic spindle orientation and chromosomal stability, participates in SOCS1-mediated K63-ubiquitylation-dependent DNA double-strand break repair, suppresses autophagy initiation by binding PHD1-hydroxylated Beclin 1 to block ATG14L association, and regulates mitochondrial respiration through CHCHD4 (PMID:19620968, PMID:23455319, PMID:38360997, PMID:30338240). pVHL stability is itself regulated by SUMOylation, K11-linked ubiquitination by UBE2S, and antagonistic interactions with Daam2 and RSUME, and its HIF-α-binding pocket has been co-opted pharmacologically as a recruitment module for targeted protein degradation (PMID:20844582, PMID:38915206, PMID:29053101, PMID:25500545, PMID:40555806).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1993 High

    Positional cloning identified VHL as the gene mutated in von Hippel–Lindau disease and sporadic renal cell carcinoma, establishing it as a tumor suppressor but leaving its biochemical function unknown.

    Evidence Positional cloning, restriction fragment analysis, and sequencing of VHL patient cell lines and sporadic RCC

    PMID:8493574

    Open questions at the time
    • Protein function and binding partners were entirely unknown
    • Mechanism of tumor suppression was unclear
  2. 1995 High

    Discovery that pVHL binds Elongin B/C via a region recurrently mutated in tumors provided the first physical interactors and linked disease mutations to a specific protein–protein interface.

    Evidence In vitro binding assays, co-immunoprecipitation, and peptide competition with tumor-derived mutants

    PMID:7660130

    Open questions at the time
    • The physiological substrate of the putative complex was unknown
    • Whether the complex had enzymatic activity was untested
  3. 1999 High

    Connecting pVHL to oxygen-dependent HIF-α degradation answered the central question of what substrate VHL targets, and the crystal structure of the VCB ternary complex revealed how disease mutations map to two functional surfaces.

    Evidence Co-immunoprecipitation and genetic rescue in VHL-defective cells; X-ray crystallography at 2.7 Å

    PMID:10205047 PMID:10353251

    Open questions at the time
    • The post-translational modification on HIF-α that licenses pVHL binding was unknown
    • Direct E3 ligase activity had not been reconstituted biochemically
  4. 2000 High

    Biochemical reconstitution of a purified VHL–ElonginB/C–Cul2–Rbx1 complex that ubiquitinates HIF-1α established pVHL as a bona fide E3 ubiquitin ligase, and domain mapping showed the β-domain recruits substrate while the α-domain scaffolds the ligase.

    Evidence In vitro ubiquitination with purified recombinant proteins; domain mutagenesis and complementation in VHL-null RCC extracts

    PMID:10823831 PMID:10878807 PMID:10973499

    Open questions at the time
    • The oxygen-sensing modification on HIF-α had not been identified
    • The enzyme responsible for HIF-α modification was unknown
  5. 2001 High

    Identification of prolyl hydroxylation as the oxygen-dependent signal read by pVHL completed the core oxygen-sensing circuit: PHD enzymes use O₂ and Fe²⁺ to hydroxylate HIF-α Pro564 (and a second site), creating the pVHL-binding degron.

    Evidence Mass spectrometry, in vitro binding with hydroxylated versus unmodified peptides, enzymatic reconstitution of PHD activity, RNAi in Drosophila cells

    PMID:11292861 PMID:11292862 PMID:11566883 PMID:11598268

    Open questions at the time
    • Structural basis for hydroxyproline discrimination was unresolved
    • Whether HIF was the sole tumor-relevant VHL substrate was untested
  6. 2002 High

    High-resolution crystal structures of hydroxylated HIF-α peptide bound to pVHL revealed the atomic mechanism of hydroxyproline recognition, and in vivo epistasis showed HIF escape overrides VHL-mediated tumor suppression, confirming HIF as a critical effector; separately, a VHL R200W mutation was shown to cause Chuvash polycythemia via EPO deregulation.

