Androgen receptor signaling pathway (WP138)

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 vescicle, 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. Genome Biology. 11:R3. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP138 CPTAC Assay Portal]
last edited

Authors

A.Pandey, MaintBot, Nsalomonis, Andra, AlexanderPico, Khanspers, MartijnVanIersel, NetPath, Robertbaertsch, Mkutmon, Zari, L Dupuis, Egonw, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: androgen signaling pathway

Participants

Label Type Compact Identifier
KDM1A Protein ncbigene:23028
BMF Rna ncbigene:90427
PIAS3 Protein ncbigene:10401
SIRT1 Protein ncbigene:23411
SMARCE1 Protein ncbigene:6605
RNF6 Protein ncbigene:6049
NR2C2 Protein ncbigene:7182
RAD9A Protein ncbigene:5883
RHOA Protein ncbigene:387
RHOB Protein ncbigene:388
PSMC3IP Protein ncbigene:29893
SMAD4 Protein ncbigene:4089
FKBP4 Protein ncbigene:2288
NCOR2 Protein ncbigene:9612
PIAS1 Protein ncbigene:8554
SUMO1 Protein ncbigene:7341
AR Protein ncbigene:367
RUNX2 Protein ncbigene:860
RAC1 Protein ncbigene:5879
PRDX1 Protein ncbigene:5052
KAT2B Protein ncbigene:8850
CDC42 Protein ncbigene:998
NCOR1 Protein ncbigene:9611
STAT3 Protein ncbigene:6774
ROCK1 Protein ncbigene:6093
EGFR Protein ncbigene:1956
HDAC1 Protein ncbigene:3065
PIK3R2 Protein ncbigene:5296
CREB1 Protein ncbigene:1385
RLN1 GeneProduct ncbigene:6013
FOXO1 Protein ncbigene:2308
MYST2 Protein ncbigene:11143
SIN3A Protein ncbigene:25942
DSTN Protein ncbigene:11034
RB1 Protein ncbigene:5925
AES Protein ncbigene:166
CARM1 Protein ncbigene:10498
PATZ1 Protein ncbigene:23598
TGIF1 Protein ncbigene:7050
KLK3 Rna ncbigene:354
PPAP2A Rna ncbigene:8611
NCOA3 Protein ncbigene:8202
TZF Protein ncbigene:24149
SMAD3 Protein ncbigene:4088
PARK7 Protein ncbigene:11315
ZMIZ1 Protein ncbigene:57178
CDKN1A Rna ncbigene:1026
EFCAB6 Protein ncbigene:64800
DAXX Protein ncbigene:1616
RELA Protein ncbigene:5970
BAG1 Protein ncbigene:573
LIMK2 Protein ncbigene:3985
AR Protein ncbigene:367
MDM2 Protein ncbigene:4193
STUB1 Protein ncbigene:10273
SP1 Protein ncbigene:6667
ROCK2 Protein ncbigene:9475
PTK2 Protein ncbigene:5747
PAK6 Protein ncbigene:56924
UBE3A Protein ncbigene:7337
ETV5 Protein ncbigene:2119
NR0B2 Protein ncbigene:8431
CAV1 Protein ncbigene:857
SRC Protein ncbigene:6714
NCOA1 Protein ncbigene:8648
RAN Protein ncbigene:5901
RNF14 Protein ncbigene:9604
PIAS4 Protein ncbigene:51588
FLNA Protein ncbigene:2316
EP300 Protein ncbigene:2033
CTNNB1 Protein ncbigene:1499
GNB2L1 Protein ncbigene:10399
CALR Protein ncbigene:811
PIK3R1 Protein ncbigene:5295
AKT1 Protein ncbigene:207
PTEN Protein ncbigene:5728
AR Protein ncbigene:367
UBE2I Protein ncbigene:7329
PIAS2 Protein ncbigene:9063
AR Protein ncbigene:367
BRCA1 Protein ncbigene:672
CCND1 Protein ncbigene:595
FHL2 Protein ncbigene:2274
CREBBP Protein ncbigene:1387
NCOA4 Protein ncbigene:8031
JUN Protein ncbigene:3725
NCOA2 Protein ncbigene:10499
GSK3B Protein ncbigene:2932
TGFB1I1 Protein ncbigene:7041
AR Protein ncbigene:367
AR Protein ncbigene:367
KAT5 Protein ncbigene:10524
CCNE1 Protein ncbigene:898
RNF4 Protein ncbigene:6047

References

  1. Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GSS, Venugopal AK, et al. NetPath: a public resource of curated signal transduction pathways. Genome Biol. 2010 Jan 12;11(1):R3. PubMed Europe PMC Scholia