VHL_MOUSE
ID VHL_MOUSE Reviewed; 181 AA.
AC P40338;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1995, sequence version 1.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=von Hippel-Lindau disease tumor suppressor;
DE AltName: Full=pVHL;
GN Name=Vhl; Synonyms=Vhlh;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND DEVELOPMENTAL STAGE.
RC STRAIN=ICR; TISSUE=Brain;
RX PubMed=8521303; DOI=10.1007/bf03401583;
RA Kessler P.M., Vasavada S.P., Rackley R.R., Stackhouse T., Duh F.-M.,
RA Latif F., Lerman M.I., Zbar B., Williams B.R.;
RT "Expression of the Von Hippel-Lindau tumor suppressor gene, VHL, in human
RT fetal kidney and during mouse embryogenesis.";
RL Mol. Med. 1:457-466(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7850784;
RA Gao J., Naglich J.G., Laidlaw J., Whaley J.M., Seizinger B.R., Kley N.;
RT "Cloning and characterization of a mouse gene with homology to the human
RT von Hippel-Lindau disease tumor suppressor gene: implications for the
RT potential organization of the human von Hippel-Lindau disease gene.";
RL Cancer Res. 55:743-747(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE.
RC STRAIN=129/SvJ;
RA Kuzmin I., Geil L., Schmidt L., Duh F.-M., Feigenbaum L., Nickerson M.L.,
RA Ma W., Stanbridge E.J., Zbar B., Lerman M.I.;
RT "Human DNA blueprints protecting the VHL promoter and CpG island from
RT methylation are functional in the mouse.";
RL Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Liver, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Involved in the ubiquitination and subsequent proteasomal
CC degradation via the von Hippel-Lindau ubiquitination complex. Seems to
CC act as a target recruitment subunit in the E3 ubiquitin ligase complex
CC and recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic
CC conditions. Involved in transcriptional repression through interaction
CC with HIF1A, HIF1AN and histone deacetylases. Ubiquitinates, in an
CC oxygen-responsive manner, ADRB2 (By similarity). {ECO:0000250}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Component of the VBC (VHL-Elongin BC-CUL2) complex; this
CC complex acts as a ubiquitin-ligase E3 and directs proteasome-dependent
CC degradation of targeted proteins. Interacts with CUL2; this interaction
CC is dependent on the integrity of the trimeric VBC complex. Interacts
CC (via the beta domain) with HIF1A (via the NTAD domain); this
CC interaction mediates degradation of HIF1A in normoxia and, in hypoxia,
CC prevents ubiquitination and degradation of HIF1A by mediating hypoxia-
CC induced translocation to the nucleus, a process which requires a
CC hypoxia-dependent regulatory signal. Interacts with ADRB2; the
CC interaction, in normoxia, is dependent on hydroxylation of ADRB2 and
CC the subsequent VCB-mediated ubiquitination and degradation of ADRB2.
CC Under hypoxia, hydroxylation, interaction with VHL, ubiquitination and
CC subsequent degradation of ADRB2 are dramatically decreased. Interacts
CC with RNF139, USP33 and JADE1 (By similarity). Found in a complex
CC composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts with LIMD1
CC (via LIM zinc-binding 2). Interacts with AJUBA (via LIM domains) and
CC WTIP (via LIM domains) (By similarity). Interacts with EPAS1. Interacts
CC with CARD9 (By similarity). Interacts with DCUN1D1 independently of
CC CUL2; this interaction engages DCUN1D1 in the VCB complex and triggers
CC CUL2 neddylation and consequently cullin ring ligase (CRL) substrates
CC polyubiquitylation (By similarity). Interacts with ALAS1 (hydroxylated
CC form) (By similarity). {ECO:0000250|UniProtKB:P40337}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Membrane {ECO:0000250};
CC Peripheral membrane protein {ECO:0000250}. Nucleus {ECO:0000250}.
CC Note=Colocalizes with ADRB2 at the cell membrane. {ECO:0000250}.