    Evidence X-ray crystallography at 1.85 Å; nude mouse xenograft with HIF escape mutant; genetic linkage and sequencing in Chuvash polycythemia families

    PMID:11987242 PMID:12004076 PMID:12050673 PMID:12086860

    Open questions at the time
    • HIF-independent tumor-suppressive functions of VHL were not yet characterized
    • Whether additional substrates use the same hydroxylation-recognition mechanism was unknown
  7. 2006 Medium

    Identification of pVHL as a stabilizer of p53 and a regulator of E-cadherin expression expanded the functional repertoire beyond HIF degradation, linking VHL loss to defective apoptosis and epithelial–mesenchymal transition in renal cancer.

    Evidence Co-IP of pVHL–p53, Mdm2 ubiquitination assays, VHL re-expression restoring E-cadherin in VHL-null RCC lines

    PMID:16585181 PMID:16969113

    Open questions at the time
    • p53 regulation by VHL was demonstrated in a single lab and awaits independent confirmation
    • Whether E-cadherin suppression is solely HIF-dependent in all tissue contexts was not resolved
  8. 2009 High

    Demonstration that pVHL localizes to the mitotic spindle and stabilizes astral microtubules, with VHL disease mutants unable to rescue spindle misorientation, established a HIF-independent role in chromosomal stability.

    Evidence Immunofluorescence, spindle orientation and chromosomal instability assays, disease mutant re-expression in mammalian cells

    PMID:19620968

    Open questions at the time
    • Direct molecular target on microtubules was not identified
    • Whether this function is separable from E3 ligase activity was unclear
  9. 2010 Medium

    Multiple regulatory layers on pVHL itself were uncovered: SUMOylation at Lys171 promotes nuclear retention and stability, VHL loss causes primary cilium regression via HIF-dependent Aurora A induction, and Drosophila VHL stabilizes microtubule bundles for epithelial polarity.

    Evidence SUMO/Ub fusion proteins with subcellular fractionation; RNAi of Aurora A in VHL-null cells; Drosophila genetics with paclitaxel rescue

    PMID:20388653 PMID:20844582 PMID:20864688

    Open questions at the time
    • The SUMO E3 ligase for VHL was not identified
    • Whether cilium loss is a primary driver of ccRCC was untested
    • Microtubule-stabilizing mechanism not structurally resolved
  10. 2013 Medium

    New dimensions of VHL biology emerged: SOCS1-driven K63-ubiquitylation recruits VHL to DNA damage sites for homologous recombination repair; Daam2 targets VHL for degradation in glioma; missense VHL mutants are unstable but catalytically competent and can be rescued by HDAC inhibitors; and VHL maintains β-cell identity by suppressing Sox9.

    Evidence Co-IP, HR repair assays, comet assays; ubiquitination assays with Daam2; chaperonin binding and HDAC inhibitor treatment in xenografts; conditional Vhl KO in mouse pancreas

    PMID:23318261 PMID:23455319 PMID:24298056 PMID:29053101

    Open questions at the time
    • SOCS1-VHL DDR axis lacks structural characterization
    • Daam2–VHL antagonism reported from a single group
    • HDAC-inhibitor stabilization of mutant VHL not yet in clinical testing
  11. 2016 High

    ID2 was identified as an endogenous inhibitor that displaces Cullin 2 from the VHL complex to block HIF-2α ubiquitylation, with this inhibition reversed by DYRK1-mediated phosphorylation of ID2 under normoxia, revealing a second oxygen-dependent regulatory tier over VHL activity.

    Evidence Co-IP, ubiquitination assays, kinase assays with phospho-mutagenesis, in vivo glioblastoma models

    PMID:26735018

    Open questions at the time
    • Whether ID2 regulation is active in renal epithelium was not shown
    • Structural basis of ID2–VHL interaction unknown
  12. 2017 High

    Genome-wide chromatin studies demonstrated that VHL loss stabilizes HIF2α–HIF1β at enhancers recruiting p300, establishing a pervasive enhancer reprogramming mechanism in ccRCC; separately, VHL loss alone induces replication stress that constrains growth, with PBRM1 co-deletion rescuing this barrier to enable carcinoma.

