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FLASH GENE
Symbol VHL contributors: mct/shn - updated : 13-07-2018
HGNC name von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase
HGNC id 12687
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • N-terminal acidic domain phosphorylated by casein kinase-2 for its tumor suppressor function
  • eight copies of a repeated pentamer GEExE in the N terminal region
  • putative glycan anchored membrane protein
  • a C terminal BC-box critical motif (binding elongin B)
    • HOMOLOGY
    interspecies ortholog to Vhl, Mus musculus
    ortholog to vhl, Danio rerio
    ortholog to Vhl, Rattus norvegicus
    Homologene
    FAMILY
  • ubiquitin ligase family
    • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus,nucleoplasm
    text
  • highly mobile cytoplasmic protein, which becomes an immobile centrosomal protein after ATP-depletion in living cells
    • basic FUNCTION
  • direct role in fibronectin matrix assembly (
  • tumor suppressor protein, playing a role in ciliary maintenance
  • control of extracellular matrix formation and cell cycle exit
  • having a crucial role in endochondral bone development and is necessary for normal chondrocyte proliferation
  • represses oncogenic beta-catenin signaling in renal carcinoma cells
  • ciliary protein that controls ciliogenesis in kidney cells, needed to orient the growth of microtubules toward the cell periphery
  • participates in many cellular processes including oxygen sensing, microtubule stability and primary cilia regulation
  • promoting E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and SNAIl
  • powerful putative tumour suppressor gene in human breast cancer
  • participates in the hypoxia-mediated degradation of plasma membrane Na-K-ATPase in a HIF-independent manner
  • functions as part of an E3 ubiquitin ligase complex that targets proteins for proteasomal degradation
  • probably requires additional co-operating signalling pathways for clear-cell RCC (renal cell carcinoma) initiation and tumorigenesis
  • controls cilia function and its inactivation may result in both malignant or nonmalignant growth of epithelial cells and that this effect is in part mediated through the accumulation of hypoxia-inducible factors
  • with RNF4 regulate the proteasomal degradation of SUMO-conjugated HIF2A
  • interferes with angiogenesis and also controls cell adhesion and invasion
  • destabilizes the F-box protein SKP2, a chief component of Skp, Cullin, F-box-containing complex that promotes DNA synthesis in the S phase
  • plays an important role in regulation of cytokinesis
  • directly binds SOCS1 to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction
  • VHL limits EGFR signaling by promoting CBL-independent poly-ubiquitylation of the activated receptor, which likely results in its degradation by proteasome
  • in the retinal pigment epithelium (RPE) is essential for normal ocular growth and vascular development
  • VHL-dependent regulation of HIF1A in the RPE is essential for normal RPE and iris development, ocular growth and vascular development in the anterior chamber, whereas VHL-dependent regulation of other downstream pathways is crucial for normal development and maintenance of the retinal vasculature
  • inhibits Hedgehog-Gli activation through suppression of GLI1 nuclear localization
  • inhibits ribosome biogenesis and protein synthesis
  • novel function of VHL in the response to DNA damage, demonstrating a negative-feedback loop between VHL and E2F1, which may shed new light on the explanation of the role of VHL in tumour suppression
  • direct evidence for a key role of VHL in mediating oriented cell division and faithful mitotic checkpoint function in the renal epithelium, emphasizing the importance of VHL as a controller of mitotic fidelity
  • regulates bone morphogenesis as its loss considerably alters size, shape and overall development of the skeletal elements
  • is important for endochondral bone development, since loss of VHL in chondrocytes causes severe dwarfism
  • subcellular translocation of VHL plays an important role in microtubular structure alteration-induced HIF1A regulation (pMID: 25779090)
    • CELLULAR PROCESS cell cycle
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • complexing with CUL2, elongin B, C complex Rbx/ROC1, VBP1 and an ubiquitin conjugating enzyme other than CDC34, either UBE2B, UBE2D1, UBE2L6 or others to form an active E3 ubiquitin ligase complex named the VCB-CUL2 complex
  • component of the E3 ubiquitin ligase complex
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • Elongin B and C (
  • von Hippel-Lindau binding protein 1, VBP1 (
  • cullin 2, CUL2 (
  • Sp1 transcription factor, Sp1 (
  • Fibronectin (
  • tricellulin, TRiC (
  • Hypoxia inducible factor-alpha, HIF-alpha (
  • heteronuclear ribonucleoprotein a2, hnRNPA2 (
  • Hypoxia-inducible factor 1, HIF1 (