CC -!- DEVELOPMENTAL STAGE: Expressed throughout fetal nephrogenesis,
CC abdominal and thoracic organogenesis, and nervous system development
CC between day 10.5 and day 16.5. In the developing lung, differential
CC expression within the endodermally derived cuboidal epithelial lining
CC of the terminal and respiratory bronchioles. In the developing eye,
CC high expression in both the inner and outer neuroblastic layers of the
CC retina and lens. {ECO:0000269|PubMed:8521303}.
CC -!- DOMAIN: The Elongin BC complex binding domain is also known as BC-box
CC with the consensus [APST]-L-x(3)-C-x(3)-[AILV].
CC -!- SIMILARITY: Belongs to the VHL family. {ECO:0000305}.
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DR EMBL; U12570; AAA20662.1; -; mRNA.
DR EMBL; S76748; AAB33363.1; -; mRNA.
DR EMBL; AF513984; AAM53645.1; -; Genomic_DNA.
DR EMBL; BC052417; AAH52417.2; -; mRNA.
DR CCDS; CCDS20429.1; -.
DR RefSeq; NP_033533.1; NM_009507.3.
DR PDB; 1HV2; NMR; -; B=123-137.
DR PDBsum; 1HV2; -.
DR AlphaFoldDB; P40338; -.
DR SMR; P40338; -.
DR BioGRID; 204518; 21.
DR IntAct; P40338; 7.
DR MINT; P40338; -.
DR STRING; 10090.ENSMUSP00000039418; -.
DR iPTMnet; P40338; -.
DR PhosphoSitePlus; P40338; -.
DR EPD; P40338; -.
DR PaxDb; P40338; -.
DR PeptideAtlas; P40338; -.
DR PRIDE; P40338; -.
DR ProteomicsDB; 300168; -.
DR DNASU; 22346; -.
DR Ensembl; ENSMUST00000035673; ENSMUSP00000039418; ENSMUSG00000033933.
DR GeneID; 22346; -.
DR KEGG; mmu:22346; -.
DR UCSC; uc009dha.1; mouse.
DR CTD; 7428; -.
DR MGI; MGI:103223; Vhl.
DR VEuPathDB; HostDB:ENSMUSG00000033933; -.
DR eggNOG; KOG4710; Eukaryota.
DR GeneTree; ENSGT00390000014353; -.
DR HOGENOM; CLU_116090_0_0_1; -.
DR InParanoid; P40338; -.
DR OMA; VGHPWLF; -.
DR OrthoDB; 1509532at2759; -.
DR PhylomeDB; P40338; -.
DR TreeFam; TF318985; -.
DR Reactome; R-MMU-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
DR Reactome; R-MMU-3232142; SUMOylation of ubiquitinylation proteins.
DR Reactome; R-MMU-8951664; Neddylation.
DR Reactome; R-MMU-9706019; RHOBTB3 ATPase cycle.
DR Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 22346; 26 hits in 72 CRISPR screens.
DR PRO; PR:P40338; -.
DR Proteomes; UP000000589; Chromosome 6.
DR RNAct; P40338; protein.
DR Bgee; ENSMUSG00000033933; Expressed in spermatid and 243 other tissues.
DR ExpressionAtlas; P40338; baseline and differential.
DR Genevisible; P40338; MM.
DR GO; GO:0005929; C:cilium; IDA:MGI.
DR GO; GO:0031462; C:Cul2-RING ubiquitin ligase complex; IDA:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; ISO:MGI.
DR GO; GO:0005730; C:nucleolus; IDA:MGI.
DR GO; GO:0005654; C:nucleoplasm; IDA:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0098794; C:postsynapse; IEA:GOC.
DR GO; GO:0030891; C:VCB complex; ISO:MGI.
DR GO; GO:0140297; F:DNA-binding transcription factor binding; ISO:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:MGI.
DR GO; GO:0003711; F:transcription elongation regulator activity; ISO:MGI.
DR GO; GO:1990756; F:ubiquitin ligase-substrate adaptor activity; ISO:MGI.
DR GO; GO:0001525; P:angiogenesis; IMP:MGI.
DR GO; GO:0043534; P:blood vessel endothelial cell migration; IMP:MGI.
DR GO; GO:0048593; P:camera-type eye morphogenesis; IMP:MGI.
DR GO; GO:0061073; P:ciliary body morphogenesis; IMP:MGI.
DR GO; GO:0045446; P:endothelial cell differentiation; IMP:MGI.
