ID:VHL_HUMAN DESCRIPTION: RecName: Full=Von Hippel-Lindau disease tumor suppressor; AltName: Full=Protein G7; AltName: Full=pVHL; FUNCTION: Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Seems to act as target recruitment subunit in the E3 ubiquitin ligase complex and recruits hydroxylated hypoxia- inducible factor (HIF) under normoxic conditions. Involved in transcriptional repression through interaction with HIF1A, HIF1AN and histone deacetylases. Ubiquitinates, in an oxygen-responsive manner, ADRB2. PATHWAY: Protein modification; protein ubiquitination. SUBUNIT: Component of the VCB (VHL-Elongin BC-CUL2) complex; this complex acts as a ubiquitin-ligase E3 and directs proteasome- dependent degradation of targeted proteins. Interacts with CUL2; this interaction is dependent on the integrity of the trimeric VBC complex. Interacts (via the beta domain) with HIF1A (via the NTAD domain); this interaction mediates degradation of HIF1A in normoxia and, in hypoxia, prevents ubiqitination and degradation of HIF1A by mediating hypoxia-induced translocation to the nucleus, a process which requires a hypoxia-dependent regulatory signal. Interacts with ADRB2; the interaction, in normoxia, is dependent on hydroxylation of ADRB2 and the subsequent VCB- mediated ubiquitination and degradation of ADRB2. Under hypoxia, hydroxylation, interaction with VHL, ubiquitination and subsequent degradation of ADRB2 are dramatically decreased. Interacts with RNF139, USP33 and PHF17. Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, TCEB2 AND CUL2. Isoform 1 and isoform 3 interact with LIMD1 (via LIM zinc-binding 2), AJUBA (via LIM domains) and WTIP (via LIM domains). Interacts with EPAS1. INTERACTION: O75912:DGKI; NbExp=3; IntAct=EBI-301270, EBI-1765520; Q9UM11:FZR1; NbExp=2; IntAct=EBI-3504450, EBI-724997; P63244:GNB2L1; NbExp=9; IntAct=EBI-301246, EBI-296739; Q16665:HIF1A; NbExp=6; IntAct=EBI-301246, EBI-447269; Q8WU17:RNF139; NbExp=2; IntAct=EBI-301246, EBI-1551681; P21980:TGM2; NbExp=10; IntAct=EBI-301246, EBI-727668; SUBCELLULAR LOCATION: Isoform 1: Cytoplasm. Membrane; Peripheral membrane protein. Nucleus. Note=Found predominantly in the cytoplasm and with less amounts nuclear or membrane-associated. Colocalizes with ADRB2 at the cell membrane. SUBCELLULAR LOCATION: Isoform 3: Cytoplasm. Nucleus. Note=Equally distributed between the nucleus and the cytoplasm but not membrane-associated. TISSUE SPECIFICITY: Expressed in the adult and fetal brain and kidney. DEVELOPMENTAL STAGE: At 4-10 weeks pc, strong expression in the developing central nervous system, kidneys, testis and lung. Differentially expressed within renal tubules. DOMAIN: The Elongin BC complex binding domain is also known as BC- box with the consensus [APST]-L-x(3)-C-x(3)-[AILV]. DISEASE: Defects in VHL are a cause of susceptibility to pheochromocytoma (PCC) [MIM:171300]. A catecholamine-producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent. DISEASE: Defects in VHL are the cause of von Hippel-Lindau disease (VHLD) [MIM:193300]. VHLD is a dominantly inherited familial cancer syndrome characterized by the development of retinal angiomatosis, cerebellar and spinal hemangioblastoma, renal cell carcinoma (RCC), phaeochromocytoma and pancreatic tumors. VHL type 1 is without pheochromocytoma, type 2 is with pheochromocytoma. VHL type 2 is further subdivided into types 2A (pheochromocytoma, retinal angioma, and hemangioblastomas without renal cell carcinoma and pancreatic cyst) and 2B (pheochromocytoma, retinal angioma, and hemangioblastomas with renal cell carcinoma and pancreatic cyst). VHL type 2C refers to patients with isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma. The estimated incidence is 3/100000 births per year and penetrance is 97% by age 60 years. DISEASE: Defects in VHL are the cause of familial erythrocytosis type 2 (ECYT2) [MIM:263400]; also called VHL-dependent polycythemia or Chuvash type polycythemia. ECYT2 is an autosomal recessive disorder characterized by an increase in serum red blood cell mass, hypersensitivity of erythroid progenitors to erythropoietin, increased erythropoietin serum levels, and normal oxygen affinity. Patients with ECYT2 carry a high risk for peripheral thrombosis and cerebrovascular events. DISEASE: Defects in VHL are a cause of renal cell carcinoma (RCC) [MIM:144700]. