MCB Accepts, published online ahead of print on 2 September 2008

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Mol. Cell. Biol. doi:10.1128/MCB.00118-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. 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, John T. Lahusen, Christopher D. Chien, Mark P. Fereshteh, Xiaolong Zhang, Sivanesan Dakshanamurthy, Jianming Xu, Benjamin L. Kagan, Anton Wellstein, and Anna T. Riegel^*

Department of Oncology, and Pharmacology, Lombardi Cancer Center, Georgetown University, Washington, D.C. 20057; ProtTech, Inc. Norristown, Pennsylvania 19403, U.S.A.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, U.S.A.

^* To whom correspondence should be addressed. Email: ariege01{at}georgetown.edu.

Overexpression and activation of the steroid receptor coactivator AIB1/SRC-3 has been shown to have a critical role in oncogenesis; 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 IGF-1, EGF or estrogen treatment of breast cancer cells. Phosphorylated Y1357 is increased in HER2/neu mammary tumor epithelia and is required to modulate AIB1/SRC-3 coactivation of ER, PR-B, NF-kB and AP-1 dependent promoters. c-Abl 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 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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