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) , . 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 , .
Binding of Testosterone or
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)) . Androgen
receptor with co-regulators induces expression of target
genes, such as Prostate specific antigen Kallikrein-related peptidase 3
(Kallikrein 3 (PSA)) in prostate ,
cyclin-dependent kinase inhibitor Cyclin-dependent kinase inhibitor 1A
(p21) , Ezrin
(VIL2(ezrin)) , Matrix metalloproteinase 2
(MMP-2)  and SREBF chaperone
(SCAP) . Besides co-activators,
Androgen receptor can also recruit co-repressors such as
Cyclin D1 , RAD9 homologs
(RAD9) , Nuclear receptor co-repressor 1
(N-CoR)  and others.
Androgen receptor activity
is tightly regulated by distinct growth factor cascades, which can induce
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 .
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) kinase, in turn, phosphorylates and activates
Androgen receptor itself and
Androgen receptor co-activators
such as NCOA1 (SRC1) and NCOA2 (GRIP1/TIF2)
EGF enhances activity of
Androgen receptor through
activation of MAPK cascade , .
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 .
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 , , . 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 .
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
transcriptional activity in context-dependent manner .
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 .
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 .
Proline-rich tyrosine kinase 2
(Pyk2(FAK2)) can repress
transactivation via inactivation of Androgen
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
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