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J. Biol. Chem., Vol. 277, Issue 32, 29304-29314, August 9, 2002
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From the Departments of Activation of signal transduction kinase
cascades has been shown to alter androgen receptor (AR) activity.
Although it has been suggested that changes in AR phosphorylation might
be directly responsible, the basal and regulated phosphorylations of
the AR have not been fully determined. We have identified the major
sites of AR phosphorylation on ARs expressed in COS-1 cells using a combination of peptide mapping, Edman degradation, and mass
spectrometry. We describe the identification of seven AR
phosphorylation sites, show that the phosphopeptides seen with
exogenously expressed ARs are highly similar to those seen with
endogenous ARs in LNCaP cells and show that specific agonists
differentially regulate the phosphorylation state of endogenous ARs in
LNCaP prostate cancer cells. Treatment of LNCaP cells with the
synthetic androgen, R1881, elevates phosphorylation of serines 16, 81, 256, 308, 424, and 650. Ser-94 appears constitutively phosphorylated.
Forskolin, epidermal growth factor, and phorbol 12-myristate 13-acetate
increase the phosphorylation of Ser-650. The kinetics of
phosphorylation of most sites in response to hormone or forskolin is
temporally delayed, reaching a maximum at 2 h post-stimulation.
The exception is Ser-81, which continues to display increasing
phosphorylation at 6 h. These data provide a basis for analyzing
mechanisms of cross-talk between growth factor signaling and androgen
in prostate development, physiology, and cancer.
Androgen Receptor Phosphorylation
REGULATION AND IDENTIFICATION OF THE PHOSPHORYLATION SITES*
§,
,,,,
Microbiology and Cancer
Center, ** Pathology, ¶ Chemistry, and
Pharmacology and Molecular Medicine Program, University of
Virginia Health Sciences Center, Charlottesville, Virginia 22908
*
This work was supported by a gift from CaP CURE,
a grant from the Mellon Prostate Cancer Research Institute at the
University of Virginia, and United States Public Health Service Grants
CA39076, CA76465, CA40042 (to M. J. W.), and GM37537 (to D. F. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 434-924-5052;
Fax: 434-982-0689; E-mail: MJW@Virginia.edu.
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