title: 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.
abstract: The 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 × 10-8m 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.
authors: From the Barbara Ann Karmanos Cancer Institute and Department of Oncology.|Wayne State University School of Medicine, Detroit, Michigan 48201-2013 and.
authors: Rayna
authors: R
authors: Rosati
authors: From the Barbara Ann Karmanos Cancer Institute and Department of Oncology.|Wayne State University School of Medicine, Detroit, Michigan 48201-2013 and.
authors: Mugdha
authors: M
authors: Patki
authors: From the Barbara Ann Karmanos Cancer Institute and Department of Oncology.
authors: Venkatesh
authors: V
authors: Chari
authors: From the Barbara Ann Karmanos Cancer Institute and Department of Oncology.
authors: Selvakumar
authors: S
authors: Dakshnamurthy
authors: From the Barbara Ann Karmanos Cancer Institute and Department of Oncology.|Wayne State University School of Medicine, Detroit, Michigan 48201-2013 and.
authors: Thomas
authors: T
authors: McFall
authors: the School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom.
authors: Janice
authors: J
authors: Saxton
authors: From the Barbara Ann Karmanos Cancer Institute and Department of Oncology.|Wayne State University School of Medicine, Detroit, Michigan 48201-2013 and.
authors: Benjamin L
authors: BL
authors: Kidder
authors: the School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom.
authors: Peter E
authors: PE
authors: Shaw
authors: From the Barbara Ann Karmanos Cancer Institute and Department of Oncology, ratnamm@karmanos.org.|Wayne State University School of Medicine, Detroit, Michigan 48201-2013 and.
authors: Manohar
authors: M
authors: Ratnam
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D006367:HeLa Cells; D006801:Humans; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C494112:ELK1 protein, human; D011944:Receptors, Androgen; D050807:ets-Domain Protein Elk-1; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: ETS transcription factor family; androgen receptor; extracellular signal-regulated kinase (ERK); prostate cancer; transcription