  • VHL-interacting deubiquitinating enzyme 1, VDU1 (
  • translocation in renal carcinoma on chromosome 8 protein, TRC8 (
  • VDU1 and VDU2 (
  • Jade-1 (
  • HIF-3 alpha (
  • hyperphosphorylated Rpb1 (
  • RNA polymerase II subunit B7, RPB7 (
  • Tat-binding protein-1, TBP1 (
  • iron regulatory protein 2, IRP2 (
  • tumorous imaginal discs protein Tid56 homolog, TID1
  • p53 (
  • p22phox (
  • myogenin, MYOG (
  • PKCzetaII (
  • endogenously binds the neuronal kinesin-2 complex, KIF5C
  • beta(2)-adrenergic receptor, beta(2)AR (
  • SUMO E3 ligase PIASy
  • S-phase kinase-associated protein 2, E3 ubiquitin protein ligase, SKP2
  • MYBBPC1A is a novel substrate of VHL
  • SOCS1-cooperative negative regulator of JAK2
  • VHL inactivation decreases H3K4Me3 levels through KDM5C, which alters gene expression and suppresses tumor growth
  • ARF tumor suppressor interacts with VHL30, a longer VHL isoform
  • sprouty homolog 2 (Drosophila), SPRY2
  • controls hypoxia-inducible transcription factor (HIF1A)-mediated adaptation
  • possible regulation of VHL by NEK1 that may contribute to ciliary homeostasis and cystogenesis
  • VHL is a downstream target of E2F1, which harbours an E2F1-binding site in its promoter
  • suppresses androgen-induced cell proliferation, implicating a physiological role of VHL in androgen-induced signaling pathway
  • novel function of VHL in the regulation of AR transcription activity
  • CTNNB1 links VHL to AURKA and loss of primary cilia in renal cell carcinoma
  • NEK8 may be a new HIF target gene and VHL can down-regulate NEK8 via HIFs to maintain the primary cilia structure in human renal cancer cells
  • functional RWDD3/VHL interaction in VHL-related tumor progression
  • CUL2 interacts with both the VHL BC box and cullin box and a novel ELOC site
  • ZNF350 is a novel VHL interacting protein
  • VHL is confirmed to serve as a bridge component for the association of ZNF350 and EP300, which leads to an increase in ZNF350 transcriptional activity in the VHL promoter
  • mediate the ubiquitination of HIF1A in the nuclear compartment prior to HIF1A exportation to the cytoplasm, and VHL dynamic nuclear-cytoplasmic trafficking is indicated to be involved in the process of HIF1A degradation
  • VHL/CDKN2A interaction is specifically mediated by the 53 residue long pVHL30 N-terminal region, suggesting that this N-terminus acts as a further VHL interaction interface
  • VHL is an important regulator of CERKL, and VHL ubiquitinates CERKL for proteasomal degradation
  • DAAM2 promotes tumorigenesis by suppressing VHL expression
  • ZHX2 was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability
  • TFAM is hydroxylated by EGLN3 and subsequently bound by VHL, which stabilizes TFAM by preventing mitochondrial proteolysis
    • cell & other
    REGULATION
    Other downregulation HIF1A
    regulation by KIF5C (KIF5C driven mobility of cytoplasmic VHL might enable VHL to function as a tumour suppressor)
    ASSOCIATED DISORDERS
    corresponding disease(s) VHL , RCC1 , ECYT2
    related resource VonHippel-Lindau disease
    von Hippel-Lindau disease germline mutation database
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   LOH    
    in pheochromocytomas (in VHL, not sporadic)
    tumoral     --low  
    leading to constitutively elevated cyclin D1 and abnormal proliferation
    tumoral somatic mutation      
    in clear cell renal carcinoma associated with end-stage renal disease/acquired cystic disease
    tumoral       loss of function
    in kidney carcinoma, disrupting iron homeostasis in renal carcinoma cells
    tumoral somatic mutation      
    confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma
    tumoral       loss of function
    central role of VHL inactivation in the molecular pathogenesis of both familial and sporadic hemangioblastomas
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • extracellular fibronectin matrix assembly by VHL-/- mouse embryos and mouse embryo fibroblasts (MEFs)was grossly impaired (
  • loss of DVhl in Drosophila resulted in an ventral midline defect (
  • deletion of the Von Hippel-Lindau gene (Vhlh) from intrinsic glomerular cells of mice is sufficient to initiate a necrotizing crescentic glomerulonephritis and the clinical features that accompany rapidly progressive glomerulonephritis (
  • murine embryonic depletion of Vhlh within the pancreatic epithelium causes postnatal lethality due to severe hypoglycemia
  • mice homozygous for the R200W mutation developed polycythemia (
  • Vhlh-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca(2+) concentration, electrical activity, and insulin secretion, which culminate in impaired systemic glucose tolerance (
  • Vhl(2B/2B) mice displayed mid-gestational embryonic lethality, whereas adult Vhl(2B/+) mice exhibited susceptibility to carcinogen-promoted renal neoplasia (
  • pVHL-deficient RCC 786-O cells were multinucleated and polyploid (