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Molecular and Cellular Biology, November 2008, p. 6580-6593, Vol. 28, No. 21
0270-7306/08/$08.00+0     doi:10.1128/MCB.00118-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Tyrosine Phosphorylation of the Nuclear Receptor Coactivator AIB1/SRC-3 Is Enhanced by Abl Kinase and Is Required for Its Activity in Cancer Cells ^,

Annabell S. Oh,¹ John T. Lahusen,¹ Christopher D. Chien,¹ Mark P. Fereshteh,² Xiaolong Zhang,³ Sivanesan Dakshanamurthy,¹ Jianming Xu,⁴ Benjamin L. Kagan,¹ Anton Wellstein,^1,2 and Anna T. Riegel^1,2*

Departments of Oncology,¹ Pharmacology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057,² ProtTech, Inc., Norristown, Pennsylvania 19403,³ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030⁴

Received 22 January 2008/ Returned for modification 29 February 2008/ Accepted 6 August 2008

Overexpression and activation of the steroid receptor coactivator amplified in breast cancer 1 (AIB1)/steroid receptor coactivator-3 (SRC-3) have been shown to have a critical role in oncogenesis and are required for both steroid and growth factor signaling in epithelial tumors. Here, we report a new mechanism for activation of SRC coactivators. We demonstrate regulated tyrosine phosphorylation of AIB1/SRC-3 at a C-terminal tyrosine residue (Y1357) that is phosphorylated after insulin-like growth factor 1, epidermal growth factor, or estrogen treatment of breast cancer cells. Phosphorylated Y1357 is increased in HER2/neu (v-erb-b2 erythroblastic leukemia viral oncogene homolog 2) mammary tumor epithelia and is required to modulate AIB1/SRC-3 coactivation of estrogen receptor alpha (ER), progesterone receptor B, NF-B, and AP-1-dependent promoters. c-Abl (v-Abl Abelson murine leukemia viral oncogene homolog 1) tyrosine kinase directly phosphorylates AIB1/SRC-3 at Y1357 and modulates the association of AIB1 with c-Abl, ER, the transcriptional cofactor p300, and the methyltransferase coactivator-associated arginine methyltransferase 1, CARM1. AIB1/SRC-3-dependent transcription and phenotypic changes, such as cell growth and focus formation, can be reversed by an Abl kinase inhibitor, imatinib. Thus, the phosphorylation state of Y1357 can function as a molecular on/off switch and facilitates the cross talk between hormone, growth factor, and intracellular kinase signaling pathways in cancer.

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* Corresponding author. Mailing address: Department of Oncology, Lombardi Cancer Center, Georgetown University, Research Building E307, 3970 Reservoir Rd. NW, Washington, DC 20007-2197. Phone: (202) 687-1479. Fax: (202) 687-4821. E-mail: ariege01{at}georgetown.edu

Published ahead of print on 2 September 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, November 2008, p. 6580-6593, Vol. 28, No. 21
0270-7306/08/$08.00+0     doi:10.1128/MCB.00118-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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