UniProt functional annotation for P10275



	UniProt functional annotation for P10275

UniProt code: P10275.

Organism: Homo sapiens (Human).

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

Function: Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues (PubMed:19022849). Transcription factor activity is modulated by bound coactivator and corepressor proteins like ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024). Transcription activation is also down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3. {ECO:0000269|PubMed:14664718, ECO:0000269|PubMed:15563469, ECO:0000269|PubMed:17591767, ECO:0000269|PubMed:17911242, ECO:0000269|PubMed:18084323, ECO:0000269|PubMed:19022849, ECO:0000269|PubMed:19345326, ECO:0000269|PubMed:20812024, ECO:0000269|PubMed:20980437, ECO:0000269|PubMed:25091737}.

Function: [Isoform 3]: Lacks the C-terminal ligand-binding domain and may therefore constitutively activate the transcription of a specific set of genes independently of steroid hormones. {ECO:0000269|PubMed:19244107}.

Function: [Isoform 4]: Lacks the C-terminal ligand-binding domain and may therefore constitutively activate the transcription of a specific set of genes independently of steroid hormones. {ECO:0000269|PubMed:19244107}.

Activity regulation: AIM-100 (4-amino-5,6-biaryl-furo[2,3-d]pyrimidine) suppresses TNK2-mediated phosphorylation at Tyr-269. Inhibits the binding of the Tyr-269 phosphorylated form to androgen-responsive enhancers (AREs) and its transcriptional activity. {ECO:0000269|PubMed:20623637}.

Subunit: Binds DNA as a homodimer. Part of a ternary complex containing AR, EFCAB6/DJBP and PARK7. Interacts with HIPK3 and NR0B2 in the presence of androgen. The ligand binding domain interacts with KAT7/HBO1 in the presence of dihydrotestosterone. Interacts with EFCAB6/DJBP, PQBP1, RANBP9, RBAK, SPDEF, SRA1, TGFB1I1 and RREB1. Interacts with ZMIZ1/ZIMP10 and ZMIZ2/ZMIP7 which both enhance its transactivation activity. Interacts with SLC30A9 and RAD54L2/ARIP4. Interacts with MACROD1 (via macro domain) (PubMed:19022849). Interacts via the ligand-binding domain with LXXLL and FXXLF motifs from NCOA1, NCOA2, NCOA3, NCOA4 and 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. Interacts with HIP1 (via coiled coil domain). Interacts (via ligand-binding domain) with TRIM68. Interacts with TNK2. Interacts with USP26. Interacts with RNF6. Interacts (regulated by RNF6 probably through polyubiquitination) with RNF14; regulates AR transcriptional activity. Interacts with PRMT2 and TRIM24. Interacts with RACK1. Interacts with RANBP10; this interaction enhances dihydrotestosterone-induced AR transcriptional activity. Interacts with PRPF6 in a hormone-independent way; this interaction enhances dihydrotestosterone-induced AR transcriptional activity. Interacts with STK4/MST1. Interacts with ZIPK/DAPK3. Interacts with LPXN. Interacts with MAK. Part of a complex containing AR, MAK and NCOA3. Interacts with CRY1. Interacts with CCAR1 and GATA2. Interacts with ZNF318 (By similarity). Interacts with BUD31 (PubMed:25091737). Interacts with ARID4A (PubMed:23487765). Interacts with ARID4B (By similarity). Interacts (via NR LBD domain) with ZBTB7A; the interaction is direct and androgen-dependent (PubMed:20812024). Interacts with NCOR1 (PubMed:20812024). Interacts with NCOR2 (PubMed:20812024). Interacts with CRY2 in a ligand-dependent manner (By similarity). {ECO:0000250|UniProtKB:P15207, ECO:0000250|UniProtKB:P19091, ECO:0000269|PubMed:10075738, ECO:0000269|PubMed:10332029, ECO:0000269|PubMed:10383460, ECO:0000269|PubMed:10400640, ECO:0000269|PubMed:10625666, ECO:0000269|PubMed:10930412, ECO:0000269|PubMed:12039962, ECO:0000269|PubMed:12361945, ECO:0000269|PubMed:12612053, ECO:0000269|PubMed:12958311, ECO:0000269|PubMed:14609956, ECO:0000269|PubMed:14664718, ECO:0000269|PubMed:15525515, ECO:0000269|PubMed:15563469, ECO:0000269|PubMed:16027218, ECO:0000269|PubMed:16051670, ECO:0000269|PubMed:16951154, ECO:0000269|PubMed:17311914, ECO:0000269|PubMed:17494760, ECO:0000269|PubMed:17550981, ECO:0000269|PubMed:17587566, ECO:0000269|PubMed:17591767, ECO:0000269|PubMed:17711855, ECO:0000269|PubMed:17911242, ECO:0000269|PubMed:18007036, ECO:0000269|PubMed:18084323, ECO:0000269|PubMed:18222118, ECO:0000269|PubMed:18451096, ECO:0000269|PubMed:18451177, ECO:0000269|PubMed:19022849, ECO:0000269|PubMed:19345326, ECO:0000269|PubMed:19909775, ECO:0000269|PubMed:20501646, ECO:0000269|PubMed:20812024, ECO:0000269|PubMed:20980437, ECO:0000269|PubMed:21512132, ECO:0000269|PubMed:22170608, ECO:0000269|PubMed:23487765, ECO:0000269|PubMed:23887938, ECO:0000269|PubMed:25091737}.

