E3 ubiquitin-protein ligase HUWE1; ARF-binding protein 1; ARF-BP1; HECT, UBA & WWE domain-containing protein 1; homologous to E6AP carboxyl terminus homologous protein 9; HectH9; large structure of UREB1; LASU1; Mcl-1 ubiquitin ligase E3; mule; upstream regulatory element-binding protein 1; URE-B1; URE-binding protein 1 (HUWE1, KIAA0312, KIAA1578, UREB1, HSPC272)
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Function
- E3 ubiquitin-protein ligase
- mediates ubiquitination & subsequent proteasomal degradation of target proteins
- regulates apoptosis by catalyzing polyubiquitination & degradation of MCL1
- also ubiquitinates the p53 tumor suppressor & core histones including H1, H2A, H2B, H3 & H4
- binds to an upstream initiator-like sequence in the preprodynorphin gene
- regulates neural differentiation & proliferation by catalyzing polyubiquitination & degradation of MYCN
- may regulate abundance of CDC6 after DNA damage by polyubiquitinating & targeting CDC6 to degradation
- protein modification; protein ubiquitination
- phosphorylated on Tyr; phosphorylation is probably required for its ability to inhibit TP53 transactivation
- phosphorylated upon DNA damage, probably by ATM or ATR
- interacts with isoform p14ARF of CDKN2A which strongly inhibits HUWE1 ubiquitin ligase activity
- interacts with MYCN & CDC6
Structure
- the HECT domain mediates inhibition of the transcriptional activity of p53
- belongs to the TOM1/PTR1 family
- contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain
- contains 1 UBA domain
- contains 1 UIM (ubiquitin-interacting motif) repeat
- contains 1 WWE domain
Compartment
- cytoplasm, nucleus
- mainly expressed in the cytoplasm of most tissues,
- in the nucleus of spermatogonia, primary spermatocytes & neuronal cells
- predominantly cytosolic or perinuclear in some colorectal carcinoma cells
Alternative splicing
named isoforms=3
Expression
- weakly expressed in heart, brain & placenta
- expressed in a number of cell lines, predominantly in those from colorectal carcinomas
Pathology
- defects in HUWE1 are the cause of mental retardation syndromic X-linked Turner type
- chromosomal microduplication involving HUWE1 & HSD17B10 is the cause of mental retardation X-linked type 17
More general terms
References
Database
- Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=10075
- Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:10075
- OMIM: https://mirror.omim.org/entry/300697
- OMIM: https://mirror.omim.org/entry/300705
- OMIM: https://mirror.omim.org/entry/300706
- UniProt: http://www.uniprot.org/uniprot/Q7Z6Z7.html