Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Androgen Receptor (AR)

  • Hatice Zeynep Nenseth
  • Martina Tesikova
  • Fahri Saatcioglu
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_514


Historical Background

Androgen receptor (AR) mediates the effects of androgens that are responsible for diverse biological functions, such as development and maintenance of the male reproductive system, as well as involvement in disease states, such as prostate cancer (PCa) (for a review, see Brinkmann (2011)). AR is a ligand-activated transcription factor (TF) that belongs to the steroid hormone receptor (SHR) family within the nuclear receptor (NR) superfamily of TFs (for a review, see Huang et al. (2010)). In addition to AR, the SHR family contains the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), and the estrogen receptor (ER). SHRs are structurally and functionally related and mediate the action of steroid hormones that affect nearly all aspects of development and homeostasis; they are also implicated in a number of pathological conditions.

The first evidence for the protein nature of AR from androgen target tissues were published at the end of the 1960s (Fang et al. 1969; Mainwaring 1969; Baulieu and Jung 1970). During the 1970s and 1980s, much effort went into the purification and further characterization of AR from different sources. The human AR cDNA was finally cloned in 1988 and 1989 independently by several groups just a few years after cloning of the GR in 1984 (Chang et al. 1988; Lubahn et al. 1988; Trapman et al. 1988; Tilley et al. 1989). AR is expressed at low to moderate levels in a variety of cell types with high levels present especially in male and female reproductive tissues, adrenal gland, kidney, and skeletal muscle. In addition to androgens, AR can be activated in an androgen-independent manner through other signaling pathways which can significantly contribute to the diversity of AR action.

AR Domains and Function

Similar to other SHRs, AR has four distinct functional domains: N-terminal domain (NTD), DNA-binding domain (DBD), hinge region, and ligand-binding domain (LBD) located at the C-terminus. The NTD generally serves as a docking site for transcriptional coregulators and TFs and mediates the ligand-independent transactivation function (AF-1). The DBD contains two zinc finger motifs that are essential for direct receptor binding to DNA recognition sequences in target genomic regions. The nuclear localization signal sequence (NLS) of AR is located in the hinge region. The LBD is composed of 12 α-helices forming a globular structure, surrounding a ligand-binding pocket. Ligand binding induces conformational changes in AR and affects interaction with coregulators. The structural variations of the bound ligand contribute to selective AR action on chromatin (for a review, see Lamb et al. (2001)) (Fig. 1). In addition to intermolecular interactions, intramolecular interactions occur between the NTD and LBD, which are important for AR activity and binding to chromatin (e.g., Wilson (2011)). Alternatively spliced AR isoforms have been identified both in normal tissue and in pathological conditions (for a review, see Dehm and Tindall (2011)). For example, several studies have reported alternatively spliced AR transcripts encoding truncated AR isoforms that lack the LBD in castration-resistant PCa (Caffo et al. 2016). Many of these truncated ARs function as constitutively active, ligand-independent TFs which may have implications in disease states.
Androgen Receptor (AR), Fig. 1

Schematic representation of the human AR protein. Structural and functional domains of AR are shown (UniProtKB – P10275 (ANDR_HUMAN)). The AR N-terminal domain (NTD) contains a ligand-independent activation function (AF-1) with two transactivation units, TAU-1 and TAU-5, containing binding motifs for coregulators. The 23FQNLF27 motif contributes to the interaction between the NTD and ligand-binding domain (LBD), whereas the 433WHTLF437 motif may influence AR signaling by acting as an autonomous activation domain. The total length of the human AR protein can vary due to polyglutamine ((Q)n) and a poly-glycine ((G)n) stretch of variable lengths in the NTD. The nuclear localization signal (NLS) resides in the flexible hinge region. The LBD also harbors a ligand-dependent AF-2 and the nuclear export signal (NES). The numbering of amino acids shown is based on 21 and 23 residues in the polyglutamine and poly-glycine repeats, respectively

In the absence of ligand, AR is inactive and exists in the cytosol in a complex with heat shock proteins (HSPs), such as Hsp56, Hsp70, and Hsp90, as well as cytoskeletal proteins and other chaperones (for reviews, see Lamb et al. (2001) and Brinkmann (2011)). Upon ligand binding, AR undergoes a conformational change, dissociates from HSPs and other chaperones, dimerizes, and translocates to the nucleus. Although AR usually acts as a homodimer, it has been shown to form heterodimers with other nuclear receptors including ER, GR, and testicular orphan receptor-4 (TR4) (Centenera et al. 2008). However, the functional consequences of these interactions in vivo are currently unclear. Once in the nucleus, AR binds chromatin in the vicinity of target genes at specific sites known as androgen response elements (AREs); recruits various coregulators, other TFs, and components of the general transcription machinery; and modulates gene expression (van de Wijngaart et al. 2012) (Fig. 2).
Androgen Receptor (AR), Fig. 2

