Translation - Non-genomic (rapid) action of Androgen Receptor

Non-genomic (rapid) action of Androgen Receptor

Androgen is the active metabolic product, 5alpha-Dihydrotestosterone (DHT), 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 such as Testosterone and DHT is predominantly meditated by its binding to the Androgen receptor, a member of the nuclear receptor superfamily that functions as a ligand-activated transcription factor [3], [4].

However, androgens also induce rapid activation of kinase-signaling cascades and modulate intracellular calcium levels. These effects are considered non-genomic, as they occur in cells in the presence of inhibitors of transcription and translation and occur too rapidly to involve transcription [5], [6].

For efficient non-genomic activity, Androgen receptor is recruited to plasma membrane microdomains via interaction with Caveolin 1, caveolae protein, 22kDa (Caveolin-1) [7].

In response to DHT, Androgen receptor interacts with the SH3 domain of tyrosine kinase v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (c-Src) [8].This interaction results in stimulation of two members of the mitogen-activated protein kinase (MAPK) signaling cascade, v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1) and Mitogen-activated protein kinase 1 (ERK2(MAPK1)) [6], [9].

Androgen receptor also can activate Phosphoinositide-3-kinase (PI3K)/ V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)) kinase pathway through direct interaction with the Phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PI3K reg class IA (p85-alpha)) in response to natural androgens [9]. Such androgenic activation of PI3K leads to phosphorylation of AKT(PKB) [9], [10].

Androgens treatment results in higher FK506 binding protein 12-rapamycin associated protein 1 (mTOR) activity mediated by AKT(PKB) protein kinase. AKT(PKB) phosphorylates and inhibits Tuberous sclerosis 2 (Tuberin), this prevents inhibition of mTOR and leads to phosphorylation of the downstream mTOR targets Ribosomal protein S6 kinase, 70kDa, polypeptide 1 (p70 S6 kinase 1), Eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) and subsequently activates protein synthesis [11].

Activation of PI3K signaling pathway by Androgen receptor then may lead to various complex regulatory circuits such as positive and negative feedback loops.

Activated AKT(PKB) phosphorylates and stabilizes Mdm2 p53 binding protein homolog (MDM2), which can ubiquitinilate Androgen receptor and target it to degradation via proteasome [12].

Moreover, transcription factor Forkhead box O3 (FOXO3A) can induce Androgen receptor expression [13]. AKT(PKB) phosphorylates FOXO3A thus inactivating its transactivation function. This leads to reducing Androgen receptor expression on mRNA level.

Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kB) is an activator of Androgen receptor gene transcription in Sertoli cells and may be an important determinant of androgen activity during spermatogenesis [14].

An interaction between epidermal growth factor receptor Epidermal growth factor receptor (EGFR) and Androgen receptor results in decreasing of EGFR-mediated MAPK signaling and Epidermal growth factor (EGF)-stimulated PI3K activity, mediated through adaptor protein Insulin receptor substrate 1 (IRS-1) [15], [16].

In contrast, stimulation by EGF, Neuregulin 1 and Heparin-binding EGF-like growth factor (HB-EGF) activates downstream signaling of co-receptors EGFR/ v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (ErbB2) including MAPK and PI3K/ AKT(PKB pathways, which stabilizes Androgen receptor protein level and optimizes binding of Androgen receptor to promoter/enhancer regions of androgen-regulated genes [17], [18], [19].

The interaction between phosphatase Phosphatase and tensin homolog (PTEN) and Androgen receptor inhibits Androgen receptor nuclear translocation and promotes its degradation, which results in suppression of Androgen receptor transactivation and induction of apoptosis [20], [21].

Androgen receptor can also inhibit WNT signaling pathway via interaction with beta-catenin. This interaction may lead to inhibition of transactivation function of Catenin (cadherin-associated protein), beta 1 (Beta-catenin) [22], [23]. Glycogen synthase kinase 3 beta (GSK3 beta) is also involved in WNT cascade and can inhibit Androgen receptor via its phosphorylation [21].

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