Subcellular location: Nucleus {ECO:0000269|PubMed:12958311, ECO:0000269|PubMed:15634333, ECO:0000269|PubMed:17587566, ECO:0000269|PubMed:19244107, ECO:0000269|PubMed:19345326, ECO:0000269|PubMed:25091737}. Cytoplasm {ECO:0000269|PubMed:12958311, ECO:0000269|PubMed:17587566, ECO:0000269|PubMed:19244107}. Note=Detected at the promoter of target genes (PubMed:25091737). Predominantly cytoplasmic in unligated form but translocates to the nucleus upon ligand-binding. Can also translocate to the nucleus in unligated form in the presence of RACK1. {ECO:0000269|PubMed:12958311, ECO:0000269|PubMed:17587566, ECO:0000269|PubMed:25091737}.

Tissue specificity: [Isoform 2]: Mainly expressed in heart and skeletal muscle. {ECO:0000269|PubMed:15634333}.

Tissue specificity: [Isoform 3]: Expressed in basal and stromal cells of the prostate (at protein level). {ECO:0000269|PubMed:19244107}.

Domain: Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain. In the presence of bound steroid the ligand-binding domain interacts with the N-terminal modulating domain, and thereby activates AR transcription factor activity. Agonist binding is required for dimerization and binding to target DNA. The transcription factor activity of the complex formed by ligand-activated AR and DNA is modulated by interactions with coactivator and corepressor proteins (PubMed:25091737). Interaction with RANBP9 is mediated by both the N-terminal domain and the DNA- binding domain. Interaction with EFCAB6/DJBP is mediated by the DNA- binding domain. {ECO:0000269|PubMed:25091737}.

Ptm: Sumoylated on Lys-388 (major) and Lys-521. Ubiquitinated. Deubiquitinated by USP26. 'Lys-6' and 'Lys-27'-linked polyubiquitination by RNF6 modulates AR transcriptional activity and specificity. {ECO:0000269|PubMed:11121022, ECO:0000269|PubMed:19345326, ECO:0000269|PubMed:20501646}.

Ptm: Phosphorylated in prostate cancer cells in response to several growth factors including EGF. Phosphorylation is induced by c-Src kinase (CSK). Tyr-535 is one of the major phosphorylation sites and an increase in phosphorylation and Src kinase activity is associated with prostate cancer progression. Phosphorylation by TNK2 enhances the DNA- binding and transcriptional activity and may be responsible for androgen-independent progression of prostate cancer. Phosphorylation at Ser-83 by CDK9 regulates AR promoter selectivity and cell growth. Phosphorylation by PAK6 leads to AR-mediated transcription inhibition. {ECO:0000269|PubMed:14573606, ECO:0000269|PubMed:17045208, ECO:0000269|PubMed:17494760, ECO:0000269|PubMed:20623637, ECO:0000269|PubMed:20980437, ECO:0000269|PubMed:21512132}.

Ptm: Palmitoylated by ZDHHC7 and ZDHHC21. Palmitoylation is required for plasma membrane targeting and for rapid intracellular signaling via ERK and AKT kinases and cAMP generation. {ECO:0000269|PubMed:22031296}.