    Evidence ChIP-seq and ATAC-seq across primary tumors and cell lines with VHL re-expression; conditional Vhl/Pbrm1 double-KO mouse developing multifocal carcinomas

    PMID:28893800 PMID:29229903

    Open questions at the time
    • How PBRM1 loss alleviates VHL-induced replication stress mechanistically was not defined
    • Enhancer targets driving metastasis versus primary tumor growth were not separated
  13. 2019 High

    TBK1 was identified as a hydroxylation-dependent VHL substrate analogue: PHD-mediated hydroxylation of TBK1 Pro48 promotes VHL binding and PPM1B-mediated dephosphorylation, linking VHL loss to innate immune kinase hyperactivation and p62-dependent renal cancer proliferation.

    Evidence Co-IP, MS-confirmed hydroxylation, kinase assay, genetic KO, xenograft

    PMID:31810986

    Open questions at the time
    • Whether TBK1 is polyubiquitinated and degraded by VHL or only dephosphorylated needs clarification
    • Extent of PHD-dependent but HIF-independent VHL substrates not systematically catalogued
  14. 2024 High

    A HIF-independent tumor-suppressive arm was defined: pVHL binds PHD1-hydroxylated Beclin 1 at Pro54, blocking Beclin 1–ATG14L interaction and autophagy initiation; separately, UBE2S was shown to catalyze K11-linked ubiquitination of VHL at Lys171/Lys196 without an E3 ligase, destabilizing VHL in hepatocellular carcinoma.

    Evidence Hydroxylation and binding assays with Beclin 1 P54A mutant, autophagy initiation assays, mouse tumor models; E3-independent ubiquitination assay with UBE2S, mutagenesis

    PMID:38360997 PMID:38915206

    Open questions at the time
    • Relative contribution of autophagy suppression versus HIF degradation to VHL tumor suppression is unquantified
    • UBE2S E3-independent mechanism awaits structural characterization
  15. 2025 High

    The HIF-α-binding pocket on pVHL was pharmacologically hijacked by a molecular glue degrader that recruits the neosubstrate CDO1 into the VHL E3 ligase complex for selective degradation, validating pVHL as a versatile drug-induced proximity module.

    Evidence Protein array screen, mutagenesis, X-ray crystallography of ternary pVHL–degrader–CDO1 complex, in-cell degradation assay

    PMID:40555806

    Open questions at the time
    • In vivo efficacy and selectivity of molecular glue degraders using VHL are early-stage
    • Structural basis for neosubstrate selectivity beyond CDO1 is unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • A systematic inventory of all PHD-dependent, hydroxylation-licensed VHL substrates beyond HIF-α, TBK1, and Beclin 1 is lacking, and how pVHL's HIF-independent functions (microtubule stabilization, DDR, autophagy suppression) are coordinately regulated remains undefined.
  • No proteome-wide hydroxylation-dependent VHL interactome has been published
  • Structural basis of VHL–microtubule interaction unknown
  • Relative contribution of each VHL function to tumor suppression in different tissues not delineated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016874 ligase activity 5 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005634 nucleus 2 GO:0005856 cytoskeleton 2 GO:0005829 cytosol 1 GO:0005929 cilium 1
Pathway
R-HSA-8953897 Cellular responses to stimuli 7 R-HSA-392499 Metabolism of proteins 6 R-HSA-1643685 Disease 4 R-HSA-1640170 Cell Cycle 2 R-HSA-73894 DNA Repair 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
BECN1CUL2DAAM2ELOBELOCEPAS1HIF1ASOCS1
Complex memberships
VCB-Cul2 (VHL–ElonginB–ElonginC–Cullin2–Rbx1 E3 ligase)

