Tyrosine phosphorylation of the nuclear receptor coactivator AIB1/SRC-3 is enhanced by Abl kinase and is required for its activity in cancer cells

Mol Cell Biol. 2008 Nov;28(21):6580-93. doi: 10.1128/MCB.00118-08. Epub 2008 Sep 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Epidermal Growth Factor / pharmacology
  • Female
  • Fusion Proteins, bcr-abl
  • Histone Acetyltransferases / metabolism*
  • Humans
  • Insulin-Like Growth Factor I / pharmacology
  • Mice
  • Nuclear Receptor Coactivator 3
  • Phosphorylation / drug effects
  • Phosphotyrosine / metabolism*
  • Promoter Regions, Genetic / genetics
  • Protein Binding / drug effects
  • Protein Interaction Mapping
  • Protein-Tyrosine Kinases / metabolism*
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism


  • Trans-Activators
  • Transcription Factors
  • Phosphotyrosine
  • Epidermal Growth Factor
  • Insulin-Like Growth Factor I
  • Histone Acetyltransferases
  • NCOA3 protein, human
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 3
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl