Androgens, mainly testosterone and 5alpha-dihydrotestosterone (DHT) play significant role in the growth and development of the male reproductive organs. These steroid hormones bring about their biological functions through their associations with Androgen receptor (AR), a 110 KDa ligand dependent transcription factor that falls under the group of nuclear receptor superfamily. DHT binds the receptor with high affinity compared to testosterone. The AR gene is located in the X chromosome at Xq11-12 site. AR is cytosolic protein, which in the ligand unbound state, is present as a complex with various Heat shock proteins primarily Hsp70, 90 and 56 as well as p23. Upon ligand binding, it dissociates from the complex. AR is found to be expressed in a number of tissues and cells including prostate, testis, seminal vesicle, epididymis, skin, skeletal muscle, cardiac muscle, liver and central nervous system. The protein has four functional domains- an N terminal domain (NTD), a DNA binding domain (DBD), a hinge region and a Ligand binding Domain (LBD). The DBD is a 658 amino acid residue region that has ZNF motifs which allows it bind to DNA. The rest of the domains are involved in dimerization and ligand binding. Two phosphorylation events are proposed to play very important role in the activation of the receptor upon ligand binding. The first phosphorylation event releases the ligand binding domain for hormone binding. The subsequent phosphorylation event is triggered upon hormone binding. Activated AR upon ligand binding undergoes conformational change to form a homodimer and interacts tightly with the Androgen Response Element (ARE). The androgen receptor is known to bind to many co-regulators at different time points and in different cell types. This DNA protein complex triggers the expression of various target genes that are associated with the male phenotype. Modulation of the AR activity is carried out by several transcription factors like ARA70, TR4, SRC family members and CBP/p300 and other associated proteins. FXXLF and WXXLF motifs containing coactivators such as the p160 members bind with the AF2 region of the Ligand Binding Domain of the AR. Androgen receptors are known to induce apoptosis under certain conditions. Various regulators that regulate androgen induced apoptosis include BRCA1 and Smad3 and Akt. Mutation in AR are also known to be associated in a number of diseases including spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease and Androgen Insensitivity syndrome (AIS). Abnormal amplification of the androgen gene as well as deregulation of AR gene expression have been shown to be associated with prostate cancer. Please access this pathway at [http://www.netpath.org/netslim/ar_pathway.html NetSlim] database. If you use this pathway, please cite following paper: Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., Gollapudi, S. K., Tattikota, S. G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H. K. C., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y. L., Rahiman, B. A., Prasad, T. S. K., Lin, J., Houtman, J. C. D., Desiderio, S., Renauld, J., Constantinescu, S. N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G. D., Sander, C., Leonard, W. J. and Pandey, A. (2010). NetPath: A public resource of curated signal transduction pathways. <i>Genome Biology</i>. 11:R3. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP138 CPTAC Assay Portal] ace DHT and testosterone induces phosphorylation of FAK in LNCaP cells. Stimulation with DHT induces phosphorylation of CREB at Ser-183 (NP_604391.1) in LnCAP cells. Androgen stimulates the phosphorylation of p85 alpha protein in MCF7 cells. Androgen stimulation leads to induced phosphorylation of AKT1 in HEK293 cells. Stimulation with Androgen induces AR phosphorylation at Ser-80, Ser-93 and Ser-641 in LNCaP cells. On androgen stimulation, HDAC1 interacts with AR and induces the deacetylation of AR in COS-7 cells. On stimulation by DHT, EP300 acetylates ARat Lys residues at 631, 633,634 in DU145 cells. R1881 induces the interaction of AES with N-terminal region of AR in PC3 cells. AES is acts as repressor of AR. SIRT1, a corepressor interacts with the conserved lysine motif of Androgen receptor in LNCaP cells. AR and HDAC1 are ubiquitinated by MDM2 in response to Androgen in LNCaP cells. DHT induces the interaction of NCOA3 with N-terminal and ligand binding domiains of Androgen receptor in Yeast cells. Stimulation with Androgen induces the interaction of SP1 with AR which results in the induction of p21 transcription in SK-N-BE(2)-C tumor cells. DHT induces the interaction between AR and HBO1 in CV-1 and PC-3 cells. DHT induces the interaction between Androgen receptor and STAT3 in LNCaP cells. AR and HDAC1 are ubiquitinated by MDM2 in response to Androgen in LNCaP cells. Stimulation with DHT induces the interaction of androgen receptor with Zimp10 in CV1 cells. hZimp10 is capable of enhancing the sumoylation of AR. Stimualtion with DHT induces the interaction of NT and DB domain of AR with RB in DU145 cells. Testosterone induces the between Androgen Receptor and RELA in COS-1 cells. Stimulation with androgen induces the interaction of AR with PATZ in CV-1 cells. Stimulation with DHT induces the interaction of CHIP with NH2-terminal conserved motif of AR in COS-7 cells. CHIP functions as a negative regulator of AR transcriptional activity by promoting AR degradation. Stimulation with androgen induces the interaction of LBD domain of NCOR with AR in LNCaP cells. AR interacts with TBPIP both in the presence and absence of DHT in LNCaP cells and in vitro. It acts as a positive regulator of AR transactivation. DHT induces TR4 interaction with Androgen receptor in H1299 cells. Stimulation with DHT induces the interaction between Androgen receptor and BAF57 in LNCaP and LB1-Luc cells. AR interacts with CBP in COS-1 cells. Foxo1 is recruited by liganded AR to the chromatin of AR target gene promoters, where it interferes with AR-DNA interactions. SMAD3 which acts both coactivator and repressor of AR induces the expression of PSA in LNCaP cells. Stimulation with Androgen induces the interaction of LSD1 with AR in mouse testis. LSD1 demethylates histone and stimulate androgen receptor-dependent gene transcription. BAG1L interacts with NH2-terminal region of AR in COS-7 cells. Testpsterone stimulation induces destrin phosphorylation in vitro Stimulatio nwith DHT induces the interaction of TZF with activation function-1 (AF-1) domain of AR in LNCaP cells. SRC-1 and TIF2 forms a complex and interacts with AR in LNCaP and androgen independent CDC2 cells. Stimulation with Androgen induces the interaction of DAXX with N-terminal and the DNA-binding domain of AR in LNCaP and COS-1 cells. Stimulation with androgen induces the interaction of SMAD4 with DB and LB domains of AR in LNCaP cells. Stimulation with androgen induces the interaction PAK6 with DB and LB domain of AR in CV1 cells. PAK6 is an activator of AR. Stimulation with Androgen induces the interaction of SP1 with AR in LNCaP-FGC and SK-N-BE(2)-C cells. Stimulation with DHT induces the interaction between Androgen Receptor and PRDX1 in COS-7 cells. Stimulation with DHT induces interaction of AR with CREB and this interaction is mediated by CBP in COS 7 cells. Ligand binding domain of AR interacts with RAD9 in 293T cells and CWR22R cell lines. Stimulation with DHT induces the interaction of FKBP52 with AR in rabbit reticulocyte. Activation of RhoA/B and ROCK is implicated in membrane androgen receptor-dependent actin polymerization. DHT stimulation induces the interaction of PIAS3 with AR in LNCaP cells. PIAS3 acts as both activator and repressor of AR. AR interacts with RNF4 in CV-1 cells. Androgen stimulates the interaction between Androgen receptor and PARK7 in LNCaP cells. Stimulation with R1881 induces interaction between E6-AP and androgen receptor in prostrate cancer cell lines. DHT and testosterone induces activation of Rac1and CDC42 in LNCaP cells. CARM1 an activator of AR interacts with AR. Stimulation with androgen receptor with DHT induces the interaction of androgen receptor with FHL2 in CV1 cells. Testosterone stimulation leads to the activation of ROCK1 in DU145 and LNCaP cells. RNF6, an coactivator of AR induces the expression of RLN1. Stimulation with Androgen indices the interaction of iDNA binding domain of Androgen receptor interacts with LXXLL motifs of PIAS1 in COS-1 cells. PIAS1 acts as both coactivator and repressor of androgen receptor. Stimulation with DHT induces the