Polymorphism: The poly-Gln region of AR is highly polymorphic and the number of Gln varies in the population (from 17 to 26). A smaller size of the poly-Gln region may be associated with the development of prostate cancer. Long poly-Gln alleles (>23) may be associated with higher testosterone levels and severe clinical outcome in COVID-19 disease (PubMed:33647767). {ECO:0000269|PubMed:1561105, ECO:0000269|PubMed:2062380, ECO:0000269|PubMed:33647767, ECO:0000269|PubMed:8292051, ECO:0000269|PubMed:9096391}.

Polymorphism: The poly-Gly region of AR is polymorphic and ranges from 24 to 31 Gly. A poly-Gly region shorter or equal to 23 may be associated with the development of androgenetic alopecia. {ECO:0000269|PubMed:11231320, ECO:0000269|PubMed:15902657}.

Disease: Androgen insensitivity syndrome (AIS) [MIM:300068]: An X- linked recessive form of pseudohermaphroditism due end-organ resistance to androgen. Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal 46,XY karyotype. {ECO:0000269|PubMed:10022458, ECO:0000269|PubMed:10221692, ECO:0000269|PubMed:10221770, ECO:0000269|PubMed:10404311, ECO:0000269|PubMed:10458483, ECO:0000269|PubMed:10571951, ECO:0000269|PubMed:10590024, ECO:0000269|PubMed:10690872, ECO:0000269|PubMed:11587068, ECO:0000269|PubMed:11744994, ECO:0000269|PubMed:1307250, ECO:0000269|PubMed:1316540, ECO:0000269|PubMed:1426313, ECO:0000269|PubMed:1430233, ECO:0000269|PubMed:1464650, ECO:0000269|PubMed:14756668, ECO:0000269|PubMed:1480178, ECO:0000269|PubMed:1487249, ECO:0000269|PubMed:1569163, ECO:0000269|PubMed:1609793, ECO:0000269|PubMed:16129672, ECO:0000269|PubMed:16595706, ECO:0000269|PubMed:1775137, ECO:0000269|PubMed:1999491, ECO:0000269|PubMed:2082179, ECO:0000269|PubMed:2594783, ECO:0000269|PubMed:7537149, ECO:0000269|PubMed:7581399, ECO:0000269|PubMed:7633398, ECO:0000269|PubMed:7641413, ECO:0000269|PubMed:7671849, ECO:0000269|PubMed:7929841, ECO:0000269|PubMed:7962294, ECO:0000269|PubMed:7970939, ECO:0000269|PubMed:7981687, ECO:0000269|PubMed:7981689, ECO:0000269|PubMed:7993455, ECO:0000269|PubMed:8040309, ECO:0000269|PubMed:8096390, ECO:0000269|PubMed:8103398, ECO:0000269|PubMed:8162033, ECO:0000269|PubMed:8224266, ECO:0000269|PubMed:8281140, ECO:0000269|PubMed:8325950, ECO:0000269|PubMed:8339746, ECO:0000269|PubMed:8413310, ECO:0000269|PubMed:8446106, ECO:0000269|PubMed:8626869, ECO:0000269|PubMed:8647313, ECO:0000269|PubMed:8683794, ECO:0000269|PubMed:8723113, ECO:0000269|PubMed:8768864, ECO:0000269|PubMed:8809734, ECO:0000269|PubMed:8830623, ECO:0000269|PubMed:8918984, ECO:0000269|PubMed:8990010, ECO:0000269|PubMed:9001799, ECO:0000269|PubMed:9007482, ECO:0000269|PubMed:9039340, ECO:0000269|PubMed:9106550, ECO:0000269|PubMed:9160185, ECO:0000269|PubMed:9252933, ECO:0000269|PubMed:9255042, ECO:0000269|PubMed:9302173, ECO:0000269|PubMed:9328206, ECO:0000269|PubMed:9544375, ECO:0000269|PubMed:9554754, ECO:0000269|PubMed:9610419, ECO:0000269|PubMed:9627582, ECO:0000269|PubMed:9698822, ECO:0000269|PubMed:9851768, ECO:0000269|PubMed:9856504, ECO:0000269|Ref.115, ECO:0000269|Ref.181}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Spinal and bulbar muscular atrophy X-linked 1 (SMAX1) [MIM:313200]: An X-linked recessive form of spinal muscular atrophy. Spinal muscular atrophy refers to a group of neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMAX1 occurs only in men. Age at onset is usually in the third to fifth decade of life, but earlier involvement has been reported. It is characterized by slowly progressive limb and bulbar muscle weakness with fasciculations, muscle atrophy, and gynecomastia. The disorder is clinically similar to classic forms of autosomal spinal muscular atrophy. {ECO:0000269|PubMed:15851746}. Note=The disease is caused by variants affecting the gene represented in this entry. Caused by trinucleotide CAG repeat expansion. In SMAX1 patients the number of Gln ranges from 38 to 62. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.

