Androgen Receptor (NR3C4)


Androgen receptors (ARs) (also known as dihydrotestosterone receptors) are nuclear hormone receptors of the NR3C class, which also includes mineralocorticoid, progesterone and glucocorticoid receptors. They are expressed in bone marrow, mammary gland, prostate, testicular and muscle tissues where they exist as dimers coupled to Hsp90 and HMGB proteins, which are shed upon ligand binding. Activated androgen receptors bind to nuclear response elements of the genome, with an inverted palindromic 15 nucleotide sequence, to regulate gene transcription. Androgen receptors also effect gene expression through interaction with transcription factors including AP-1, NF-kappaB and STAT. Target genes of androgen receptors include insulin-like growth factor 1 (IGF-1) and genes involved in the development of primary and secondary male sexual characteristics, maintenance of sexual function and possibly have a causative role in aggressive behavior. Furthermore, androgen receptors have recently been shown to have actions that are independent of DNA interactions. Congential mutations in androgen receptors are associated with androgen insensitivity syndromes, virility and spinal and bulbar muscular atrophy. Perturbations in androgen receptor expression is also a common feature of prostate cancer. The human gene encoding the androgen receptor has been localized to Xq11-12.

For more information, see a short research article HERE

AR Signaling

AR Genomic Signaling

(From GeneGo)

Androgen is the active metabolic product, 5alpha-Dihydrotestosterone, which is produced from the transformation ofTestosteronecatalyzed by the Steroid-5-alpha-reductase, alpha polypeptides 1 and 2 ( S5AR1and S5AR2[1][2]. Biological activity of androgens is mediated by binding to the Androgenreceptor, a member of the nuclear receptor superfamily that functions as a ligand-activated transcription factor [3][4].

Binding of Testosteroneor 5alpha-Dihydrotestosteroneto Androgenreceptorinduces its dimerization, which is needed for binding to Androgenreceptor's cognate response element and recruitment of co-regulators, such as transcriptional co-activator protein E1A binding protein p300 ( p300), Nuclear receptor co-activators 1 and 2 ( NCOA1 (SRC1)NCOA2 (GRIP1/TIF2)[5].Androgenreceptorwith co-regulators induces expression of target genes, such as Prostate specific antigen Kallikrein-related peptidase 3 ( Kallikrein 3 (PSA)) in prostate [6], cyclin-dependent kinase inhibitor Cyclin-dependent kinase inhibitor 1A ( p21[7], Ezrin ( VIL2(ezrin)[8], Matrix metalloproteinase 2 ( MMP-2[9]and SREBF chaperone ( SCAP[10]. Besides co-activators,Androgen receptorcan also recruit co-repressors such as Cyclin D1[11], RAD9 homologs ( RAD9[12], Nuclear receptor co-repressor 1 ( N-CoR[13]and others.

Androgenreceptoractivity is tightly regulated by distinct growth factor cascades, which can induce Androgenreceptormodifications, including phosphorylation and acetylation or changes in interactions of Androgenreceptorwith other cofactors. Epidermal growth factor ( EGF),Insulin-like growth factor 1 ( IGF-1), Interleukin-6 ( IL-6) and ligands stimulating the Protein kinase A, cAMP-dependent ( PKA-cat (cAMP-dependent)) pathways activate Androgenreceptorby phosphorylation in the absence of androgens either directly or indirectly via mitogen-activated protein kinase (MAPK) cascade and other signaling pathways in certain prostate cancer cells and, thereby, contribute to Androgenreceptor-induced gene expression [14].

Binding of IGF-1ligands to Insulin-like growth factor 1 receptor ( IGF-1 receptor) leads to activation of MAPK cascade. Phosphorylated IGF-1 receptorcan directly interact with and phosphorylate adaptor protein SHC (Src homology 2 domain containing) transforming protein 1 ( Shc), resulting in the recruitment of the complex containing Growth factor receptor-bound protein 2 ( GRB2) and Son of sevenless homolog ( SOS) and activation of small GTPase v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras), v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1), and the MAPK cascade Mitogen-activated protein kinase kinase 1 (MEK1(MAP2K1))/ Mitogen-activated protein kinase 1 ( ERK2(MAPK1)[14].

ERK2(MAPK1)kinase, in turn, phosphorylates and activates Androgenreceptoritself and Androgenreceptorco-activators such as NCOA1 (SRC1)and NCOA2 (GRIP1/TIF2)[15].