DR GO; GO:0030198; P:extracellular matrix organization; IMP:MGI.
DR GO; GO:0048069; P:eye pigmentation; IMP:MGI.
DR GO; GO:0048877; P:homeostasis of number of retina cells; IMP:MGI.
DR GO; GO:0097411; P:hypoxia-inducible factor-1alpha signaling pathway; IMP:MGI.
DR GO; GO:0061072; P:iris morphogenesis; IMP:MGI.
DR GO; GO:0006582; P:melanin metabolic process; IMP:MGI.
DR GO; GO:0045602; P:negative regulation of endothelial cell differentiation; IMP:MGI.
DR GO; GO:0010629; P:negative regulation of gene expression; IMP:MGI.
DR GO; GO:1902072; P:negative regulation of hypoxia-inducible factor-1alpha signaling pathway; IMP:MGI.
DR GO; GO:0070244; P:negative regulation of thymocyte apoptotic process; IMP:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:MGI.
DR GO; GO:0030182; P:neuron differentiation; ISO:MGI.
DR GO; GO:0003310; P:pancreatic A cell differentiation; IMP:MGI.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IMP:MGI.
DR GO; GO:0010498; P:proteasomal protein catabolic process; IMP:MGI.
DR GO; GO:0030163; P:protein catabolic process; IMP:MGI.
DR GO; GO:0015031; P:protein transport; IDA:MGI.
DR GO; GO:0016567; P:protein ubiquitination; IBA:GO_Central.
DR GO; GO:2001233; P:regulation of apoptotic signaling pathway; IGI:MGI.
DR GO; GO:0042069; P:regulation of catecholamine metabolic process; ISO:MGI.
DR GO; GO:0010468; P:regulation of gene expression; IMP:MGI.
DR GO; GO:0099175; P:regulation of postsynapse organization; IDA:SynGO.
DR GO; GO:0099576; P:regulation of protein catabolic process at postsynapse, modulating synaptic transmission; IDA:SynGO.
DR GO; GO:0032880; P:regulation of protein localization; IMP:MGI.
DR GO; GO:0070243; P:regulation of thymocyte apoptotic process; IGI:MGI.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISO:MGI.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; ISO:MGI.
DR GO; GO:0003309; P:type B pancreatic cell differentiation; IMP:MGI.
DR CDD; cd05468; pVHL; 1.
DR Gene3D; 1.10.750.10; -; 1.
DR Gene3D; 2.60.40.780; -; 1.
DR InterPro; IPR002714; VHL.
DR InterPro; IPR024048; VHL_alpha_dom.
DR InterPro; IPR037139; VHL_alpha_dom_sf.
DR InterPro; IPR024053; VHL_beta_dom.
DR InterPro; IPR037140; VHL_beta_dom_sf.
DR InterPro; IPR036208; VHL_sf.
DR InterPro; IPR022772; VHL_tumour_suppress_b/a_dom.
DR PANTHER; PTHR15160:SF10; PTHR15160:SF10; 1.
DR Pfam; PF01847; VHL; 1.
DR Pfam; PF17211; VHL_C; 1.
DR SUPFAM; SSF49468; SSF49468; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytoplasm; Membrane; Nucleus; Reference proteome;
KW Tumor suppressor; Ubl conjugation pathway.
FT CHAIN 1..181
FT /note="von Hippel-Lindau disease tumor suppressor"
FT /id="PRO_0000065810"
FT REGION 1..30
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 123..132
FT /note="Interaction with Elongin BC complex"
FT /evidence="ECO:0000250"
FT HELIX 124..136
FT /evidence="ECO:0007829|PDB:1HV2"
SQ SEQUENCE 181 AA; 20770 MW; AE8B2E8DDD3EE987 CRC64;
MPRKAASPEE AAGEPGPEEM EAGRPRPVLR SVNSREPSQV IFCNRSPRVV LPLWLNFDGE
PQPYPILPPG TGRRIHSYRG HLWLFRDAGT HDGLLVNQTE LFVPSLNVDG QPIFANITLP
VYTLKERCLQ VVRSLVKPEN YRRLDIVRSL YEDLEDYPSV RKDIQRLSQE HLESQHLEEE
P