Disease: Note=Defects in AR may play a role in metastatic prostate cancer. The mutated receptor stimulates prostate growth and metastases development despite of androgen ablation. This treatment can reduce primary and metastatic lesions probably by inducing apoptosis of tumor cells when they express the wild-type receptor. {ECO:0000269|PubMed:10363963, ECO:0000269|PubMed:10569618, ECO:0000269|PubMed:1562539, ECO:0000269|PubMed:16129672, ECO:0000269|PubMed:17311914, ECO:0000269|PubMed:2260966, ECO:0000269|PubMed:25091737, ECO:0000269|PubMed:8187068, ECO:0000269|PubMed:8274409, ECO:0000269|PubMed:8827083}.

Disease: Androgen insensitivity, partial (PAIS) [MIM:312300]: A disorder that is characterized by hypospadias, hypogonadism, gynecomastia, genital ambiguity, normal XY karyotype, and a pedigree pattern consistent with X-linked recessive inheritance. Some patients present azoospermia or severe oligospermia without other clinical manifestations. {ECO:0000269|PubMed:10022458, ECO:0000269|PubMed:10221692, ECO:0000269|PubMed:10470409, ECO:0000269|PubMed:10502786, ECO:0000269|PubMed:10543676, ECO:0000269|PubMed:11587068, ECO:0000269|PubMed:1303262, ECO:0000269|PubMed:1307250, ECO:0000269|PubMed:1316540, ECO:0000269|PubMed:1424203, ECO:0000269|PubMed:1430233, ECO:0000269|PubMed:14756668, ECO:0000269|PubMed:2010552, ECO:0000269|PubMed:7581399, ECO:0000269|PubMed:7649358, ECO:0000269|PubMed:7671849, ECO:0000269|PubMed:7909256, ECO:0000269|PubMed:7910529, ECO:0000269|PubMed:7929841, ECO:0000269|PubMed:7970939, ECO:0000269|PubMed:7981687, ECO:0000269|PubMed:8033918, ECO:0000269|PubMed:8097257, ECO:0000269|PubMed:8126121, ECO:0000269|PubMed:8205256, ECO:0000269|PubMed:8281139, ECO:0000269|PubMed:8325932, ECO:0000269|PubMed:8325950, ECO:0000269|PubMed:8446106, ECO:0000269|PubMed:8550758, ECO:0000269|PubMed:8809734, ECO:0000269|PubMed:8823308, ECO:0000269|PubMed:8824883, ECO:0000269|PubMed:9039340, ECO:0000269|PubMed:9196614, ECO:0000269|PubMed:9302173, ECO:0000269|PubMed:9329414, ECO:0000269|PubMed:9543136, ECO:0000269|PubMed:9607727, ECO:0000269|PubMed:9768671, ECO:0000269|PubMed:9856504, ECO:0000269|Ref.123}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Hypospadias 1, X-linked (HYSP1) [MIM:300633]: A common malformation in which the urethra opens on the ventral side of the penis, due to developmental arrest of urethral fusion. The opening can be located glandular, penile, or even more posterior in the scrotum or perineum. Hypospadias is a feature of several syndromic disorders, including the androgen insensitivity syndrome and Opitz syndrome. {ECO:0000269|PubMed:8097257}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: In the absence of ligand, steroid hormone receptors are thought to 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.

Miscellaneous: Transcriptional activity is enhanced by binding to RANBP9.

Miscellaneous: The level of tyrosine phosphorylation may serve as a diagnostic tool to predict patient outcome in response to hormone- ablation therapy. Inhibition of tyrosine phosphorylation may be an effective intervention target for hormone-refractory prostate cancer.

Miscellaneous: [Isoform 3]: Minor isoform up-regulated in prostate cancer cells. {ECO:0000269|PubMed:19244107}.

Miscellaneous: [Isoform 4]: Minor isoform identified in prostate cancer cells. {ECO:0000269|PubMed:19244107}.