EGFenhances activity of Androgenreceptorthrough activation of MAPK cascade [16][17].

IL-6enhances Androgenreceptortransactivation mainly via Signal transducer and activator of transcription 3 ( STAT3), which associates with Androgen receptorand is also able to induce Androgenreceptor-mediated gene activation [18].

There is a cross talk between members of wingless-type MMTV integration site family ( WNT) and androgen signaling pathways. Catenin (cadherin-associated protein), beta 1 (Beta-catenin)protein, is a critical molecular component of canonical WNTsignaling, flowing through Galpha(q)-specific frizzled GPCRsand Dishevelled ( Dsh). Beta-cateninpromotes androgen signaling through binding to Androgenreceptorin a ligand-dependent fashion and the follow-up transcription activation of androgen-regulated genes[19][20][21]. Glycogen synthase kinase 3 beta ( GSK3 beta) involved in WNTsignaling pathway, also functions as a repressor ofAndrogenreceptor-mediated transactivation and cell growth via direct phosphorylation of Androgenreceptor[22].

Transforming growth factor, beta 1 ( TGF-beta 1) - mediated action follows a complex signaling pathway from its binding to Transforming growth factor, beta receptors 1 and II ( TGF-beta receptor type ITGF-beta receptor type II) and their phosphorylation to activation of transcription factor SMAD family member 3 ( SMAD3). SMAD3interacts with Androgenreceptorand activate Androgenreceptortranscriptional activity in context-dependent manner [23].

p21 protein (Cdc42/Rac)-activated kinase 6 ( PAK6) is a serine/threonine kinase from the p21-activated kinase family. Active PAK6phosphorylates Androgenreceptorand inhibits its nuclear translocation [24].

Activation of the Phosphoinositide-3-kinase/ v-akt murine thymoma viral oncogene homolog 1 ( AKT1) pathway results in AKT1-dependent phosphorylation of Androgen Receptor, suppression of Androgenreceptortarget genes, such as p21, and the decrease of androgen/ Androgenreceptor-mediated apoptosis [25].

Proline-rich tyrosine kinase 2 ( Pyk2(FAK2)) can repress Androgenreceptortransactivation via inactivation of Androgenreceptorco-activator Transforming growth factor beta 1 induced transcript 1 ( Hic-5/ARA55). This inactivation may result from the direct phosphorylation of Hic-5/ARA55by Pyk2(FAK2)at tyrosine 43, impairing the co-activator activity of Hic-5/ARA55and/or its sequestering to reduce the interaction with Androgenreceptor[26].


  1. Wilson JD 

    The role of 5alpha-reduction in steroid hormone physiology.Reproduction, fertility, and development 2001;13(7-8):673-8

  2. Heinlein CA, Chang C 

    Androgen receptor in prostate cancer.Endocrine reviews 2004 Apr;25(2):276-308

  3. Gelmann EP 

    Molecular biology of the androgen receptor.Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2002 Jul 1;20(13):3001-15

  4. McEwan IJ 

    Molecular mechanisms of androgen receptor-mediated gene regulation: structure-function analysis of the AF-1 domain.Endocrine-related cancer 2004 Jun;11(2):281-93

  5. Roy AK, Tyagi RK, Song CS, Lavrovsky Y, Ahn SC, Oh TS, Chatterjee B 

    Androgen receptor: structural domains and functional dynamics after ligand-receptor interaction.Annals of the New York Academy of Sciences 2001 Dec;949:44-57

  6. Kim J, Coetzee GA 

    Prostate specific antigen gene regulation by androgen receptor.Journal of cellular biochemistry 2004 Oct 1;93(2):233-41

  7. Lu S, Liu M, Epner DE, Tsai SY, Tsai MJ 

    Androgen regulation of the cyclin-dependent kinase inhibitor p21 gene through an androgen response element in the proximal promoter.Molecular endocrinology (Baltimore, Md.) 1999 Mar;13(3):376-84

  8. Chuan YC, Pang ST, Cedazo-Minguez A, Norstedt G, Pousette A, Flores-Morales A 

    Androgen induction of prostate cancer cell invasion is mediated by ezrin.The Journal of biological chemistry 2006 Jul 26;

  9. Li BY, Liao XB, Fujito A, Thrasher JB, Shen F, Xu PY 

    Dual androgen-response elements mediate androgen regulation of mmp-2 gene expression in prostate cancer cells.Asian journal of andrology 2006 Aug 4;