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 The VHL gene was identified by positional cloning as the von Hippel-Lindau disease tumor suppressor gene; it encodes two widely expressed transcripts and its intragenic mutations were found in VHL patient cell lines and sporadic renal cell carcinomas. Positional cloning, restriction fragment analysis, sequencing Science High 8493574
1995 pVHL binds directly to Elongin B and Elongin C via a short colinear region that is frequently mutated in human tumors; a peptide from this region inhibited binding in vitro, and a tumor-associated point mutant abolished inhibition. In vitro binding assay, in vivo co-immunoprecipitation, peptide competition Science High 7660130
1999 pVHL is required for oxygen-dependent proteolysis of HIF-α subunits; in VHL-defective cells HIF-α is constitutively stabilized and HIF-1 is activated; re-expression of pVHL restores oxygen-dependent instability. pVHL and HIF-α co-immunoprecipitate and the interaction is iron-dependent. Co-immunoprecipitation, reexpression of pVHL in VHL-defective cells, reporter assays Nature High 10353251
1999 Crystal structure of the VHL–ElonginC–ElonginB ternary complex at 2.7 Å resolution revealed two interfaces: one between VHL and ElonginC, and another between ElonginC and ElonginB. Tumorigenic mutations cluster in the 35-residue ElonginC-binding domain of VHL, and a separate mutational patch on VHL indicates a second macromolecular binding site. The structural similarity to the SCF complex supports VHL functioning as an F-box protein equivalent. X-ray crystallography (2.7 Å), structure-based mutagenesis analysis Science High 10205047
2000 pVHL, through its β-domain, binds directly to HIF-α and targets it for ubiquitination in an α-domain-dependent manner; pVHL functions analogously to an F-box protein recruiting substrates to a ubiquitination machine. VHL-deficient renal carcinoma cell extracts have a specific defect in HIF-α ubiquitylation activity complemented by exogenous pVHL. Co-immunoprecipitation, ubiquitination assay, domain mutagenesis Nature Cell Biology High 10878807
2000 A reconstituted purified recombinant VHL complex (with Elongin B/C, Cullin2, Rbx1) functions with E1 and E2 enzymes to activate HIF-1α ubiquitination in vitro, providing direct biochemical evidence that VHL is an E3 ubiquitin ligase for HIF-1α. In vitro ubiquitination reconstitution with purified recombinant proteins Proceedings of the National Academy of Sciences High 10973499
2000 Short conserved sequences within the internal transactivation domains of HIF-α are sufficient for recognition by pVHL; tumor-associated β-domain mutations in pVHL disrupt HIF-α interaction and abolish HIF-α ubiquitylation and regulation. Co-immunoprecipitation, ubiquitylation assay, mutagenesis, deletion analysis Journal of Biological Chemistry High 10823831
2000 VHL-mediated ubiquitination of HIF-1α under normoxic conditions requires its interaction with the core oxygen-dependent degradation domain of HIF-1α; one tumor-associated VHL mutation impaired HIF-1α interaction and degradation. HIF-1α stabilization requires both nuclear translocation and an intranuclear hypoxia-dependent signal, and VHL is not released from HIF-1α during this process. Co-immunoprecipitation, ubiquitination assay, domain mutagenesis, cell fractionation The EMBO Journal High 10944113
2001 HIF-1α is targeted for VHL-mediated destruction by oxygen- and Fe2+-dependent prolyl hydroxylation: pVHL binds to a HIF-derived peptide only when a conserved proline residue at its core is hydroxylated, linking O2 availability directly to HIF stability. In vitro binding assay with hydroxylated peptide, mass spectrometry, cell-based reporter Science High 11292862
2001 HIF-α prolyl-hydroxylase (HIF-PH/PHD) hydroxylates Pro564 of HIF-1α; this modification requires dioxygen as a cosubstrate and iron as cofactor, targeting HIF-1α for recognition by the pVHL E3 ligase complex. This identifies HIF-PH as a direct cellular oxygen sensor. Mass spectrometry, in vitro hydroxylation assay, site-directed mutagenesis, cell-based degradation assay Science High 11292861
