Search
androgen receptor; dihydrotestosterone receptor; nuclear receptor subfamily 3 group C member 4 (AR, DHTR, NR3C4)
Function:
- nuclear hormone receptor
- agonist binding is required for dimerization & binding to target DNA
- transcription factor activity of the complex formed by ligand-activated AR & DNA is modulated by interactions with coactivator & corepressor proteins
- cytoplasmic anchoring &/or assembly associated with heat shock proteins hsp70 & hsp90 & immunophilin p59FKBP
- in the absence of ligand, steroid hormone receptors may be weakly associated with nuclear components
- hormone binding greatly increases receptor affinity
- the hormone-receptor complex appears to recognize discrete DNA sequences upstream of transcriptional start sites
- transcriptional activity is enhanced by binding to RANBP9
- transcription activation is down-regulated by NR0B2
- activated, but not phosphorylated, by HIPK3
- binds DNA as a homodimer
- part of a ternary complex containing AR, EFCAB6/DJBP & PARK7
- interacts with HIPK3 & NR0B2 in the presence of androgen
- the ligand binding domain interacts with MYST2/HBO1 in the presence of dihydrotestosterone
- interacts with EFCAB6/DJBP, PELP1, PQBP1, RANBP9, RBAK, SPDEF, SRA1, TGFB1I1, ZNF318 & RREB1
- interacts with ZMIZ1/ZIMP10 & ZMIZ2/ZMIP7 which both enhance its transactivation activity
- interacts with SLC30A9 & RAD54L2/ARIP4 (putative)
- interacts via the ligand-binding domain with LXXLL & FXXLF motifs from NCOA1, NCOA2, NCOA3, NCOA4 & MAGEA11
- The AR N-terminal poly-Gln region binds Ran resulting in enhancement of AR-mediated transactivation; Ran-binding decreases as the poly-Gln length increases
- sumoylated on Lys-386 (major) & Lys-520
- phosphorylated in prostate cancer cells in response to several growth factors including EGF
- phosphorylation is induced by c-Src kinase (CSK)
- Tyr-534 is one of the major phosphorylation sites & an increase in phosphorylation & Src kinase activity is associated with prostate cancer progression
Structure:
- composed of three domains:
a) modulating N-terminal domain
b) DNA-binding domain
c) C-terminal steroid-binding domain
- in the presence of bound steroid, ligand-binding domain interacts with the N-terminal modulating domain, & thus activates AR transcription factor activity
- interaction with RANBP9 is mediated by both the N-terminal domain & the DNA-binding domain
- interaction with EFCAB6/DJBP is mediated by the DNA-binding domain
- belongs to the nuclear hormone receptor family, NR3 subfamily
- contains 1 nuclear receptor DNA-binding domain
Compartment: nucleus
Polymorphism:
- the poly-Gln region of AR is highly polymorphic; the number of Gln varies in the population (17-26); a smaller size of the poly-Gln region may be associated with the development of prostate cancer
- the poly-Gly region of AR is polymorphic & ranges from 24-31 gly; a poly-Gly region =< 23 may be associated with development of androgenetic alopecia
Pathology:
- genetic variation in AR can be responsible of androgenetic alopecia
- defects in AR may play a role in prostate cancer
a) metastatic prostate cancer
b) level of tyrosine phosphorylation may serve as a diagnostic tool to predict patient outcome with hormone-ablation therapy
c) inhibition of tyrosine phosphorylation may be an effective intervention target for hormone-refractory prostate cancer
- defects in AR are the cause of
a) androgen insensibility syndrome
b) X-linked bulbospinal muscular atrophy
c) infertility male syndrome
d) Reifenstein syndrome (partial androgen insensitivity)
Laboratory:
- androgen receptor Ag in tissue
Related
androgen or anabolic steroid
androgen receptor gene
prostate cancer
X-linked bulbospinal muscular atrophy (Kennedy's disease)
General
nuclear hormone receptor NR3 subfamily
steroid receptor
Properties
SIZE: entity length = 919 aa
MW = 99 kD
COMPARTMENT: cell nucleus
MOTIF: Modulating {1-558}
MOTIF: glutamine-rich region {58-89}
MOTIF: glutamine residue (SEVERAL)
glutamine-rich region {58-78}
MOTIF: glutamine residue (SEVERAL)
glutamine-rich region {84-89}
MOTIF: glutamine residue (SEVERAL)
glutamine-rich region {193-197}
MOTIF: glutamine residue (SEVERAL)
Tyr phosphorylation site {Y223}
Tyr phosphorylation site {Y267}
Tyr phosphorylation site {Y307}
Tyr phosphorylation site {Y346}
Tyr phosphorylation site {Y357}
Tyr phosphorylation site {Y362}
Tyr phosphorylation site {Y363}
proline-rich region
SITE: 372-381
MOTIF: proline residue (SEVERAL)
Tyr phosphorylation site {Y393}
alanine-rich region {396-402}
MOTIF: alanine residue (SEVERAL)
glycine-rich region {449-472}
Tyr phosphorylation site {Y534}
Tyr phosphorylation site {Y551}
DNA-binding motif
SITE: 559-631
MOTIF: Zn finger C4-type
SITE: 559-579
EFFECTOR-BOUND: Zn+2
HIPK3 interaction {571-661}
MOTIF: Zn finger C4-type
SITE: 595-619
EFFECTOR-BOUND: Zn+2
MYST2 interaction {624-919}
MOTIF: binding site
SITE: 690-919
FOR-BINDING-OF: ligand
binding site
SITE: 705-705
FOR-BINDING-OF: androgen
lysine residue {720}
binding site
SITE: 752-752
FOR-BINDING-OF: androgen
binding site
SITE: 877-877
FOR-BINDING-OF: androgen
glutamate residue {897}
Tyr phosphorylation site {Y915}
Database Correlations
OMIM correlations
MORBIDMAP 313700
UniProt P10275
PFAM correlations
Kegg hsa:367
References
- Simental JA, Sar M, Lane MV, French FS, Wilson EM.
Transcriptional activation and nuclear targeting signals of
the human androgen receptor.
J Biol Chem. 1991 Jan 5;266(1):510-8.
PMID: 1985913
- Ross CA, McInnis MG, Margolis RL, Li SH.
Genes with triplet repeats: candidate mediators of
neuropsychiatric disorders.
Trends Neurosci. 1993 Jul;16(7):254-60. Review.
PMID: 7689767
- Androgen receptor gene mutations database
http://www.mcgill.ca/androgendb/
- GeneReviews
https://www.genecards.org/cgi-bin/carddisp.pl?gene=AR
- Wikipedia; Note: androgen receptor entry
http://en.wikipedia.org/wiki/androgen_receptor
- UniProt :accession P10275