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/VHLID132.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/VHL";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P40337
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000122 negative regulation of transcription from RNA polymerase II promoter GO:0000902 cell morphogenesis GO:0006355 regulation of transcription, DNA-templated GO:0006508 proteolysis GO:0008285 negative regulation of cell proliferation GO:0010629 negative regulation of gene expression GO:0016567 protein ubiquitination GO:0043066 negative regulation of apoptotic process GO:0043687 post-translational protein modification GO:0045597 positive regulation of cell differentiation GO:0045893 positive regulation of transcription, DNA-templated GO:0046426 negative regulation of JAK-STAT cascade GO:0050821 protein stabilization GO:0061418 regulation of transcription from RNA polymerase II promoter in response to hypoxia GO:0061428 negative regulation of transcription from RNA polymerase II promoter in response to hypoxia
L15409 - Homo sapiens (clone g7) von Hippel-Lindau disease tumor suppressor mRNA sequence. LF384169 - JP 2014500723-A/191672: Polycomb-Associated Non-Coding RNAs. AK315799 - Homo sapiens cDNA, FLJ96920, Homo sapiens von Hippel-Lindau syndrome (VHL), mRNA. BC058831 - Homo sapiens von Hippel-Lindau tumor suppressor, mRNA (cDNA clone MGC:61974 IMAGE:6457060), complete cds. BC027957 - Homo sapiens cDNA clone IMAGE:5210077, partial cds. AK304002 - Homo sapiens cDNA FLJ51515 complete cds, highly similar to Von Hippel-Lindau disease tumor suppressor. JD342865 - Sequence 323889 from Patent EP1572962. AB528056 - Synthetic construct DNA, clone: pF1KB7932, Homo sapiens VHL gene for von Hippel-Lindau tumor suppressor, without stop codon, in Flexi system. KU178386 - Homo sapiens von Hippel-Lindau tumor suppressor isoform 1 (VHL) mRNA, partial cds. KU178387 - Homo sapiens von Hippel-Lindau tumor suppressor isoform 2 (VHL) mRNA, partial cds. HQ257941 - Synthetic construct Homo sapiens clone IMAGE:100072250 Unknown protein gene, encodes complete protein. KJ897734 - Synthetic construct Homo sapiens clone ccsbBroadEn_07128 VHL gene, encodes complete protein. KR711283 - Synthetic construct Homo sapiens clone CCSBHm_00022221 VHL (VHL) mRNA, encodes complete protein. KR711284 - Synthetic construct Homo sapiens clone CCSBHm_00022229 VHL (VHL) mRNA, encodes complete protein. KR711285 - Synthetic construct Homo sapiens clone CCSBHm_00022297 VHL (VHL) mRNA, encodes complete protein. KR711286 - Synthetic construct Homo sapiens clone CCSBHm_00022370 VHL (VHL) mRNA, encodes complete protein. AK309560 - Homo sapiens cDNA, FLJ99601. JD550093 - Sequence 531117 from Patent EP1572962. JD288393 - Sequence 269417 from Patent EP1572962. JD521555 - Sequence 502579 from Patent EP1572962. JD242191 - Sequence 223215 from Patent EP1572962. JD157214 - Sequence 138238 from Patent EP1572962. JD073160 - Sequence 54184 from Patent EP1572962. JD244007 - Sequence 225031 from Patent EP1572962. JD237481 - Sequence 218505 from Patent EP1572962. JD284551 - Sequence 265575 from Patent EP1572962. JD234796 - Sequence 215820 from Patent EP1572962. JD536794 - Sequence 517818 from Patent EP1572962. JD052313 - Sequence 33337 from Patent EP1572962. JD567002 - Sequence 548026 from Patent EP1572962. JD513585 - Sequence 494609 from Patent EP1572962. JD523052 - Sequence 504076 from Patent EP1572962. JD119346 - Sequence 100370 from Patent EP1572962. JD257493 - Sequence 238517 from Patent EP1572962. JD513877 - Sequence 494901 from Patent EP1572962. JD069696 - Sequence 50720 from Patent EP1572962. JD414669 - Sequence 395693 from Patent EP1572962. JD305556 - Sequence 286580 from Patent EP1572962. JD314117 - Sequence 295141 from Patent EP1572962. JD384663 - Sequence 365687 from Patent EP1572962. JD246037 - Sequence 227061 from Patent EP1572962. JD563883 - Sequence 544907 from Patent EP1572962. JD048624 - Sequence 29648 from Patent EP1572962. JD466051 - Sequence 447075 from Patent EP1572962. JD112440 - Sequence 93464 from Patent EP1572962. JD112441 - Sequence 93465 from Patent EP1572962. AF088066 - Homo sapiens full length insert cDNA clone ZD86C03. JD089541 - Sequence 70565 from Patent EP1572962. JD468729 - Sequence 449753 from Patent EP1572962. JD468730 - Sequence 449754 from Patent EP1572962. JD188874 - Sequence 169898 from Patent EP1572962. JD078260 - Sequence 59284 from Patent EP1572962. JD309029 - Sequence 290053 from Patent EP1572962. JD111761 - Sequence 92785 from Patent EP1572962. JD238567 - Sequence 219591 from Patent EP1572962. JD453145 - Sequence 434169 from Patent EP1572962. JD092643 - Sequence 73667 from Patent EP1572962. JD230046 - Sequence 211070 from Patent EP1572962. JD269613 - Sequence 250637 from Patent EP1572962. JD269612 - Sequence 250636 from Patent EP1572962. JD461307 - Sequence 442331 from Patent EP1572962. JD405228 - Sequence 386252 from Patent EP1572962. JD050830 - Sequence 31854 from Patent EP1572962. JD364569 - Sequence 345593 from Patent EP1572962. JD185401 - Sequence 166425 from Patent EP1572962. JD185402 - Sequence 166426 from Patent EP1572962. JD185400 - Sequence 166424 from Patent EP1572962. JD366586 - Sequence 347610 from Patent EP1572962. JD366587 - Sequence 347611 from Patent EP1572962. JD366585 - Sequence 347609 from Patent EP1572962. JD517774 - Sequence 498798 from Patent EP1572962. JD517769 - Sequence 498793 from Patent EP1572962. JD517770 - Sequence 498794 from Patent EP1572962. JD105990 - Sequence 87014 from Patent EP1572962. JD105992 - Sequence 87016 from Patent EP1572962. JD105991 - Sequence 87015 from Patent EP1572962. JD105623 - Sequence 86647 from Patent EP1572962. JD158863 - Sequence 139887 from Patent EP1572962. JD208666 - Sequence 189690 from Patent EP1572962. JD112002 - Sequence 93026 from Patent EP1572962. JD221273 - Sequence 202297 from Patent EP1572962. JD411980 - Sequence 393004 from Patent EP1572962. JD083368 - Sequence 64392 from Patent EP1572962. JD557962 - Sequence 538986 from Patent EP1572962. JD264345 - Sequence 245369 from Patent EP1572962. JD388213 - Sequence 369237 from Patent EP1572962. JD439551 - Sequence 420575 from Patent EP1572962. JD054487 - Sequence 35511 from Patent EP1572962. JD123827 - Sequence 104851 from Patent EP1572962. JD388214 - Sequence 369238 from Patent EP1572962. JD118357 - Sequence 99381 from Patent EP1572962. JD309268 - Sequence 290292 from Patent EP1572962. JD092163 - Sequence 73187 from Patent EP1572962. JD267255 - Sequence 248279 from Patent EP1572962. JD182288 - Sequence 163312 from Patent EP1572962. JD349974 - Sequence 330998 from Patent EP1572962. JD510434 - Sequence 491458 from Patent EP1572962. JD351600 - Sequence 332624 from Patent EP1572962. JD522789 - Sequence 503813 from Patent EP1572962. JD139852 - Sequence 120876 from Patent EP1572962. JD451743 - Sequence 432767 from Patent EP1572962. JD365281 - Sequence 346305 from Patent EP1572962. JD518130 - Sequence 499154 from Patent EP1572962. JD518131 - Sequence 499155 from Patent EP1572962. JD518132 - Sequence 499156 from Patent EP1572962. JD530605 - Sequence 511629 from Patent EP1572962. JD353302 - Sequence 334326 from Patent EP1572962. JD353303 - Sequence 334327 from Patent EP1572962. JD419599 - Sequence 400623 from Patent EP1572962. JD058741 - Sequence 39765 from Patent EP1572962. JD504444 - Sequence 485468 from Patent EP1572962. JD518885 - Sequence 499909 from Patent EP1572962. JD356629 - Sequence 337653 from Patent EP1572962. JD506343 - Sequence 487367 from Patent EP1572962. JD374391 - Sequence 355415 from Patent EP1572962. JD441355 - Sequence 422379 from Patent EP1572962. JD381001 - Sequence 362025 from Patent EP1572962. JD381002 - Sequence 362026 from Patent EP1572962. JD211898 - Sequence 192922 from Patent EP1572962. JD476181 - Sequence 457205 from Patent EP1572962. JD407055 - Sequence 388079 from Patent EP1572962. JD481488 - Sequence 462512 from Patent EP1572962. JD211142 - Sequence 192166 from Patent EP1572962. JD522441 - Sequence 503465 from Patent EP1572962. JD086587 - Sequence 67611 from Patent EP1572962. JD542369 - Sequence 523393 from Patent EP1572962. JD211831 - Sequence 192855 from Patent EP1572962. JD196756 - Sequence 177780 from Patent EP1572962. JD410439 - Sequence 391463 from Patent EP1572962. JD443934 - Sequence 424958 from Patent EP1572962. JD336555 - Sequence 317579 from Patent EP1572962. JD136158 - Sequence 117182 from Patent EP1572962. JD079524 - Sequence 60548 from Patent EP1572962. JD197084 - Sequence 178108 from Patent EP1572962. JD529620 - Sequence 510644 from Patent EP1572962. JD170101 - Sequence 151125 from Patent EP1572962. JD532692 - Sequence 513716 from Patent EP1572962. JD531778 - Sequence 512802 from Patent EP1572962. JD176286 - Sequence 157310 from Patent EP1572962. JD333390 - Sequence 314414 from Patent EP1572962. JD182851 - Sequence 163875 from Patent EP1572962. JD089394 - Sequence 70418 from Patent EP1572962. JD546353 - Sequence 527377 from Patent EP1572962. JD221974 - Sequence 202998 from Patent EP1572962. JD230091 - Sequence 211115 from Patent EP1572962. JD269668 - Sequence 250692 from Patent EP1572962. JD496047 - Sequence 477071 from Patent EP1572962. MA619746 - JP 2018138019-A/191672: Polycomb-Associated Non-Coding RNAs.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_vegfPathway - VEGF, Hypoxia, and Angiogenesis h_hifPathway - Hypoxia-Inducible Factor in the Cardiovascular System
Reactome (by CSHL, EBI, and GO)
Protein P40337 (Reactome details) participates in the following event(s):
R-HSA-8956099 VHL:EloB,C:NEDD8-CUL2:RBX1 complex binds UBXN7 R-HSA-8956103 VHL:EloB,C:NEDD8-CUL2:RBX1 complex binds hydroxyprolyl-HIF-alpha R-HSA-1234169 Nuclear VHL:EloB,C:CUL2:RBX1 binds hydroxyprolyl-HIF-alpha R-HSA-1234183 Cytosolic VHL:EloB,C:CUL2:RBX1 binds hydroxyprolyl-HIF-alpha R-HSA-983157 Interaction of E3 with substrate and E2-Ub complex R-HSA-983147 Release of E3 from polyubiquitinated substrate R-HSA-8956106 VHL:EloB,C:NEDD8-CUL2:RBX1 complex ubiquitinylates HIF-alpha R-HSA-8955241 CAND1 binds cytosolic CRL E3 ubiquitin ligases R-HSA-1234172 Nuclear VBC complex ubiquitinylates HIF-alpha R-HSA-1234163 Cytosolic VBC complex ubiquitinylates hydroxyprolyl-HIF-alpha R-HSA-1234173 Cytosolic PHD2,3 hydroxylates proline residues on HIF3A R-HSA-1234177 Cytosolic PHD2,3 hydroxylates proline residues on HIF1A R-HSA-1234179 Cytosolic PHD2,3 hydroxylates proline residues on EPAS1 (HIF2A) R-HSA-983140 Transfer of Ub from E2 to substrate and release of E2 R-HSA-8955289 COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes R-HSA-8956040 COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes R-HSA-8951664 Neddylation R-HSA-1234176 Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha R-HSA-983168 Antigen processing: Ubiquitination & Proteasome degradation R-HSA-597592 Post-translational protein modification R-HSA-1234174 Regulation of Hypoxia-inducible Factor (HIF) by oxygen R-HSA-983169 Class I MHC mediated antigen processing & presentation R-HSA-392499 Metabolism of proteins R-HSA-2262749 Cellular response to hypoxia R-HSA-1280218 Adaptive Immune System R-HSA-2262752 Cellular responses to stress R-HSA-168256 Immune System R-HSA-8953897 Cellular responses to external stimuli