AR transcriptional activation. Testosterone (T) circulates in the blood bound to steroid hormone-binding globulin (SHBG) or albumin and enters the cells through diffusion or through a SHBG receptor at the plasma membrane. In some cells, T is converted to the more active metabolite dihydrotestosterone (DHT) through the action of 5α-reductase. Upon ligand binding, AR undergoes a conformational change followed by dissociation from the multi-subunit chaperone complex. It then forms dimers and translocates to the nucleus where it binds androgen response elements of target genes and recruits coregulators (some examples of which are shown) and the basal transcription machinery resulting in transcriptional regulation. HSP heat shock protein, CBP CREB-binding protein, SRC steroid receptor coactivator, BRM Brahma, SWI/SNF a chromatin modifying complex

Based on biochemical studies and similar to other TFs, AR binds stably to its chromatin template in the presence of the ligand. However, development of live cell imaging and advances in green fluorescent protein (GFP) technology have demonstrated dynamic interactions of AR with its specific regulatory sites. Using fluorescence recovery after photobleaching (FRAP) analysis, residence times of these transient interactions were found to be on a time scale of seconds and were influenced by the nature of the ligand (Klokk et al. 2007).

Given the importance of androgens in normal physiology and disease states, several studies have sought to elucidate AR-mediated gene regulatory mechanisms by integrating differential gene expression analysis and identified genome-wide AR target sites using ChIP-chip and ChIP-seq (for a review, see Mills (2014)). These studies started to identify not only the genes that are direct AR targets but also AR-interacting proteins that are important for AR activity, such as transcriptional coregulators and FOXA1 as an AR-associated pioneer factor.

In addition to regulation by its cognate ligand, AR is subject to modification by phosphorylation, acetylation, methylation, sumoylation, and ubiquitination (for a review, see Gioeli and Paschal (2011)). Posttranslational modifications of AR have impact on protein stability, interaction with other proteins, cellular localization, and structure of the receptor itself. With respect to the complexity of AR regulation, the exact consequences of these modifications to AR function in normal physiology and implications for disease states are yet not known.

The importance of posttranslational modifications to AR activity is illustrated by modulation of AR action by a number of signaling pathways initiated by growth factors, cytokines, and mitogens (Fig. 3). Several growth factors, such as insulin-like growth factor-1 (IGF-1), keratinocyte growth factor (KGF), epidermal growth factor (EGF), and interleukin-6 (IL-6), were found to transactivate AR independently of androgens (for a review, see Foradori et al. (2008)). Such cell surface signals stimulate downstream mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathways, leading to increased AR activity as well as the activity and interaction of different AR coactivators which may have important clinical implications for PCa. This increase in activity is achieved, at least in part, through phosphorylation of AR and the coactivators (for a review, see Koryakina et al. (2014)). For example, AR has been shown to be phosphorylated on Ser650 upon EGF stimulation in PCa cells. Similarly, IL-6 stimulation phosphorylates the AR coactivator SRC-1.
Androgen Receptor (AR), Fig. 3

AR-mediated cytoplasmic and nuclear signaling pathways through activation of plasma membrane receptors. Androgens (A) may activate the cytoplasmic kinase PKA via binding to a G protein-coupled receptor (GPCR) at the plasma membrane and may thereby change the intracellular levels of second messenger molecules, such as cAMP. This can lead to phosphorylation and nuclear translocation of AR where it can act as a transcription factor. Nonsteroid molecules, such as growth factors (GF), cytokines (Cyt), and mitogens (Mit) arriving at the cell surface, activate MAPK (RAS/RAF/MEK/ERK) and PI3K/AKT signaling pathways which similarly phosphorylate and activate the AR leading to its translocation into the nucleus. ERK may also increase phosphorylation of AR coactivators which may activate them and thus increase AR activity

To better understand the molecular mechanisms of AR action, several AR knockout and knockin mouse models have been generated, both systemic and tissue specific (for a review, see Matsumoto et al. (2013)). The use of these models resulted in the identification of specific AR roles in male fertility, prostate development, muscle function, metabolism and diabetes, immune function, bone metabolism, and several cancers. One such example is the identification of AR functions in Sertoli and granulosa cells in spermatogenesis and folliculogenesis, respectively. In many other target tissues, the AR function and physiology are of complex nature, such as the study of mesenchymal–epithelial interactions in accessory sex glands and relative contribution of AR and estrogen receptor-mediated signaling in the brain and bone.

Non-genomic Actions of AR

Non-genomic actions of AR, identified in a number of cell lines, are characterized by rapid cellular responses within seconds to minutes that are independent of transcription and translation of AR target genes. These activities are initiated at the plasma membrane or in the cytosol, where cytoplasmic AR triggers activation of kinase signaling, such as the extracellular signal-regulated kinase (ERK), protein kinase A (PKA), PI3K/AKT, and protein kinase C (PKC), leading to cell proliferation (for a review, see Liao et al. (2013)) (Fig. 4).
Androgen Receptor (AR), Fig. 4

Non-genomic actions of AR. Androgen-bound AR interacts with the SH3 domain of the tyrosine kinase c-SRC in the cytosol and activates the MAPK (RAF-1/MEK/ERK) signaling. This then enhances phosphorylation events that activate TFs (e.g., AP-1 or NF-κB) and promotes cell survival and growth. Liganded AR can also directly interact with the p85 subunit of PI3K and mediate activation of the protein kinase AKT which in turn phosphorylates the cytoplasmic (e.g., BAD) and nuclear (e.g., FKHR-L1) proapoptotic proteins which results in their degradation. These events promote cell survival by inhibiting apoptosis. P phospho, BAD BCL2-associated agonist of cell death, FKHR-L1 forkhead transcription factor like 1 (also known as FOXO3A)

For example, following androgen binding, AR interacts with the p85 regulatory subunit of PI3K in the cytosol which then phosphorylates and activates the downstream effector serine–threonine kinase AKT. The AR-mediated phosphorylation of AKT is inhibited by the AR antagonist bicalutamide documenting the direct involvement of AR in this process.

Another example of non-genomic AR action is where androgen-bound AR physically interacts with and activates the tyrosine kinase c-SRC blocking its auto-inhibitory effect. This stimulates the c-SRC/RAF-1/MEK/ERK-2 signaling cascade. One of the targets of c-SRC is the adaptor molecule SH2-containing protein (SHC) which is an upstream regulator of MAPK. c-SRC-activated MAPK pathway modulates AR-mediated transcription by phosphorylating AR and p160 family of steroid receptor coactivators (SRCs) and thereby regulates several cellular processes such as cell proliferation, migration, and differentiation.

Non-genomic AR signaling may also occur in an ERK-independent manner, via activation of mammalian target of rapamycin (mTOR) pathway, or through plasma membrane G protein-coupled receptors (GPCRs) that modulate intracellular Ca2+ concentration.

AR and Disease States

Given the diverse role of androgens in a variety of tissues, perturbation to AR action has been linked to a number of disease conditions. For example, AR dysregulation has been associated with cancer (e.g., prostate, testicular, colorectal), cardiovascular defects (coronary artery disease), immune disease (e.g., type I diabetes), metabolic disorders (i.e., obesity and androgen insensitivity syndrome, osteoporosis), neurological conditions (e.g., Alzheimer’s disease), and other diseases such as Kennedy’s syndrome (for reviews, see Matsumoto et al. (2013) and Shukla et al. (2016)).

AR has been most widely studied in terms of its involvement in PCa (for a review, see Attard et al. (2016)). The key role of androgens in PCa genesis and progression was first observed in 1940s and has formed the basis of androgen ablation/castration therapies. Although initially highly effective, this therapy ultimately fails, and the disease progresses to a castration-resistant state which is associated with a poor prognosis. It has been shown that one of the key proteins in both the androgen-sensitive and castration-resistant PCa is AR. During the progression to castration resistance, AR signaling is maintained despite reduced levels of circulating androgens. Several mechanisms involving AR are activated, such as local PCa tissue androgen production, AR mutations or truncations, AR gene amplification or posttranslational modifications, AR splice variants, increased mitogen signaling, increased expression of AR coactivators, and increased sensitivity of AR to low androgen levels (for a review, see Wang and Tindall (2011)).

