The amino-terminal domain of the androgen receptor co-opts extracellular signal-regulated kinase (ERK) docking sites in ELK1 protein to induce sustained gene activation that supports prostate cancer cell growthTools Rosati, Rayna, Patki, Mugdha, Chari, Venkatesh, Dakshnamurthy, Selvakumar, McFall, Thomas, Saxton, Janice, Kidder, Benjamin L., Shaw, Peter E. and Ratnam, Manohar (2016) The amino-terminal domain of the androgen receptor co-opts extracellular signal-regulated kinase (ERK) docking sites in ELK1 protein to induce sustained gene activation that supports prostate cancer cell growth. Journal of Biological Chemistry, 291 (50). pp. 25983-25998. ISSN 1083-351X Full text not available from this repository.
Official URL: https://doi.org/10.1074/jbc.M116.745596
AbstractThe ETS domain transcription factor ELK1 is in a repressive association with growth genes and is transiently activated through phosphorylation by ERK1/2. In prostate cancer (PCa) cells the androgen receptor (AR) is recruited by ELK1, via its amino-terminal domain (A/B), as a transcriptional co-activator, without ELK1 hyper-phosphorylation. Here we elucidate the structural basis of the interaction of AR with ELK1. The ELK1 polypeptide motifs required for co-activation by AR versus those required for activation of ELK1 by ERK were systematically mapped using a mammalian two-hybrid system and confirmed using a co-immunoprecipitation assay. The mapping precisely identified the two ERK-docking sites in ELK1, the D-box and the DEF (docking site for ERK, FXFP) motif, as the essential motifs for its cooperation with AR(A/B) or WTAR. In contrast, the transactivation domain in ELK1 was only required for activation by ERK. ELK1-mediated transcriptional activity of AR(A/B) was optimal in the absence of ELK1 binding partners, ERK1/2 and serum-response factor. Purified ELK1 and AR bound with a dissociation constant of 1.9 × 10−8 m. A purified mutant ELK1 in which the D-box and DEF motifs were disrupted did not bind AR. An ELK1 mutant with deletion of the D-box region had a dominant-negative effect on androgen-dependent growth of PCa cells that were insensitive to MEK inhibition. This novel mechanism in which a nuclear receptor impinges on a signaling pathway by co-opting protein kinase docking sites to constitutively activate growth genes could enable rational design of a new class of targeted drug interventions.
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