2001 Two independent destruction domains in HIF-α, each containing a core prolyl hydroxylation motif, are independently and non-redundantly targeted for ubiquitylation by the VHL E3 ligase; both sites differ in sequence and conditions of pVHL binding. In vitro and in vivo ubiquitylation assays, mutagenesis, deletion constructs The EMBO Journal High 11566883
2001 HIF-1α Pro564 hydroxylation is the primary regulator of VHL binding, demonstrated by in vivo co-immunoprecipitation with a panel of HIF-1α point mutants and by mass spectrometry and in vitro binding assays. Co-immunoprecipitation, mass spectrometry, in vitro binding assay, mutagenesis Proceedings of the National Academy of Sciences High 11504942
2001 Factor inhibiting HIF-1 (FIH-1) binds to both HIF-1α and VHL; VHL also functions as a transcriptional corepressor by recruiting histone deacetylases to inhibit HIF-1α transactivation function independently of its ubiquitin-mediated degradation role. Co-immunoprecipitation, reporter assay, HDAC inhibitor treatment Genes & Development High 11641274
2001 A conserved family of prolyl-4-hydroxylases (HPH/PHD enzymes) hydroxylates HIF-α; overexpression of HPH attenuates inappropriate HIF-1α accumulation under normoxia, and RNAi suppression of HPH in Drosophila cells elevates hypoxia-inducible gene expression under normoxia. Overexpression, RNAi knockdown, reporter assay Science High 11598268
2002 Crystal structure of an HIF-1α hydroxypeptide–pVHL–ElonginB–ElonginC complex at 1.85 Å resolution showed that HIF-1α binds pVHL in an extended β strand-like conformation; the hydroxyproline inserts into a hydrophobic gap in pVHL at a tumorigenic mutation hotspot, with its 4-hydroxyl recognized by buried Ser and His residues, explaining strict specificity. X-ray crystallography (1.85 Å) Science High 12004076
2002 Crystal structure of hydroxylated HIF-1α peptide bound to VCB (pVHL, Elongin C, Elongin B) revealed a single conserved hydroxyproline-binding pocket in pVHL; optimized hydrogen bonding to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues. X-ray crystallography, solution binding assays Nature High 12050673
2002 ARD1 acetyltransferase directly binds HIF-1α and acetylates it, enhancing pVHL interaction and HIF-1α ubiquitination, identifying acetylation as an additional post-translational modification that promotes pVHL-mediated HIF-1α proteasomal degradation. Co-immunoprecipitation, in vitro acetylation assay, ubiquitination assay, mutagenesis Cell High 12464182
2002 HIF is a critical downstream target required for tumor suppression by pVHL: a HIF variant that escapes pVHL control overrides tumor suppression in nude mouse xenograft experiments with VHL−/− renal carcinoma cells. Nude mouse xenograft tumor formation, HIF escape mutant overexpression Cancer Cell High 12086860
2002 A homozygous R200W mutation in VHL causes Chuvash polycythemia, an autosomal recessive disorder associated with elevated erythropoietin levels, demonstrating that disruption of pVHL function leads to failure to degrade HIF-1α, upregulation of EPO, and polycythemia. Genome-wide linkage screen, gene sequencing, family segregation analysis Blood Cells, Molecules & Diseases High 11987242
2003 pVHL negatively regulates CXCR4 chemokine receptor expression through its capacity to target HIF for degradation under normoxic conditions; hypoxia and VHL loss lead to HIF-dependent CXCR4 upregulation, linking VHL/HIF to organ-specific metastasis. Reporter assay, immunohistochemistry, cell-based CXCR4 expression with pVHL re-expression Nature High 13679920
2006 VHL inactivation induces down-regulation of E-cadherin in renal cancer cells via HIF activation; re-expression of VHL in VHL-defective cell lines restores E-cadherin expression, and HIF activation is both necessary and sufficient to suppress E-cadherin. VHL re-expression in VHL-defective cell lines, HIF dominant-negative/overexpression, western blot, immunohistochemistry Cancer Research High 16585181