Another disease in which dysregulation of AR has a role is spinal and bulbar muscular atrophy (SBMA) or Kennedy’s disease (Kumar et al. 2011). The SBMA is characterized by the degeneration of the motor neurons which are located in the spinal cord and bulbar regions that express AR. It leads to weakness, atrophy, and fasciculation in the limb and bulbar muscles for which no curative treatment is available. This condition is caused by expansion of the CAG repeat encoding a poly-Q stretch in the AR NTD: whereas ~20 repeats are normal in adults, 40–62 repeats result in SBMA. The expanded poly-Q stretch leads to hormone-dependent AR unfolding and toxic gain of function that contributes to the disease phenotype.

A third AR-linked disease, androgen insensitivity syndrome (AIS), is characterized by partial or complete lack of response to androgens in cells which normally would be androgen sensitive (for a review, see Mongan et al. (2015)). This results in the failure of normal masculinization in 46XY male individuals. In AIS patients, the AR gene is frequently mutated in the DBD and/or the LBD making AR lose its function. Mutations can range from complete or partial deletions of the AR gene, which are rare, to point mutations and frame shift mutations. These can disrupt the DNA binding, AR expression levels, ligand-binding specificity, or efficacy which results in at least a partial functional loss in AR. The AIS can present a wide range of phenotypes depending on the degree of residual AR function.


AR is a ligand-activated TF which mediates the biological effects of androgens in diverse tissues. Upon ligand binding, AR translocates into the nucleus, binds AREs on target genes, and regulates transcription. In addition, AR interacts with other TFs or cofactors, as well as initiating rapid non-genomic cellular responses by direct interactions with several signaling molecules at the plasma membrane or in the cytoplasm. Conversely, AR can also be activated by mitogens, cytokines, and growth factors through signaling pathways which can regulate AR/coactivator activity through posttranslational modifications. Dysregulation of AR expression and/or function has been associated with a variety of disease states, including PCa, SBMA, and AIS. Thus, understanding AR function and structure is important for developing therapies in AR-related clinical conditions.