interaction of DNA binding domain of AR with PST and RUNT domians of RUNX2 in MC3T3-E1 and PC3 cells. AR abrogates RUNX2 its recruitment to DNA. PCAF acetylates AR at Lys-631, Lys-633, Lys-634by and thus enhances AR activity. Stimulation with synthetic androgen R1881 induces the interaction of AR with EGFR in PC3 cells. DHT induces interaction between AR and ERM in CV-1 cells. On AR ligand dependant activation, NR0B2 interacts with AR at the NTD and LBD domain and inhibits AR transcriptional activity in yeast cells and CV-1 and CHO cells respectively. Testosterone induces the interaction between Androgen Receptor and ARIP3 in HeLa, COS-1 and mammalian cells and in vitro. low amounts of coexpressed ARIP3 enhanced AR-dependent transactivation up to 4-fold, but the effect vanished gradually with increasing amounts of ARIP3 expression plasmid in COS-1 cells. On androgen stimulation, CALR interacts with AR in PC3 and Cos-7 cells and inhibits AR transcriptional activities in vivo. DHT induces interaction of AR with BRCA1 in prostate cancer DU145 and PC-3 cells . DHT induces the interaction between AR and ARA54 in HepG2, DU145 cells and enhances trans-activation of AR. DHT and testosterone induces the interaction between AR and ARA70 in HepG2, DU145 cells and yeast. Stimulation with Androgen induces the interaction of region of AR between the DNA and ligand binding domains with the leucine zipper region of c-Jun in a ligand dependent manner in LNcap cells. c-Jun acts as both activator and repressor of AR. DNA binding domain of AR interacts with PIAS4 in vitro. AR interacts with ARA55 in H1299 human lung cancer cells in a ligand dependent manner. hinge region of AR interacts with FLNA in a ligand enhanced manner in LNCaP cells (cell line) DHT stimulation leads to the interaction between AR and CAV1 in PC3 cell lines. Overexpression of CAV1 enhances AR-mediated transcriptional activity and increases the sensitivity of AR to ligand-dependent activation in HEK 293 cells. N-terminal domain of AR interacts with Cyclin D1 in CV1 and LNCaP cells in a ligand-dependent manner and inhibits its transcriptional ability. Stimulation of Androgen receptor with DHT induces the interaction of ligand binding domain of AR with RACK1 in LNCaP cells(cell line) On stimulation with DHT, CTNNB1 interacts with AR in CV1 cells. On stimulation with DHT, interaction of androgen receptor with TCF4 in CV1 cells. ARA24 interacting with AR from the DHT-treated LNCaP cells Stimulation of Androgen receptor with DHT induces the interaction of Androgen receptor with PTEN in LNCaP cells Upon stimulation of Androgen receptor with androgen leads to the interaction and phosphorylation of ligand binding domain of AR by GSK3beta in DU-145, LNCaP , PC3 and COS-1 cells(cell line). This results in the suppression of androgen receptor activity. Testosterone induces the sumoylation of Androgen receptor in HeLa cells. Androgen stimulation leads to interaction of androgen receptor with SRC and p85 alpha subunit of PI3-kinase in HEK293 cells. Stimulation with Androgen induces the interaction of SmAD3 withLB domina of AR in LNCaP cells. SmAD3 acts as both coactivator and repressor of AR. DHT induces the interaction between TGIF and SIN3A and HDAC1 in CV1 cells.This complex suppresses AR transactivation. Testosterone stimulation induces phoshorylation of LIMK2 in vitro. Stimulation of Androgen receptor with DHT induces the interaction of Androgen receptor with PTEN in LNCaP cells. KAT5 acetylates AR in COS-7 cells. Androgen receptor interacts with CCNE1 in MDAH041 cells. RNF6 ubiquitinates AR at Lys-846 and Lys-848 in CWR-R1, LNCaP and COS-1 cells. PATZ1 interacts with RNF4 in CV-1 cells. 20067622 PubMed NetPath: a public resource of curated signal transduction pathways. Genome Biol 2010 Kandasamy K Mohan SS Raju R Keerthikumar S Kumar GS Venugopal AK Telikicherla D Navarro JD Mathivanan S Pecquet C Gollapudi SK Tattikota SG Mohan S Padhukasahasram H Subbannayya Y Goel R Jacob HK Zhong J Sekhar R Nanjappa V Balakrishnan L Subbaiah R Ramachandra YL Rahiman BA Prasad TS Lin JX Houtman JC Desiderio S Renauld JC Constantinescu SN Ohara O Hirano T Kubo M Singh S Khatri P Draghici S Bader GD Sander C Leonard WJ Pandey A androgen signaling pathway PW:0000564 Pathway Ontology