UBE3A (ubiquitin protein ligase E3A)

2008-11-01   Konstantin Matentzoglu  , Martin Scheffner  

Laboratory of cellular biochemistry, Department of biology, Box 642, University of Konstanz, D-78457 Konstanz, Germany

Identity

HGNC
UBE3A
LOCATION
15q11.2
LOCUSID
7337
ALIAS
ANCR,AS,E6-AP,EPVE6AP,HPVE6A
FUSION GENES
Show Gene Fusions

DNA/RNA

Description

The UBE3A gene is located on Chr. 15 (23133489-23235221); 13 exons.

Transcription

3 Isoforms through alternative splicing; mRNA Isoform 1: 4491 bp, ORF: 2556 bp; mRNA Isoform 2: 4516 bp, ORF: 2625 bp; mRNA Isoform 3: 5164 bp, ORF: 2616 bp.

Proteins

Description

The UBE3A gene product is commonly referred to as E6AP (E6 associated protein).
Isoform 1: 852 amino acids, Isoform 2: 875 amino acids, Isoform 3: 872 amino acids. Migration in SDS-PAGE with an approximate molecular mass of 100 kDa.
HECT (Homologous to the E6AP C terminus) domain: amino acids 500-852; Active cysteine residue at position 820 (amino acid positions refer to Isoform 1).
Posttranslational modifications: ubiquitylation.
Binding partners and interaction sites on E6AP: Human papillomavirus (HPV) E6 oncoprotein: amino acids 378-395; Herc2 (unpublished): amino acids 150-200; Steroid hormone receptors (AR, ER, PR): amino acids 386-390 and 638-642 (LxxLL motif); Hepatitis C virus core protein: amino acids 395-494 (amino acid positions refer to Isoform 1).

Expression

Monoallelically expressed (maternal allele) in Purkinje neurons, a subset of hippocampal neurons, and neurons of the olfactory bulb. Biallelically expressed in most other tissues.

Localisation

Predominantly cytoplasmic.

Function

Ubiquitin-protein ligase. In complex with the E6 oncoprotein of cervical cancer-associated HPVs, E6AP targets p53 and other cellular proteins (e.g. hDLG, Scribble, E6TP1, NFX1-91) for ubiquitylation and proteasomal degradation. E6-independent substrates include HHR23A and HHR23B, BLK, BAK, MCM7, and AIB1. Loss-of-function results in Angelman Syndrome.
Coactivator of the nuclear hormone receptor superfamily. This function appears to be independent of the ubiquitin ligase function and its role in human disease remains unknown.

Homology

E6AP shares homology from fly to man and is highly conserved in vertebrates.

Mutations

Note

All known disease-associated mutations (maternal allele) result in an inactivation of the ubiquitin ligase function and have been etiologically associated with the Angelman Syndrome. Mutations in the UBE3A gene have not been associated with cancer development.

Implicated in

Entity name
Cervical Cancer
Oncogenesis
The E6 oncoprotein of so-called high risk HPVs that have been etiologically associated with malignant lesion of the anogenital tract (most notably, cervical cancer) have the ability to bind to E6AP. The E6/E6AP complex binds to the p53 tumor suppressor, thereby targeting p53 for ubiquitylation and proteasomal degradation. It is commonly assumed that this (p53 degradation and, thus, inactivation) represents a critical step in the development of cervical cancer. Although additional targets of the E6/E6AP complex have been described (see above), the relevance of these interactions for cervical carcinogenesis is currently unclear. Furthermore, E6AP itself is a target for E6-dependent autoubiquitylation and degradation. However, if this contributes to HPV-induced cervical carcinogenesis is currently unknown.
Entity name
Angelman Syndrome
Disease
Angelman Syndrome is a severe neurological disorder, genetically linked to UBE3A. Almost 95 % of all known mutations hit the maternal UBE3A allele or its relevant imprinting center, resulting in inactivation of the ubiquitin ligase function of E6AP.

Article Bibliography

Pubmed IDLast YearTitleAuthors
90538581997Antisense targeting of E6AP elevates p53 in HPV-infected cells but not in normal cells.Beer-Romero P et al
159948232005Growth suppression induced by downregulation of E6-AP expression in human papillomavirus-positive cancer cell lines depends on p53.Hengstermann A et al
83931401993Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins.Huibregtse JM et al
108646522000Human papillomavirus type 16 E6 induces self-ubiquitination of the E6AP ubiquitin-protein ligase.Kao WH et al
157312672005The global transcriptional effects of the human papillomavirus E6 protein in cervical carcinoma cell lines are mediated by the E6AP ubiquitin ligase.Kelley ML et al
89881711997UBE3A/E6-AP mutations cause Angelman syndrome.Kishino T et al
117536702001The human papillomavirus E6 protein and its contribution to malignant progression.Mantovani F et al
187931392008Ubiquitin ligase E6-AP and its role in human disease.Matentzoglu K et al
89881721997De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome.Matsuura T et al
98910521999The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily.Nawaz Z et al
125075572003Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system.Scheffner M et al
91435031997The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing.Yamamoto Y et al
120440102002Papillomaviruses and cancer: from basic studies to clinical application.zur Hausen H et al

Other Information

Locus ID:

