Non-genomic (rapid) action of Androgen
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) , . 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 , .
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 , .
For efficient non-genomic activity, Androgen
receptor is recruited to plasma membrane microdomains via
interaction with Caveolin 1, caveolae protein, 22kDa
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) .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)) , .
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 . Such androgenic activation of
PI3K leads to phosphorylation of
AKT(PKB) , .
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 .
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 .
Moreover, transcription factor Forkhead box O3 (FOXO3A)
can induce Androgen receptor
expression . 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 .
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) , .
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 , , .
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 , .
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) , . Glycogen synthase
kinase 3 beta (GSK3 beta) is also
involved in WNT
cascade and can inhibit Androgen
receptor via its phosphorylation .
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