  10. Heemers H, Verrijdt G, Organe S, Claessens F, Heyns W, Verhoeven G, Swinnen JV 

    Identification of an androgen response element in intron 8 of the sterol regulatory element-binding protein cleavage-activating protein gene allowing direct regulation by the androgen receptor.The Journal of biological chemistry 2004 Jul 16;279(29):30880-7

  11. Petre CE, Wetherill YB, Danielsen M, Knudsen KE 

    Cyclin D1: mechanism and consequence of androgen receptor co-repressor activity.The Journal of biological chemistry 2002 Jan 18;277(3):2207-15

  12. Wang L, Hsu CL, Ni J, Wang PH, Yeh S, Keng P, Chang C 

    Human checkpoint protein hRad9 functions as a negative coregulator to repress androgen receptor transactivation in prostate cancer cells.Molecular and cellular biology 2004 Mar;24(5):2202-13

  13. Wu Y, Kawate H, Ohnaka K, Nawata H, Takayanagi R 

    Nuclear compartmentalization of N-CoR and its interactions with steroid receptors.Molecular and cellular biology 2006 Sep;26(17):6633-55

  14. Culig Z 

    Androgen receptor cross-talk with cell signalling pathways.Growth factors (Chur, Switzerland) 2004 Sep;22(3):179-84

  15. Rowan BG, Weigel NL, O'Malley BW 

    Phosphorylation of steroid receptor coactivator-1. Identification of the phosphorylation sites and phosphorylation through the mitogen-activated protein kinase pathway.The Journal of biological chemistry 2000 Feb 11;275(6):4475-83

  16. Reinikainen P, Palvimo JJ, Janne OA 

    Effects of mitogens on androgen receptor-mediated transactivation.Endocrinology 1996 Oct;137(10):4351-7

  17. Gupta C 

    Modulation of androgen receptor (AR)-mediated transcriptional activity by EGF in the developing mouse reproductive tract primary cells.Molecular and cellular endocrinology 1999 Jun 25;152(1-2):169-78

  18. De Miguel F, Lee SO, Onate SA, Gao AC 

    Stat3 enhances transactivation of steroid hormone receptors.Nuclear receptor [electronic resource]. 2003 Jun 13;1(1):3

  19. Song LN, Herrell R, Byers S, Shah S, Wilson EM, Gelmann EP 

    Beta-catenin binds to the activation function 2 region of the androgen receptor and modulates the effects of the N-terminal domain and TIF2 on ligand-dependent transcription.Molecular and cellular biology 2003 Mar;23(5):1674-87

  20. Chesire DR, Isaacs WB 

    Beta-catenin signaling in prostate cancer: an early perspective.Endocrine-related cancer 2003 Dec;10(4):537-60

  21. Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC 

    Interaction of Nuclear Receptors with Wnt/{beta}-catenin/Tcf Signalling: Wnt you like to know?Endocrine reviews 2005 Aug 26;

  22. Wang L, Lin HK, Hu YC, Xie S, Yang L, Chang C 

    Suppression of androgen receptor-mediated transactivation and cell growth by the glycogen synthase kinase 3 beta in prostate cells.The Journal of biological chemistry 2004 Jul 30;279(31):32444-52

  23. Kang HY, Huang KE, Chang SY, Ma WL, Lin WJ, Chang C 

    Differential modulation of androgen receptor-mediated transactivation by Smad3 and tumor suppressor Smad4.The Journal of biological chemistry 2002 Nov 15;277(46):43749-56

  24. Schrantz N, da Silva Correia J, Fowler B, Ge Q, Sun Z, Bokoch GM 

    Mechanism of p21-activated kinase 6-mediated inhibition of androgen receptor signaling.The Journal of biological chemistry 2004 Jan 16;279(3):1922-31

  25. Lin HK, Yeh S, Kang HY, Chang C 

    Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor.Proceedings of the National Academy of Sciences of the United States of America 2001 Jun 19;98(13):7200-5

  26. Wang X, Yang Y, Guo X, Sampson ER, Hsu CL, Tsai MY, Yeh S, Wu G, Guo Y, Chang C 

    Suppression of androgen receptor transactivation by Pyk2 via interaction and phosphorylation of the ARA55 coregulator.The Journal of biological chemistry 2002 May 3;277(18):15426-31