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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

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.

	Abstract

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.