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Molecular and Cellular Biology, September 2005, p. 8273-8284, Vol. 25, No. 18
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.18.8273-8284.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Rapid Estrogen-Induced Phosphorylation of the SRC-3 Coactivator Occurs in an Extranuclear Complex Containing Estrogen Receptor

Fuzhong F. Zheng, Ray-Chang Wu, Carolyn L. Smith, and Bert W. O'Malley*

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

Received 28 April 2005/ Returned for modification 29 May 2005/ Accepted 30 June 2005

SRC-3/AIB1/ACTR/pCIP/RAC3/TRAM1 is a primary transcriptional coregulator for estrogen receptor (ER). Six SRC-3 phosphorylation sites have been identified, and these can be induced by steroids, cytokines, and growth factors, involving multiple kinase signaling pathways. Using phosphospecific antibodies for six phosphorylation sites, we investigated the mechanisms involved in estradiol (E2)-induced SRC-3 phosphorylation and found that this occurs only when either activated estrogen receptor {alpha} (ER{alpha}) or activated ERß is present. Both the activation function 1 and the ligand binding domains of ER{alpha} are required for maximal induction. Mutations in the coactivator binding groove of the ER{alpha} ligand binding domain inhibit E2-stimulated SRC-3 phosphorylation, as do mutations in the nuclear receptor-interacting domain of SRC-3, suggesting that ER{alpha} must directly contact SRC-3 for this posttranslational modification to take place. A transcriptionally inactive ER{alpha} mutant which localizes to the cytoplasm supports E2-induced SRC-3 phosphorylation. Mutations of the ER{alpha} DNA binding domain did not block this rapid E2-dependent SRC-3 phosphorylation. Together these data demonstrate that E2-induced SRC-3 phosphorylation is dependent on a direct interaction between SRC-3 and ER{alpha} and can occur outside of the nucleus. Our results provide evidence for an early nongenomic action of ER on SRC-3 that supports the well-established downstream genomic roles of estrogen and coactivators.

* Corresponding author. Mailing address: Molecular and Cellular Biology, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-6205. Fax: (713) 798-5599. E-mail: berto{at}bcm.tmc.edu.

Molecular and Cellular Biology, September 2005, p. 8273-8284, Vol. 25, No. 18
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.18.8273-8284.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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