2006 pVHL directly associates with p53 and positively regulates it by inhibiting Mdm2-mediated ubiquitination and recruiting p53-modifying enzymes; VHL-deleted RCC cells show attenuated apoptosis and abnormal cell-cycle arrest upon DNA damage, restored by pVHL re-expression. Co-immunoprecipitation, ubiquitination assay, cell-cycle analysis, apoptosis assay Cell Cycle Medium 16969113
2009 pVHL localizes to the mitotic spindle in mammalian cells; its functional inactivation causes spindle misorientation linked to unstable astral microtubules, spindle checkpoint weakening due to reduced Mad2 levels, and chromosomal instability. Re-expression of pVHL or Mad2 rescues these defects. VHL disease mutants defective in microtubule stabilization cannot rescue spindle misorientation. Immunofluorescence localization, spindle orientation assay, chromosomal instability assay, western blot, VHL mutant re-expression Nature Cell Biology High 19620968
2010 VHL inactivation induces HEF1/NEDD9 and Aurora kinase A via stabilization of HIF-1 and HIF-2; Aurora kinase A causes regression of the primary cilium by promoting HDAC-dependent tubulin depolymerization of the ciliary axoneme; suppression of this pathway improved primary cilia formation and reduced cell motility in VHL-defective renal cancer cells. Western blot, immunofluorescence, RNAi knockdown, motility assay, HIF stabilization Journal of the American Society of Nephrology High 20864688
2010 pVHL undergoes both ubiquitylation (at Lys171 and Lys196) and SUMOylation (at Lys171); ubiquitylated VHL is predominantly cytoplasmic while SUMOylated VHL shows increased stability and nuclear redistribution. Substitution of Lys171 and Lys196 abolishes VHL's inhibitory function on HIF-α transcriptional activity and tube formation. VHL-SUMO/ubiquitin fusion proteins, subcellular fractionation, reporter assay, in vitro tube formation assay, mutagenesis PLoS ONE Medium 20844582
2013 SOCS1 promotes K63-ubiquitylation and nuclear redistribution of VHL in response to DNA double-strand breaks; loss of VHL or mutations compromising its K63-ubiquitylation attenuates the DNA-damage response, decreases homologous recombination repair, and leads to persistence of DSBs. Co-immunoprecipitation, ubiquitination assay, comet assay, HR repair assay, cell fractionation Oncogene Medium 23455319
2013 Missense mutant pVHL proteins are unstable due to misfolding and imbalanced chaperonin binding, yet retain E3 ligase function including HIF degradation; HDAC inhibitors stabilize mutant pVHL by inhibiting the HDAC-Hsp90 chaperone axis, restoring activity comparable to wild-type both in vitro and in animal models. Protein stability assay, E3 ligase activity assay, chaperonin binding assay, HDAC inhibitor treatment, xenograft model Cell Reports Medium 23318261
2013 pVHL interacts with Daam2 via direct biochemical association; Daam2 promotes VHL ubiquitination and degradation, suppressing VHL expression in glioma cells and thereby driving tumorigenesis. An inverse correlation between Daam2 and VHL was confirmed across cancer types. Co-immunoprecipitation, ubiquitination assay, protein expression screening, xenograft eLife (published 2017) Medium 29053101
2014 DJ-1 (PARK7) negatively regulates VHL ubiquitination activity by inhibiting the HIF-1α–VHL interaction; DJ-1 deficiency leads to lowered HIF-1α levels under hypoxia and oxidative stress, and HIF-1α accumulation rescues DJ-1-deficient neurons against MPP+ toxicity. Co-immunoprecipitation, ubiquitination assay, HIF-1α stabilization assay, neuronal toxicity assay Journal of Neuroscience Medium 24899725
2013 pVHL in mouse kidneys controls oriented cell division and faithful mitotic checkpoint function in vivo: Vhl-deficient kidney cells after ischemic injury show spindle misorientation, lagging chromosomes, and aneuploidy; long-term, Vhl-deficient kidneys develop ccRCC precursor lesions including cysts and clear cell dysplasia. Conditional Vhl knockout mouse model, ischemic kidney injury, spindle orientation assay, cytogenetic analysis, histopathology Cancer Research High 24362914