  1. Attard G, Parker C, Eeles RA, Schroder F, Tomlins SA, Tannock I, et al. Prostate cancer. Lancet. 2016;387:70–82. doi:10.1016/S0140-6736(14)61947-4.CrossRefPubMedGoogle Scholar
  2. Baulieu EE, Jung I. A prostatic cytosol receptor. Biochem Biophys Res Commun. 1970;38:599–606.CrossRefPubMedGoogle Scholar
  3. Brinkmann AO. Molecular mechanisms of androgen action – a historical perspective. Methods Mol Biol. 2011;776:3–24. doi:10.1007/978-1-61779-243-4_1.CrossRefPubMedGoogle Scholar
  4. Caffo O, Maines F, Veccia A, Kinspergher S, Galligioni E. Splice variants of androgen receptor and prostate cancer. Oncol Rev. 2016;10:297. doi:10.4081/oncol.2016.297.PubMedCentralCrossRefPubMedGoogle Scholar
  5. Centenera MM, Harris JM, Tilley WD, Butler LM. The contribution of different androgen receptor domains to receptor dimerization and signaling. Mol Endocrinol. 2008;22:2373–82. doi:10.1210/me.2008-0017.CrossRefPubMedGoogle Scholar
  6. Chang CS, Kokontis J, Liao ST. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science. 1988;240:324–6.CrossRefPubMedGoogle Scholar
  7. Dehm S, Tindall DJ. Alternatively spliced androgen receptor variants. Endocr Relat Cancer. 2011. doi:10.1530/ERC-11-0141.PubMedCentralPubMedGoogle Scholar
  8. Fang S, Anderson KM, Liao S. Receptor proteins for androgens. On the role of specific proteins in selective retention of 17-beta-hydroxy-5-alpha-androstan-3-one by rat ventral prostate in vivo and in vitro. J Biol Chem. 1969;244:6584–95.PubMedGoogle Scholar
  9. Foradori CD, Weiser MJ, Handa RJ. Non-genomic actions of androgens. Front Neuroendocrinol. 2008;29:169–81. doi:10.1016/j.yfrne.2007.10.005.CrossRefPubMedGoogle Scholar
  10. Gioeli D, Paschal BM. Post-translational modification of the androgen receptor. Mol Cell Endocrinol. 2011. doi:10.1016/j.mce.2011.07.004.PubMedGoogle Scholar
  11. Huang P, Chandra V, Rastinejad F. Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Annu Rev Physiol. 2010;72:247–72. doi:10.1146/annurev-physiol-021909-135917.PubMedCentralCrossRefPubMedGoogle Scholar
  12. Klokk TI, Kurys P, Elbi C, Nagaich AK, Hendarwanto A, Slagsvold T, et al. Ligand-specific dynamics of the androgen receptor at its response element in living cells. Mol Cell Biol. 2007;27:1823–43. doi:10.1128/MCB.01297-06.CrossRefPubMedGoogle Scholar
  13. Koryakina Y, Ta HQ, Gioeli D. Androgen receptor phosphorylation: biological context and functional consequences. Endocr Relat Cancer. 2014;21:T131–45. doi:10.1530/ERC-13-0472.PubMedCentralCrossRefPubMedGoogle Scholar
  14. Kumar R, Atamna H, Zakharov MN, Bhasin S, Khan SH, Jasuja R. Role of the androgen receptor CAG repeat polymorphism in prostate cancer, and spinal and bulbar muscular atrophy. Life Sci. 2011;88:565–71. doi:10.1016/j.lfs.2011.01.021.CrossRefPubMedGoogle Scholar
  15. Lamb DJ, Weigel NL, Marcelli M. Androgen receptors and their biology. Vitam Horm. 2001;62:199–230.CrossRefPubMedGoogle Scholar
  16. Liao RS, Ma S, Miao L, Li R, Yin Y, Raj GV. Androgen receptor-mediated non-genomic regulation of prostate cancer cell proliferation. Transl Androl Urol. 2013;2:187–96. doi:10.3978/j.issn.2223-4683.2013.09.07.PubMedCentralPubMedGoogle Scholar
  17. Lubahn DB, Joseph DR, Sullivan PM, Willard HF, French FS, Wilson EM. Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science. 1988;240:327–30.CrossRefPubMedGoogle Scholar
  18. Mainwaring WI. A soluble androgen receptor in the cytoplasm of rat prostate. J Endocrinol. 1969;45:531–41.CrossRefPubMedGoogle Scholar
  19. Matsumoto T, Sakari M, Okada M, Yokoyama A, Takahashi S, Kouzmenko A, et al. The androgen receptor in health and disease. Annu Rev Physiol. 2013;75:201–24. doi:10.1146/annurev-physiol-030212-183656.CrossRefPubMedGoogle Scholar
  20. Mills IG. Maintaining and reprogramming genomic androgen receptor activity in prostate cancer. Nat Rev Cancer. 2014;14:187–98. doi:10.1038/nrc3678.CrossRefPubMedGoogle Scholar
  21. Mongan NP, Tadokoro-Cuccaro R, Bunch T, Hughes IA. Androgen insensitivity syndrome. Best Pract Res Clin Endocrinol Metab. 2015;29:569–80. doi:10.1016/j.beem.2015.04.005.CrossRefPubMedGoogle Scholar
  22. Shukla GC, Plaga AR, Shankar E, Gupta S. Androgen receptor-related diseases: what do we know? Andrology. 2016;4:366–81. doi:10.1111/andr.12167.CrossRefPubMedGoogle Scholar
  23. Tilley WD, Marcelli M, Wilson JD, McPhaul MJ. Characterization and expression of a cDNA encoding the human androgen receptor. Proc Natl Acad Sci U S A. 1989;86:327–31.PubMedCentralCrossRefPubMedGoogle Scholar
  24. Trapman J, Klaassen P, Kuiper GG, van der Korput JA, Faber PW, van Rooij HC, et al. Cloning, structure and expression of a cDNA encoding the human androgen receptor. Biochem Biophys Res Commun. 1988;153:241–8.CrossRefPubMedGoogle Scholar
  25. van de Wijngaart DJ, Dubbink HJ, van Royen ME, Trapman J, Jenster G. Androgen receptor coregulators: recruitment via the coactivator binding groove. Mol Cell Endocrinol. 2012;352:57–69. doi:10.1016/j.mce.2011.08.007.CrossRefPubMedGoogle Scholar
  26. Wang D, Tindall DJ. Androgen action during prostate carcinogenesis. Methods Mol Biol. 2011;776:25–44. doi:10.1007/978-1-61779-243-4_2.CrossRefPubMedGoogle Scholar
  27. Wilson EM. Analysis of interdomain interactions of the androgen receptor. Methods Mol Biol. 2011;776:113–29. doi:10.1007/978-1-61779-243-4_8.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Hatice Zeynep Nenseth
    • 1
  • Martina Tesikova
    • 1
  • Fahri Saatcioglu
    • 1
    • 2
  1. 1.Department of BiosciencesUniversity of OsloOsloNorway
  2. 2.Institute for Cancer Genetics and InformaticsOslo University HospitalOsloNorway