Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
Metalloprotease
G-alpha
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Transporter
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
DNA
RNA
Compound
Inorganic ion
Predicted metabolite or user's structure
Reaction
Generic receptor
GPCR
Receptors with enzyme activity
Mitochondria
EPR
Golgi
Nucleus
Lysosome
Peroxisome
Cytoplasm
Extracellular

Normal process
Pathological process
Binding
Cleavage
Covalent modifications
Phosphorylation
Dephosphorylation
Transformation
Transport
Catalysis
Transcription regulation
MicroRNA binding
Competition
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Translation Non-genomic (rapid) action of Androgen Receptor


Log In to Post A Comment

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].