Androgen Receptor (NR3C4)

Introduction

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].

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