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Molecular and Cellular Biology, May 2007, p. 3390-3404, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.02411-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Ligand Binding to the Androgen Receptor Induces Conformational Changes That Regulate Phosphatase Interactions{triangledown}

Chun-Song Yang,1 Hong-Wu Xin,1 Joshua B. Kelley,1,2 Adam Spencer,1 David L. Brautigan,1,3 and Bryce M. Paschal1,2*

Center for Cell Signaling,1 Department of Biochemistry and Molecular Genetics,2 Department of Microbiology, School of Medicine, University of Virginia, Charlottesville, Virginia3

Received 23 December 2006/ Accepted 14 February 2007

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.

* Corresponding author. Mailing address: Center for Cell Signaling, University of Virginia, Box 800577 Health Systems, Charlottesville, VA 22908. Phone: (434) 243-6521. Fax: (434) 924-1236. E-mail: paschal{at}virginia.edu

{triangledown} Published ahead of print on 26 February 2007.

Molecular and Cellular Biology, May 2007, p. 3390-3404, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.02411-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chen, S., Kesler, C. T., Paschal, B. M., Balk, S. P. (2009). Androgen Receptor Phosphorylation and Activity Are Regulated by an Association with Protein Phosphatase 1. J. Biol. Chem. 284: 25576-25584 [Abstract] [Full Text]  
  • Kaikkonen, S., Jaaskelainen, T., Karvonen, U., Rytinki, M. M., Makkonen, H., Gioeli, D., Paschal, B. M., Palvimo, J. J. (2009). SUMO-Specific Protease 1 (SENP1) Reverses the Hormone-Augmented SUMOylation of Androgen Receptor and Modulates Gene Responses in Prostate Cancer Cells. Mol. Endocrinol. 23: 292-307 [Abstract] [Full Text]  
  • Narayanan, R., Coss, C. C., Yepuru, M., Kearbey, J. D., Miller, D. D., Dalton, J. T. (2008). Steroidal Androgens and Nonsteroidal, Tissue-Selective Androgen Receptor Modulator, S-22, Regulate Androgen Receptor Function through Distinct Genomic and Nongenomic Signaling Pathways. Mol. Endocrinol. 22: 2448-2465 [Abstract] [Full Text]  
  • Shank, L. C., Kelley, J. B., Gioeli, D., Yang, C.-S., Spencer, A., Allison, L. A., Paschal, B. M. (2008). Activation of the DNA-dependent Protein Kinase Stimulates Nuclear Export of the Androgen Receptor in Vitro. J. Biol. Chem. 283: 10568-10580 [Abstract] [Full Text]  
  • Weigel, N. L., Moore, N. L. (2007). Steroid Receptor Phosphorylation: A Key Modulator of Multiple Receptor Functions. Mol. Endocrinol. 21: 2311-2319 [Abstract] [Full Text]  


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