title: Tyrosine phosphorylation of the nuclear receptor coactivator AIB1/SRC-3 is enhanced by Abl kinase and is required for its activity in cancer cells.
abstract: 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 (ERalpha), progesterone receptor B, NF-kappaB, 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, ERalpha, 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.
authors.affiliation: Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA.
authors.forename: Annabell S
authors.initials: AS
authors.lastname: Oh
authors.forename: John T
authors.initials: JT
authors.lastname: Lahusen
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Chien
authors.forename: Mark P
authors.initials: MP
authors.lastname: Fereshteh
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Zhang
authors.forename: Sivanesan
authors.initials: S
authors.lastname: Dakshanamurthy
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Kagan
authors.forename: Anton
authors.initials: A
authors.lastname: Wellstein
authors.forename: Anna T
authors.initials: AT
authors.lastname: Riegel