Similarity: Belongs to the nuclear hormone receptor family. NR3 subfamily. {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:		Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues (PubMed:19022849). Transcription factor activity is modulated by bound coactivator and corepressor proteins like ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024). Transcription activation is also down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3. {ECO:0000269\|PubMed:14664718, ECO:0000269\|PubMed:15563469, ECO:0000269\|PubMed:17591767, ECO:0000269\|PubMed:17911242, ECO:0000269\|PubMed:18084323, ECO:0000269\|PubMed:19022849, ECO:0000269\|PubMed:19345326, ECO:0000269\|PubMed:20812024, ECO:0000269\|PubMed:20980437, ECO:0000269\|PubMed:25091737}.



Function:		[Isoform 3]: Lacks the C-terminal ligand-binding domain and may therefore constitutively activate the transcription of a specific set of genes independently of steroid hormones. {ECO:0000269\|PubMed:19244107}.



Function:		[Isoform 4]: Lacks the C-terminal ligand-binding domain and may therefore constitutively activate the transcription of a specific set of genes independently of steroid hormones. {ECO:0000269\|PubMed:19244107}.


Activity regulation:		AIM-100 (4-amino-5,6-biaryl-furo[2,3-d]pyrimidine) suppresses TNK2-mediated phosphorylation at Tyr-269. Inhibits the binding of the Tyr-269 phosphorylated form to androgen-responsive enhancers (AREs) and its transcriptional activity. {ECO:0000269\|PubMed:20623637}.
Subunit:		Binds DNA as a homodimer. Part of a ternary complex containing AR, EFCAB6/DJBP and PARK7. Interacts with HIPK3 and NR0B2 in the presence of androgen. The ligand binding domain interacts with KAT7/HBO1 in the presence of dihydrotestosterone. Interacts with EFCAB6/DJBP, PQBP1, RANBP9, RBAK, SPDEF, SRA1, TGFB1I1 and RREB1. Interacts with ZMIZ1/ZIMP10 and ZMIZ2/ZMIP7 which both enhance its transactivation activity. Interacts with SLC30A9 and RAD54L2/ARIP4. Interacts with MACROD1 (via macro domain) (PubMed:19022849). Interacts via the ligand-binding domain with LXXLL and FXXLF motifs from NCOA1, NCOA2, NCOA3, NCOA4 and 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. Interacts with HIP1 (via coiled coil domain). Interacts (via ligand-binding domain) with TRIM68. Interacts with TNK2. Interacts with USP26. Interacts with RNF6. Interacts (regulated by RNF6 probably through polyubiquitination) with RNF14; regulates AR transcriptional activity. Interacts with PRMT2 and TRIM24. Interacts with RACK1. Interacts with RANBP10; this interaction enhances dihydrotestosterone-induced AR transcriptional activity. Interacts with PRPF6 in a hormone-independent way; this interaction enhances dihydrotestosterone-induced AR transcriptional activity. Interacts with STK4/MST1. Interacts with ZIPK/DAPK3. Interacts with LPXN. Interacts with MAK. Part of a complex containing AR, MAK and NCOA3. Interacts with CRY1. Interacts with CCAR1 and GATA2. Interacts with ZNF318 (By similarity). Interacts with BUD31 (PubMed:25091737). Interacts with ARID4A (PubMed:23487765). Interacts with ARID4B (By similarity). Interacts (via NR LBD domain) with ZBTB7A; the interaction is direct and androgen-dependent (PubMed:20812024). Interacts with NCOR1 (PubMed:20812024). Interacts with NCOR2 (PubMed:20812024). Interacts with CRY2 in a ligand-dependent manner (By