NCBI: 7337
MIM: 601623
HGNC: 12496
Ensembl: ENSG00000114062

Variants:

dbSNP: 7337
ClinVar: 7337
TCGA: ENSG00000114062
COSMIC: UBE3A

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000114062ENST00000428984Q05086
ENSG00000114062ENST00000428984Q9H2G0
ENSG00000114062ENST00000438097Q05086
ENSG00000114062ENST00000438097Q9H2G0
ENSG00000114062ENST00000566215Q05086
ENSG00000114062ENST00000566215Q9H2G0
ENSG00000114062ENST00000604860S4R306
ENSG00000114062ENST00000625681A0A0D9SFH3
ENSG00000114062ENST00000625778A0A0D9SG77
ENSG00000114062ENST00000626176A0A0D9SG63
ENSG00000114062ENST00000626589A0A0G2JQQ5
ENSG00000114062ENST00000628267A0A0D9SFU3
ENSG00000114062ENST00000628733A0A0D9SF91
ENSG00000114062ENST00000628890A0A0D9SEJ2
ENSG00000114062ENST00000629252A0A0D9SFU3
ENSG00000114062ENST00000629886A0A0D9SG54
ENSG00000114062ENST00000630424Q05086
ENSG00000114062ENST00000630424Q9H2G0
ENSG00000114062ENST00000630907A0A0D9SES7
ENSG00000114062ENST00000635914A0A1B0GVL3
ENSG00000114062ENST00000636667A0A1B0GTB3
ENSG00000114062ENST00000637886Q05086
ENSG00000114062ENST00000638011Q05086
ENSG00000114062ENST00000638011Q9H2G0
ENSG00000114062ENST00000638155Q05086
ENSG00000114062ENST00000638155Q9H2G0
ENSG00000114062ENST00000648336Q05086
ENSG00000114062ENST00000649550Q05086
ENSG00000114062ENST00000649550Q9H2G0
ENSG00000114062ENST00000650110Q05086

Expression (GTEx)

0
5
10
15
20
25
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

Pathways

PathwaySourceExternal ID
Ubiquitin mediated proteolysisKEGGko04120
Ubiquitin mediated proteolysisKEGGhsa04120
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Class I MHC mediated antigen processing & presentationREACTOMER-HSA-983169
Antigen processing: Ubiquitination & Proteasome degradationREACTOMER-HSA-983168

Protein levels (Protein atlas)

Not detected
Low
Medium
High
cerebral cortex
cerebellum
hippocampus
caudate
thyroid gland
parathyroid gland
adrenal gland
nasopharynx
bronchus
lung
oral mucosa
salivary gland
esophagus
stomach 1
stomach 2
duodenum
small intestine
colon
rectum
liver
gallbladder
pancreas
kidney
urinary bladder
testis
epididymis
seminal vesicle
prostate
vagina
ovary
fallopian tube
endometrium 1
endometrium 2
cervix, uterine
placenta
breast
heart muscle
smooth muscle
skeletal muscle
soft tissue 1
soft tissue 2
adipose tissue
skin 1
skin 2
appendix
spleen
lymph node
tonsil
bone marrow

References

Pubmed IDYearTitleCitations
383951832024LOC644656 promotes cisplatin resistance in cervical cancer by recruiting ZNF143 and activating the transcription of E6-AP.0
384232462024CircUBE3A(2,3,4,5) promotes adenylate-uridylate-rich binding factor 1 nuclear translocation to suppress prostate cancer metastasis.0
385202602024Undiagnosed rare disease clinic identifies a novel UBE3A variant in two sisters with Angelman syndrome: The end of a diagnostic odyssey.0
383951832024LOC644656 promotes cisplatin resistance in cervical cancer by recruiting ZNF143 and activating the transcription of E6-AP.0
384232462024CircUBE3A(2,3,4,5) promotes adenylate-uridylate-rich binding factor 1 nuclear translocation to suppress prostate cancer metastasis.0
385202602024Undiagnosed rare disease clinic identifies a novel UBE3A variant in two sisters with Angelman syndrome: The end of a diagnostic odyssey.0
368983822023The role of UBE3A in the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons.7
369203052023Effects of UBE3A on Cell and Liver Metabolism through the Ubiquitination of PDHA1 and ACAT1.1
374543732023UBE3A and MCM6 synergistically regulate the proliferation and migration of lung adenocarcinoma cells.0
375415882023Ubiquitin-protein ligase E3A (UBE3A) mediation of viral infection and human diseases.1
368983822023The role of UBE3A in the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons.7
369203052023Effects of UBE3A on Cell and Liver Metabolism through the Ubiquitination of PDHA1 and ACAT1.1
374543732023UBE3A and MCM6 synergistically regulate the proliferation and migration of lung adenocarcinoma cells.0
375415882023Ubiquitin-protein ligase E3A (UBE3A) mediation of viral infection and human diseases.1
348720192022Novel UBE3A pathogenic variant in a large Georgian family produces non-convulsive status epilepticus responsive to ketogenic diet.1

Citation

Konstantin Matentzoglu ; Martin Scheffner

UBE3A (ubiquitin protein ligase E3A)

Atlas Genet Cytogenet Oncol Haematol. 2008-11-01

Online version: http://atlasgeneticsoncology.org/gene/42756/teaching-explorer/js/case-report-explorer/