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 theSteroid-5-alpha-reductase, alpha polypeptides 1 and 2 ( S5AR1 and S5AR2 )[1], [2]. Biological activity of androgens such asTestosterone and DHT is predominantly meditated by its binding to theAndrogen receptor, a member of the nuclear receptor superfamily thatfunctions as a ligand-activated transcription factor [3], [4].
However, androgens also induce rapid activation of kinase-signaling cascades andmodulate intracellular calcium levels. These effects are considered non-genomic, as theyoccur in cells in the presence of inhibitors of transcription and translation and occurtoo rapidly to involve transcription [5], [6].
For efficient non-genomic activity, Androgen receptor is recruited toplasma membrane microdomains via interaction with Caveolin 1, caveolae protein, 22kDa (Caveolin-1 ) [7].
In response to DHT, Androgen receptor interacts with the SH3domain of tyrosine kinase v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (c-Src ) [8].This interaction results in stimulation of two members ofthe mitogen-activated protein kinase (MAPK) signaling cascade, v-raf-1 murine leukemiaviral oncogene homolog 1 ( c-Raf-1 ) and Mitogen-activated protein kinase 1 (ERK2(MAPK1) ) [9], [6].
Androgen receptor also can activate Phosphoinositide-3-kinase (PI3K )/ V-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ) kinasepathway through direct interaction with the Phosphoinositide-3-kinase, regulatory subunit1 (alpha) ( PI3K reg class IA (p85-alpha) ) in response to natural androgens[9]. Such androgenic activation of PI3K leads to phosphorylation ofAKT(PKB) [9], [10].
Androgens treatment results in higher FK506 binding protein 12-rapamycin associatedprotein 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 thedownstream mTOR targets Ribosomal protein S6 kinase, 70kDa, polypeptide 1 ( p70S6 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 thenmay lead to various complex regulatory circuits such as positive and negative feedbackloops.
Activated AKT(PKB) phosphorylates and stabilizes Mdm2 p53 binding proteinhomolog ( MDM2 ), which can ubiquitinilate Androgen receptor andtarget it to degradation via proteasome [12].
Moreover, transcription factor Forkhead box O3 ( FOXO3A ) can induceAndrogen receptor expression [13]. AKT(PKB)phosphorylates FOXO3A thus inactivating its transactivation function. This leadsto reducing Androgen receptor expression on mRNA level.
Nuclear factor of kappa light polypeptide gene enhancer in B-cells ( NF-kB ) isan activator of Androgen receptor gene transcription in Sertoli cells andmay be an important determinant of androgen activity during spermatogenesis [14].
An interaction between epidermal growth factor receptor Epidermal growth factorreceptor ( EGFR ) and Androgen receptor results in decreasing ofEGFR -mediated MAPK signaling and Epidermal growth factor ( EGF)-stimulated PI3K activity, mediated through adaptor protein Insulin receptorsubstrate 1 ( IRS-1 ) [15], [16].
In contrast, stimulation by EGF, N euregulin 1 and Heparin-bindingEGF-like growth factor ( HB-EGF ) activates downstream signaling of co-receptorsEGFR/ v-erb-b2 erythroblastic leukemia viral oncogene homolog 2,neuro/glioblastoma derived oncogene homolog ( ErbB2 ) including MAPK andPI3K/ AKT(PKB pathways, which stabilizes Androgen receptorprotein level and optimizes binding of Androgen receptor topromoter/enhancer regions of androgen-regulated genes [17], [18],[19].
The interaction between phosphatase Phosphatase and tensin homolog ( PTEN ) andAndrogen receptor inhibits Androgen receptor nucleartranslocation and promotes its degradation, which results in suppression ofAndrogen receptor transactivation and induction of apoptosis [20], [21].
Androgen receptor can also inhibit WNT signaling pathway viainteraction with beta-catenin. This interaction may lead to inhibition oftransactivation function of Catenin (cadherin-associated protein), beta 1(Beta-catenin) [22], [23]. Glycogen synthase kinase 3beta ( GSK3 beta ) is also involved in WNT cascade and can inhibitAndrogen receptor via its phosphorylation [21].
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