similarity). {ECO:0000250\|UniProtKB:P15207, ECO:0000250\|UniProtKB:P19091, ECO:0000269\|PubMed:10075738, ECO:0000269\|PubMed:10332029, ECO:0000269\|PubMed:10383460, ECO:0000269\|PubMed:10400640, ECO:0000269\|PubMed:10625666, ECO:0000269\|PubMed:10930412, ECO:0000269\|PubMed:12039962, ECO:0000269\|PubMed:12361945, ECO:0000269\|PubMed:12612053, ECO:0000269\|PubMed:12958311, ECO:0000269\|PubMed:14609956, ECO:0000269\|PubMed:14664718, ECO:0000269\|PubMed:15525515, ECO:0000269\|PubMed:15563469, ECO:0000269\|PubMed:16027218, ECO:0000269\|PubMed:16051670, ECO:0000269\|PubMed:16951154, ECO:0000269\|PubMed:17311914, ECO:0000269\|PubMed:17494760, ECO:0000269\|PubMed:17550981, ECO:0000269\|PubMed:17587566, ECO:0000269\|PubMed:17591767, ECO:0000269\|PubMed:17711855, ECO:0000269\|PubMed:17911242, ECO:0000269\|PubMed:18007036, ECO:0000269\|PubMed:18084323, ECO:0000269\|PubMed:18222118, ECO:0000269\|PubMed:18451096, ECO:0000269\|PubMed:18451177, ECO:0000269\|PubMed:19022849, ECO:0000269\|PubMed:19345326, ECO:0000269\|PubMed:19909775, ECO:0000269\|PubMed:20501646, ECO:0000269\|PubMed:20812024, ECO:0000269\|PubMed:20980437, ECO:0000269\|PubMed:21512132, ECO:0000269\|PubMed:22170608, ECO:0000269\|PubMed:23487765, ECO:0000269\|PubMed:23887938, ECO:0000269\|PubMed:25091737}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:12958311, ECO:0000269\|PubMed:15634333, ECO:0000269\|PubMed:17587566, ECO:0000269\|PubMed:19244107, ECO:0000269\|PubMed:19345326, ECO:0000269\|PubMed:25091737}. Cytoplasm {ECO:0000269\|PubMed:12958311, ECO:0000269\|PubMed:17587566, ECO:0000269\|PubMed:19244107}. Note=Detected at the promoter of target genes (PubMed:25091737). Predominantly cytoplasmic in unligated form but translocates to the nucleus upon ligand-binding. Can also translocate to the nucleus in unligated form in the presence of RACK1. {ECO:0000269\|PubMed:12958311, ECO:0000269\|PubMed:17587566, ECO:0000269\|PubMed:25091737}.
Tissue specificity:		[Isoform 2]: Mainly expressed in heart and skeletal muscle. {ECO:0000269\|PubMed:15634333}.
Tissue specificity:		[Isoform 3]: Expressed in basal and stromal cells of the prostate (at protein level). {ECO:0000269\|PubMed:19244107}.
Domain:		Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain. In the presence of bound steroid the ligand-binding domain interacts with the N-terminal modulating domain, and thereby activates AR transcription factor activity. Agonist binding is required for dimerization and binding to target DNA. The transcription factor activity of the complex formed by ligand-activated AR and DNA is modulated by interactions with coactivator and corepressor proteins (PubMed:25091737). Interaction with RANBP9 is mediated by both the N-terminal domain and the DNA- binding domain. Interaction with EFCAB6/DJBP is mediated by the DNA- binding domain. {ECO:0000269\|PubMed:25091737}.
Ptm:		Sumoylated on Lys-388 (major) and Lys-521. Ubiquitinated. Deubiquitinated by USP26. 'Lys-6' and 'Lys-27'-linked polyubiquitination by RNF6 modulates AR transcriptional activity and specificity. {ECO:0000269\|PubMed:11121022, ECO:0000269\|PubMed:19345326, ECO:0000269\|PubMed:20501646}.
Ptm:		Phosphorylated in prostate cancer cells in response to several growth factors including EGF. Phosphorylation is induced by c-Src kinase (CSK). Tyr-535 is one of the major phosphorylation sites and an increase in phosphorylation and Src kinase activity is associated with prostate cancer progression. Phosphorylation by TNK2 enhances the DNA- binding and transcriptional activity and may be responsible for androgen-independent progression of prostate cancer. Phosphorylation at Ser-83 by CDK9 regulates AR promoter selectivity and cell growth. Phosphorylation by PAK6 leads to AR-mediated transcription inhibition. {ECO:0000269\|PubMed:14573606, ECO:0000269\|PubMed:17045208, ECO:0000269\|PubMed:17494760, ECO:0000269\|PubMed:20623637, ECO:0000269\|PubMed:20980437, ECO:0000269\|PubMed:21512132}.
Ptm:		Palmitoylated by ZDHHC7 and ZDHHC21. Palmitoylation is required for plasma membrane targeting and for rapid intracellular signaling via ERK and AKT kinases and cAMP generation. {ECO:0000269\|PubMed:22031296}.
