UniProt functional annotation for P40337



	UniProt functional annotation for P40337

UniProt code: P40337.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Seems to act as a 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. {ECO:0000269|PubMed:10944113, ECO:0000269|PubMed:17981124, ECO:0000269|PubMed:19584355}.

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 VCB complex. Interacts (via the beta domain) with HIF1A (via the NTAD domain); this interaction mediates degradation of HIF1A in normoxia and, in hypoxia, prevents ubiquitination 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 JADE1. Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB 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. Interacts with CARD9. Interacts with DCUN1D1 independently of CUL2; this interaction engages DCUN1D1 in the VCB complex and triggers CUL2 neddylation and consequently cullin ring ligase (CRL) substrates polyubiquitylation (PubMed:23401859). {ECO:0000269|PubMed:10205047, ECO:0000269|PubMed:10635329, ECO:0000269|PubMed:10944113, ECO:0000269|PubMed:11384984, ECO:0000269|PubMed:11641274, ECO:0000269|PubMed:11739384, ECO:0000269|PubMed:12004076, ECO:0000269|PubMed:12032852, ECO:0000269|PubMed:12050673, ECO:0000269|PubMed:12169691, ECO:0000269|PubMed:17981124, ECO:0000269|PubMed:19208626, ECO:0000269|PubMed:19584355, ECO:0000269|PubMed:22286099, ECO:0000269|PubMed:23401859, ECO:0000269|PubMed:7660130, ECO:0000269|PubMed:9122164}.

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. {ECO:0000269|PubMed:8733131}.

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: 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. {ECO:0000269|PubMed:12000816, ECO:0000269|PubMed:14500403, ECO:0000269|PubMed:9663592}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Disease: von Hippel-Lindau disease (VHLD) [MIM:193300]: VHLD is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar and spinal hemangioblastoma, renal cell carcinoma (RCC), pheochromocytoma, 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). {ECO:0000269|PubMed:10408776, ECO:0000269|PubMed:10533030, ECO:0000269|PubMed:10627136, ECO:0000269|PubMed:10635329, ECO:0000269|PubMed:16502427, ECO:0000269|PubMed:7728151, ECO:0000269|PubMed:7987306, ECO:0000269|PubMed:8493574, ECO:0000269|PubMed:8592333, ECO:0000269|PubMed:8634692, ECO:0000269|PubMed:8730290, ECO:0000269|PubMed:8825918, ECO:0000269|PubMed:8956040, ECO:0000269|PubMed:9452032, ECO:0000269|PubMed:9452106, ECO:0000269|PubMed:9829911, ECO:0000269|PubMed:9829912, ECO:0000269|Ref.42}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Erythrocytosis, familial, 2 (ECYT2) [MIM:263400]: 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. {ECO:0000269|PubMed:12393546, ECO:0000269|PubMed:12844285}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: 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. Clear cell renal cell carcinoma is the most common subtype. {ECO:0000269|PubMed:11986208}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: [Isoform 1]: Major isoform.

Miscellaneous: [Isoform 3]: Produced by alternative initiation at Met- 54 of isoform 1. {ECO:0000305}.

Similarity: Belongs to the VHL family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Seems to act as a 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. {ECO:0000269\|PubMed:10944113, ECO:0000269\|PubMed:17981124, ECO:0000269\|PubMed:19584355}.


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 VCB complex. Interacts (via the beta domain) with HIF1A (via the NTAD domain); this interaction mediates degradation of HIF1A in normoxia and, in hypoxia, prevents ubiquitination 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 JADE1. Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB 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. Interacts with CARD9. Interacts with DCUN1D1 independently of CUL2; this interaction engages DCUN1D1 in the VCB complex and triggers CUL2 neddylation and consequently cullin ring ligase (CRL) substrates polyubiquitylation (PubMed:23401859). {ECO:0000269\|PubMed:10205047, ECO:0000269\|PubMed:10635329, ECO:0000269\|PubMed:10944113, ECO:0000269\|PubMed:11384984, ECO:0000269\|PubMed:11641274, ECO:0000269\|PubMed:11739384, ECO:0000269\|PubMed:12004076, ECO:0000269\|PubMed:12032852, ECO:0000269\|PubMed:12050673, ECO:0000269\|PubMed:12169691, ECO:0000269\|PubMed:17981124, ECO:0000269\|PubMed:19208626, ECO:0000269\|PubMed:19584355, ECO:0000269\|PubMed:22286099, ECO:0000269\|PubMed:23401859, ECO:0000269\|PubMed:7660130, ECO:0000269\|PubMed:9122164}.
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. {ECO:0000269\|PubMed:8733131}.
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:		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. {ECO:0000269\|PubMed:12000816, ECO:0000269\|PubMed:14500403, ECO:0000269\|PubMed:9663592}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Disease:		von Hippel-Lindau disease (VHLD) [MIM:193300]: VHLD is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar and spinal hemangioblastoma, renal cell carcinoma (RCC), pheochromocytoma, 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). {ECO:0000269\|PubMed:10408776, ECO:0000269\|PubMed:10533030, ECO:0000269\|PubMed:10627136, ECO:0000269\|PubMed:10635329, ECO:0000269\|PubMed:16502427, ECO:0000269\|PubMed:7728151, ECO:0000269\|PubMed:7987306, ECO:0000269\|PubMed:8493574, ECO:0000269\|PubMed:8592333, ECO:0000269\|PubMed:8634692, ECO:0000269\|PubMed:8730290, ECO:0000269\|PubMed:8825918, ECO:0000269\|PubMed:8956040, ECO:0000269\|PubMed:9452032, ECO:0000269\|PubMed:9452106, ECO:0000269\|PubMed:9829911, ECO:0000269\|PubMed:9829912, ECO:0000269\|Ref.42}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Erythrocytosis, familial, 2 (ECYT2) [MIM:263400]: 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. {ECO:0000269\|PubMed:12393546, ECO:0000269\|PubMed:12844285}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		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. Clear cell renal cell carcinoma is the most common subtype. {ECO:0000269\|PubMed:11986208}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		[Isoform 1]: Major isoform.
Miscellaneous:		[Isoform 3]: Produced by alternative initiation at Met- 54 of isoform 1. {ECO:0000305}.
Similarity:		Belongs to the VHL family. {ECO:0000305}.