Transcription - Androgen Receptor nuclear signaling

Androgen Receptor nuclear signaling

Androgen is the active metabolic product, 5alpha-Dihydrotestosterone, which is produced from the transformation of Testosterone catalyzed by the Steroid-5-alpha-reductase, alpha polypeptides 1 and 2 (S5AR1 and S5AR2) [1], [2]. Biological activity of androgens is mediated by binding to the Androgen receptor, a member of the nuclear receptor superfamily that functions as a ligand-activated transcription factor [3], [4].

Binding of Testosterone or 5alpha-Dihydrotestosterone to Androgen receptor induces its dimerization, which is needed for binding to Androgen receptor'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]. Androgen receptor with 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 receptor can also recruit co-repressors such as Cyclin D1 [11], RAD9 homologs (RAD9) [12], Nuclear receptor co-repressor 1 (N-CoR) [13] and others.

Androgen receptor activity is tightly regulated by distinct growth factor cascades, which can induce Androgen receptor modifications, including phosphorylation and acetylation or changes in interactions of Androgen receptor with 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 Androgen receptor by 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 Androgen receptor -induced gene expression [14].

Binding of IGF-1 ligands to Insulin-like growth factor 1 receptor (IGF-1 receptor) leads to activation of MAPK cascade. Phosphorylated IGF-1 receptor can 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 Androgen receptor itself and Androgen receptor co-activators such as NCOA1 (SRC1) and NCOA2 (GRIP1/TIF2) [15].

EGF enhances activity of Androgen receptor through activation of MAPK cascade [16], [17].

IL-6 enhances Androgen receptor transactivation mainly via Signal transducer and activator of transcription 3 (STAT3), which associates with Androgen receptor and is also able to induce Androgen receptor -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 WNT signaling, flowing through Frizzled and Dishevelled (Dsh). Beta-catenin promotes androgen signaling through binding to Androgen receptor in 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 WNT signaling pathway, also functions as a repressor of Androgen receptor -mediated transactivation and cell growth via direct phosphorylation of Androgen receptor [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 I, TGF-beta receptor type II) and their phosphorylation to activation of transcription factor SMAD family member 3 (SMAD3). SMAD3 interacts with Androgen receptor and activate Androgen receptor transcriptional 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 PAK6 phosphorylates Androgen receptor and 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 Androgen receptor target genes, such as p21, and the decrease of androgen/ Androgen receptor -mediated apoptosis [25].

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

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