Polymorphism:		The poly-Gln region of AR is highly polymorphic and the number of Gln varies in the population (from 17 to 26). A smaller size of the poly-Gln region may be associated with the development of prostate cancer. Long poly-Gln alleles (>23) may be associated with higher testosterone levels and severe clinical outcome in COVID-19 disease (PubMed:33647767). {ECO:0000269\|PubMed:1561105, ECO:0000269\|PubMed:2062380, ECO:0000269\|PubMed:33647767, ECO:0000269\|PubMed:8292051, ECO:0000269\|PubMed:9096391}.
Polymorphism:		The poly-Gly region of AR is polymorphic and ranges from 24 to 31 Gly. A poly-Gly region shorter or equal to 23 may be associated with the development of androgenetic alopecia. {ECO:0000269\|PubMed:11231320, ECO:0000269\|PubMed:15902657}.
Disease:		Androgen insensitivity syndrome (AIS) [MIM:300068]: An X- linked recessive form of pseudohermaphroditism due end-organ resistance to androgen. Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal 46,XY karyotype. {ECO:0000269\|PubMed:10022458, ECO:0000269\|PubMed:10221692, ECO:0000269\|PubMed:10221770, ECO:0000269\|PubMed:10404311, ECO:0000269\|PubMed:10458483, ECO:0000269\|PubMed:10571951, ECO:0000269\|PubMed:10590024, ECO:0000269\|PubMed:10690872, ECO:0000269\|PubMed:11587068, ECO:0000269\|PubMed:11744994, ECO:0000269\|PubMed:1307250, ECO:0000269\|PubMed:1316540, ECO:0000269\|PubMed:1426313, ECO:0000269\|PubMed:1430233, ECO:0000269\|PubMed:1464650, ECO:0000269\|PubMed:14756668, ECO:0000269\|PubMed:1480178, ECO:0000269\|PubMed:1487249, ECO:0000269\|PubMed:1569163, ECO:0000269\|PubMed:1609793, ECO:0000269\|PubMed:16129672, ECO:0000269\|PubMed:16595706, ECO:0000269\|PubMed:1775137, ECO:0000269\|PubMed:1999491, ECO:0000269\|PubMed:2082179, ECO:0000269\|PubMed:2594783, ECO:0000269\|PubMed:7537149, ECO:0000269\|PubMed:7581399, ECO:0000269\|PubMed:7633398, ECO:0000269\|PubMed:7641413, ECO:0000269\|PubMed:7671849, ECO:0000269\|PubMed:7929841, ECO:0000269\|PubMed:7962294, ECO:0000269\|PubMed:7970939, ECO:0000269\|PubMed:7981687, ECO:0000269\|PubMed:7981689, ECO:0000269\|PubMed:7993455, ECO:0000269\|PubMed:8040309, ECO:0000269\|PubMed:8096390, ECO:0000269\|PubMed:8103398, ECO:0000269\|PubMed:8162033, ECO:0000269\|PubMed:8224266, ECO:0000269\|PubMed:8281140, ECO:0000269\|PubMed:8325950, ECO:0000269\|PubMed:8339746, ECO:0000269\|PubMed:8413310, ECO:0000269\|PubMed:8446106, ECO:0000269\|PubMed:8626869, ECO:0000269\|PubMed:8647313, ECO:0000269\|PubMed:8683794, ECO:0000269\|PubMed:8723113, ECO:0000269\|PubMed:8768864, ECO:0000269\|PubMed:8809734, ECO:0000269\|PubMed:8830623, ECO:0000269\|PubMed:8918984, ECO:0000269\|PubMed:8990010, ECO:0000269\|PubMed:9001799, ECO:0000269\|PubMed:9007482, ECO:0000269\|PubMed:9039340, ECO:0000269\|PubMed:9106550, ECO:0000269\|PubMed:9160185, ECO:0000269\|PubMed:9252933, ECO:0000269\|PubMed:9255042, ECO:0000269\|PubMed:9302173, ECO:0000269\|PubMed:9328206, ECO:0000269\|PubMed:9544375, ECO:0000269\|PubMed:9554754, ECO:0000269\|PubMed:9610419, ECO:0000269\|PubMed:9627582, ECO:0000269\|PubMed:9698822, ECO:0000269\|PubMed:9851768, ECO:0000269\|PubMed:9856504, ECO:0000269\|Ref.115, ECO:0000269\|Ref.181}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Spinal and bulbar muscular atrophy X-linked 1 (SMAX1) [MIM:313200]: An X-linked recessive form of spinal muscular atrophy. Spinal muscular atrophy refers to a group of neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMAX1 occurs only in men. Age at onset is usually in the third to fifth decade of life, but earlier involvement has been reported. It is characterized by slowly progressive limb and bulbar muscle weakness with fasciculations, muscle atrophy, and gynecomastia. The disorder is clinically similar to classic forms of autosomal spinal muscular atrophy. {ECO:0000269\|PubMed:15851746}. Note=The disease is caused by variants affecting the gene represented in this entry. Caused by trinucleotide CAG repeat expansion. In SMAX1 patients the number of Gln ranges from 38 to 62. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.
