Tyrosine phosphorylation of the nuclear receptor coactivator AIB1/SRC-3 is enhanced by Abl kinase and is required for its activity in cancer cells.
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.
Mesh Terms:
Animals, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Epidermal Growth Factor, Female, Fusion Proteins, bcr-abl, Histone Acetyltransferases, Humans, Insulin-Like Growth Factor I, Mice, Nuclear Receptor Coactivator 3, Phosphorylation, Phosphotyrosine, Promoter Regions, Genetic, Protein Binding, Protein Interaction Mapping, Protein-Tyrosine Kinases, Trans-Activators, Transcription Factors
Animals, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Epidermal Growth Factor, Female, Fusion Proteins, bcr-abl, Histone Acetyltransferases, Humans, Insulin-Like Growth Factor I, Mice, Nuclear Receptor Coactivator 3, Phosphorylation, Phosphotyrosine, Promoter Regions, Genetic, Protein Binding, Protein Interaction Mapping, Protein-Tyrosine Kinases, Trans-Activators, Transcription Factors
Mol. Cell. Biol.
Date: Nov. 01, 2008
PubMed ID: 18765637
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