Site-specific Androgen Receptor Serine Phosphorylation Linked to Epidermal Growth Factor-dependent Growth of Castration-recurrent Prostate Cancer

Ponguta, Liliana Angélica; Gregory, Christopher; French, Frank S.; Wilson, Elizabeth M.

doi:10.1074/jbc.m802392200

Cited by 98 publications

(104 citation statements)

References 76 publications

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“…It is suggested that DNA-PK might play a role in the nuclear export of the AR by the double-stranded DNA-dependent pathway. Furthermore, mutation of Ser578 inhibits the interaction with Ku 70/80 and nuclear retention is promoted with hypophosphorylation at Ser515 (Ponguta et al 2008). Indeed, AR-P was found to be the rate-limiting step in nuclear export (Shank et al 2008).…”

Section: Protein Kinases Involved In Ar-pmentioning

confidence: 99%

“…At reduced androgen levels, EGF can activate the AR by phosphorylating Ser515 (Ponguta et al 2008), which can influence phosphorylation of Ser650; however, this residue does not play a role in regulating the function of the AR (Wong et al 2004). In conjunction with p-Ser515, p-Ser578 is also required for IGF1-induced AR activation at reduced androgen levels (Ponguta et al 2008).…”

Section: Ar-p Under Androgen-depleted Conditionsmentioning

confidence: 99%

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Regulation of the androgen receptor by post-translational modifications

Coffey

Robson

2012

Journal of Endocrinology

121

100

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The androgen receptor (AR) is a key molecule in prostate cancer and Kennedy's disease. Understanding the regulatory mechanisms of this steroid receptor is important in the development of potential therapies for these diseases. One layer of AR regulation is provided by post-translational modifications including phosphorylation, acetylation, sumoylation, ubiquitination and methylation. While these modifications have mostly been studied as individual events, it is becoming clear that these modifications can functionally interact with each other in a signalling pathway. In this review, the effects of all modifications are described with a focus on interplay between them and the functional consequences for the AR.

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Section: Protein Kinases Involved In Ar-pmentioning

confidence: 99%

Section: Ar-p Under Androgen-depleted Conditionsmentioning

confidence: 99%

Regulation of the androgen receptor by post-translational modifications

Coffey

Robson

2012

Journal of Endocrinology

121

100

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“…This differential activity of Q tract variants dependent on phosphorylation at S650 is intriguing because phosphorylation at this site influences AR subcellular localization (18,19). Receptor export is important for recycling and reactivation (20).…”

Section: Task 2 Determine the Role Of The Q Tract In Ligand-independmentioning

confidence: 99%

“…This was pronounced at intact levels of hormone 6 but detectable also at castrate levels (0.01 nM R1881), particularly for the hypersensitive AR12Q. The non-phosphorylatable S650A mutants showed little difference from wild type (not shown), but interestingly AR48Q activity was greatly decreased by this mutation.This differential activity of Q tract variants dependent on phosphorylation at S650 is intriguing because phosphorylation at this site influences AR subcellular localization (18,19). Receptor export is important for recycling and reactivation (20).…”

mentioning

confidence: 99%

Humanized Androgen Receptor Mice: A Genetic Model for Differential Response to Prostate Cancer Therapy

Robins¹

2011

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)2. REPORT TYPE 3. DATES COVERED (From -To) 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail:5f. WORK UNIT NUMBER In mice in which human androgen receptor (AR) replaces the endogenous murine gene, variation in the length of a polymorphic Nterminal polyglutamine tract affects initiation, progression and therapy response of prostate tumors. This provides a genetic paradigm in which to dissect AR functions that determine response to treatment. We are studying the role of the AR Q tract in ligand-independent AR activation in vitro and in a mouse model with prostate cancer ontogeny similar to human. In the mouse model, molecular correlates of differential response to castration will be determined using bioinformatic analysis of microdissected tumor samples. In the third year of this award, in in vitro studies, we showed that ARs with different Q tract lengths are differentially responsive to growth factor activation likely to be influential under castrate conditions. At least some of this differential activity appears to affected by phosphorylation at S-650. At this time, nearly all the experimental mice aged for tumorigenesis (containing a short or long Q-tract AR allele [12Q vs. 48Q], an ETV1 transgene and heterozygous loss of PTEN) have reached their time point and prostate samples have been collected for histology and biochemical analysis. Since tumorigenesis was much slower than anticipated, we performed some interim analysis on ETV1 transgenics wild type for PTEN to test AR efficacy. This will be an important control for the mice deficient in PTEN since both ETV1 and PTEN prove to directly influence AR action, which has relevance to human as well as mouse prostate cancer progression. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILIT...

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“…Phosphorylation is a common posttranslational event in the AR NH 2 -terminal region that impacts function to different extents (53)(54)(55)(56). Some of the known AR NH 2 -terminal phosphorylation sites include Ser-81, 308, and 515 phosphorylated by cyclin-dependent kinases (53,54,(57)(58)(59)(60)(61)(62), Ser-282 and 293 phosphorylated by Aurora-A kinase (63), Ser-94 (53, 54), and Ser-578 (61). None of the documented AR NH 2 -terminal phosphorylation sites has been reported to be a site of a naturally occurring mutation that caused AIS.…”

Section: Androgen Sensitivity Of Normal Human Male Sex Development-humentioning

confidence: 99%

Androgen Receptor Exon 1 Mutation Causes Androgen Insensitivity by Creating Phosphorylation Site and Inhibiting Melanoma Antigen-A11 Activation of NH2- and Carboxyl-terminal Interaction-dependent Transactivation

Lagarde

Blackwelder

Minges

et al. 2012

Journal of Biological Chemistry

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Site-specific Androgen Receptor Serine Phosphorylation Linked to Epidermal Growth Factor-dependent Growth of Castration-recurrent Prostate Cancer

Cited by 98 publications

References 76 publications

Regulation of the androgen receptor by post-translational modifications

Regulation of the androgen receptor by post-translational modifications

Humanized Androgen Receptor Mice: A Genetic Model for Differential Response to Prostate Cancer Therapy

Androgen Receptor Exon 1 Mutation Causes Androgen Insensitivity by Creating Phosphorylation Site and Inhibiting Melanoma Antigen-A11 Activation of NH2- and Carboxyl-terminal Interaction-dependent Transactivation

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