Disease:		Note=Defects in AR may play a role in metastatic prostate cancer. The mutated receptor stimulates prostate growth and metastases development despite of androgen ablation. This treatment can reduce primary and metastatic lesions probably by inducing apoptosis of tumor cells when they express the wild-type receptor. {ECO:0000269\|PubMed:10363963, ECO:0000269\|PubMed:10569618, ECO:0000269\|PubMed:1562539, ECO:0000269\|PubMed:16129672, ECO:0000269\|PubMed:17311914, ECO:0000269\|PubMed:2260966, ECO:0000269\|PubMed:25091737, ECO:0000269\|PubMed:8187068, ECO:0000269\|PubMed:8274409, ECO:0000269\|PubMed:8827083}.
Disease:		Androgen insensitivity, partial (PAIS) [MIM:312300]: A disorder that is characterized by hypospadias, hypogonadism, gynecomastia, genital ambiguity, normal XY karyotype, and a pedigree pattern consistent with X-linked recessive inheritance. Some patients present azoospermia or severe oligospermia without other clinical manifestations. {ECO:0000269\|PubMed:10022458, ECO:0000269\|PubMed:10221692, ECO:0000269\|PubMed:10470409, ECO:0000269\|PubMed:10502786, ECO:0000269\|PubMed:10543676, ECO:0000269\|PubMed:11587068, ECO:0000269\|PubMed:1303262, ECO:0000269\|PubMed:1307250, ECO:0000269\|PubMed:1316540, ECO:0000269\|PubMed:1424203, ECO:0000269\|PubMed:1430233, ECO:0000269\|PubMed:14756668, ECO:0000269\|PubMed:2010552, ECO:0000269\|PubMed:7581399, ECO:0000269\|PubMed:7649358, ECO:0000269\|PubMed:7671849, ECO:0000269\|PubMed:7909256, ECO:0000269\|PubMed:7910529, ECO:0000269\|PubMed:7929841, ECO:0000269\|PubMed:7970939, ECO:0000269\|PubMed:7981687, ECO:0000269\|PubMed:8033918, ECO:0000269\|PubMed:8097257, ECO:0000269\|PubMed:8126121, ECO:0000269\|PubMed:8205256, ECO:0000269\|PubMed:8281139, ECO:0000269\|PubMed:8325932, ECO:0000269\|PubMed:8325950, ECO:0000269\|PubMed:8446106, ECO:0000269\|PubMed:8550758, ECO:0000269\|PubMed:8809734, ECO:0000269\|PubMed:8823308, ECO:0000269\|PubMed:8824883, ECO:0000269\|PubMed:9039340, ECO:0000269\|PubMed:9196614, ECO:0000269\|PubMed:9302173, ECO:0000269\|PubMed:9329414, ECO:0000269\|PubMed:9543136, ECO:0000269\|PubMed:9607727, ECO:0000269\|PubMed:9768671, ECO:0000269\|PubMed:9856504, ECO:0000269\|Ref.123}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Hypospadias 1, X-linked (HYSP1) [MIM:300633]: A common malformation in which the urethra opens on the ventral side of the penis, due to developmental arrest of urethral fusion. The opening can be located glandular, penile, or even more posterior in the scrotum or perineum. Hypospadias is a feature of several syndromic disorders, including the androgen insensitivity syndrome and Opitz syndrome. {ECO:0000269\|PubMed:8097257}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		In the absence of ligand, steroid hormone receptors are thought to 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.
Miscellaneous:		Transcriptional activity is enhanced by binding to RANBP9.
Miscellaneous:		The level of tyrosine phosphorylation may serve as a diagnostic tool to predict patient outcome in response to hormone- ablation therapy. Inhibition of tyrosine phosphorylation may be an effective intervention target for hormone-refractory prostate cancer.
Miscellaneous:		[Isoform 3]: Minor isoform up-regulated in prostate cancer cells. {ECO:0000269\|PubMed:19244107}.
Miscellaneous:		[Isoform 4]: Minor isoform identified in prostate cancer cells. {ECO:0000269\|PubMed:19244107}.
Similarity:		Belongs to the nuclear hormone receptor family. NR3 subfamily. {ECO:0000305}.