2013 The adenoviral protein Gam1, carrying a BC-box domain, associates with Elongin B/C and promotes VHL protein degradation via a CRL-dependent mechanism, leading to HIF-1α stabilization; cellular BC-box and SOCS domain-containing proteins similarly promote VHL degradation in a SOCS domain-dependent manner. Co-immunoprecipitation, ubiquitination assay, western blot, HIF-1α reporter assay Proceedings of the National Academy of Sciences Medium 24145437
2014 RSUME physically interacts with pVHL, sumoylates it, and negatively regulates assembly of the pVHL–Elongin–Cullin (ECV) complex, inhibiting HIF-1α and HIF-2α ubiquitination and degradation. RSUME is required for the loss of function of type-2 pVHL mutants in VHL tumors. Co-immunoprecipitation, sumoylation assay, ubiquitination assay, reporter assay, xenograft Oncogene Medium 25500545
2016 ID2 binds to the VHL ubiquitin ligase complex, displaces VHL-associated Cullin 2, and impairs HIF-2α ubiquitylation and degradation; DYRK1A/B phosphorylation of ID2 at Thr27 blocks ID2–VHL interaction and preserves HIF-2α ubiquitylation; PHD1-stimulated DYRK1 activity under normoxia promotes this phosphorylation. Co-immunoprecipitation, ubiquitination assay, kinase assay, phospho-mutagenesis, in vivo glioblastoma models Nature High 26735018
2017 VHL loss stabilizes the HIF2α–HIF1β heterodimer at enhancers, subsequently recruiting histone acetyltransferase p300 to acquire active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes, driving pervasive enhancer malfunction and oncogene activation. ChIP-seq, ATAC-seq, chromatin profiling across 10 primary tumor/normal pairs and 9 cell lines, VHL re-expression Cancer Discovery High 28893800
2017 Loss of VHL alone causes DNA replication stress and damage accumulation that constrains cellular growth; concomitant loss of PBRM1 rescues VHL-induced replication stress, maintaining cellular fitness and allowing proliferation; combined Vhl/Pbrm1 deletion in mouse kidney is sufficient for fully penetrant multifocal carcinomas. DNA damage assays, replication stress markers, conditional mouse KO model, histopathology Nature Communications High 29229903
2018 VHL re-expression in pVHL-defective renal carcinoma cells elevates CHCHD4 (a mitochondrial intermembrane space protein import component) expression alongside respiratory chain subunits, and increases oxygen consumption rate, demonstrating a HIF-independent role for pVHL in regulating mitochondrial function. Western blot, oxygen consumption rate measurement, VHL mutant expression, HIF-2α knockdown Frontiers in Oncology Medium 30338240
2018 VHL deficiency in myeloid cells uplifts glycolytic metabolism and decreases respiratory capacity in alveolar macrophages via HIF1α; this metabolic shift alters epigenetic modification of the osteopontin gene, with the metabolic intermediate 3-phosphoglyceric acid as a checkpoint controller affecting type-2 innate lymphoid cell function. Conditional Vhl KO in myeloid cells, metabolic flux assays, ChIP for histone marks, HIF1α inhibition/ablation rescue Journal of Experimental Medicine Medium 30463876
2019 TBK1 is hyperactivated by VHL loss; TBK1 hydroxylation on Pro48 triggers VHL binding as well as phosphatase PPM1B binding, decreasing TBK1 phosphorylation; TBK1 phosphorylates p62/SQSTM1 on Ser366, which is essential for p62 stability and kidney cancer cell proliferation. Co-immunoprecipitation, kinase assay, mass spectrometry, hydroxylation assay, genetic KO, xenograft model Cancer Discovery High 31810986
2019 CDK4/6 activity is synthetically lethal with VHL inactivation in human ccRCC cells and Drosophila models; although HIF-2α transcriptionally induces cyclin D1, HIF-2α is not required for the increased CDK4/6 requirement of VHL-deficient cells, demonstrating a HIF-independent synthetic lethal interaction. CRISPR/RNAi screens, Drosophila genetic epistasis, CDK4/6 inhibitor treatment across cell lines and xenografts Science Signaling High 31575731
