Ligand binding to the androgen receptor induces conformational changes that regulate phosphatase interactions.
We describe a mechanism for protein phosphatase 2A (PP2A) targeting to the androgen receptor (AR) and provide insight into the more general issue of kinase and phosphatase interactions with AR. Simian virus 40 (SV40) small t antigen (ST) binding to N-terminal HEAT repeats in the PP2A A subunit induces structural changes transduced to C-terminal HEAT repeats. This enables the C-terminal HEAT repeats in the PP2A A subunit, including HEAT repeat 13, to discriminate between androgen- and androgen antagonist-induced AR conformations. The PP2A-AR interaction was used to show that an AR mutant in prostate cancer cells (T877A) is activated by multiple ligands without acquiring the same conformation as that induced by androgen. The correlation between androgen binding to AR and increased phosphorylation of the activation function 1 (AF-1) region implies that changes in AR conformation or chaperone composition are causal to kinase access to phosphorylation sites. However, AF-1 phosphorylation sites are kinase accessible prior to androgen binding. This suggests that androgens can enhance the phosphorylation state of AR either by negatively regulating the ability of the ligand-binding domain to bind phosphatases or by inducing an AR conformation that is resistant to phosphatase action. SV40 ST subverts this mechanism by promoting the direct transfer of PP2A onto androgen-bound AR, resulting in multisite dephosphorylation.
Yang
Chun-Song
CS
Center for Cell Signaling, University of Virginia, Charlottesville, VA 22908, USA.
Xin
Hong-Wu
HW
Kelley
Joshua B
JB
Spencer
Adam
A
Brautigan
David L
DL
Paschal
Bryce M
BM
D020816:Amino Acid Motifs; D000728:Androgens / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D054648:Protein Phosphatase 2; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D014158:Transcription, Genetic / Q000235:genetics; D014183:Transplantation, Heterologous
D000728:Androgens; D008024:Ligands; D021122:Protein Subunits; D011944:Receptors, Androgen; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2