2020 VHL directly interacts with Daam2; the E3 ubiquitin ligase Nedd4 stabilizes VHL via K63-linked ubiquitination; antagonism between Daam2 and VHL regulates oligodendrocyte differentiation during development and remyelination after white matter injury. Co-immunoprecipitation, conditional KO mouse models, proteomic analysis, ubiquitination assay Genes & Development Medium 32792353
2024 VHL suppresses nutrient stress-induced autophagy in a HIF-independent manner: VHL directly binds to Beclin1 after PHD1-mediated hydroxylation of Beclin1 on Pro54, inhibiting Beclin1–VPS34 complex association with ATG14L and thereby blocking autophagy initiation. Non-hydroxylatable Beclin1 P54A abolishes VHL-mediated autophagy inhibition and reduces tumor-suppressing effect of VHL in ccRCC. Co-immunoprecipitation, hydroxylation assay, autophagy initiation assay, mutagenesis, mouse tumor models The EMBO Journal High 38360997
2024 UBE2S promotes K11-linked polyubiquitination of VHL at Lys171 and Lys196 independently of an E3 ligase, leading to VHL proteasomal degradation, HIF-1α stabilization, and enhanced glycolysis in hepatocellular carcinoma. Ubiquitination assay, site-directed mutagenesis, VHL knockdown/overexpression, metabolomics Clinical and Molecular Hepatology Medium 38915206
2010 Drosophila VHL promotes epithelial morphogenesis by stabilizing microtubule bundles and aPKC; VHL mutant follicle cells show microtubule defects leading to aPKC mislocalization and loss of epithelial integrity; paclitaxel-induced microtubule stabilization rescues aPKC localization in VHL mutant cells. Drosophila genetics, immunofluorescence, pharmacological rescue (paclitaxel), ex vivo culture Development Medium 20388653
2013 VHL deletion in pancreatic β-cells triggers ectopic expression of Sox9, which normally promotes pancreas progenitor identity; β-cell-specific Sox9 overexpression causes diabetes mellitus by disrupting β-cell identity through altered Notch, Wnt, and Hedgehog signaling cascades, revealing VHL's role in maintaining β-cell differentiation state. Transgenic mouse Vhl deletion and Sox9 overexpression, gene expression analysis, histopathology Genes & Development Medium 24298056
2025 A small molecule binds the HIF1α-binding pocket on pVHL and acts as a molecular glue degrader by recruiting the neosubstrate cysteine dioxygenase 1 (CDO1) into the VHL–Cullin–RING E3 ligase complex, leading to its selective ubiquitin-dependent degradation; the CDO1 binding region was confirmed by mutagenesis, protein-protein docking, and X-ray structure of the ternary pVHL–CDO1–degrader complex. Protein array binding screen, mutagenesis, molecular dynamics, X-ray crystallography of ternary complex Nature Chemical Biology High 40555806

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science (New York, N.Y.) 4644 11292861
1999 The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 4200 10353251
2001 HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science (New York, N.Y.) 3932 11292862
1993 Identification of the von Hippel-Lindau disease tumor suppressor gene. Science (New York, N.Y.) 2390 8493574
2001 A conserved family of prolyl-4-hydroxylases that modify HIF. Science (New York, N.Y.) 2101 11598268
2013 ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in medicine : official journal of the American College of Medical Genetics 1945 23788249
1994 Mutations of the VHL tumour suppressor gene in renal carcinoma. Nature genetics 1502 7915601
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1994 Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proceedings of the National Academy of Sciences of the United States of America 1358 7937876
2000 Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nature cell biology 1295 10878807
2001 FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes & development 1173 11641274
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2002 Germ-line mutations in nonsyndromic pheochromocytoma. The New England journal of medicine 1038 12000816
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
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