Potentiation of estrogen receptor activation function 1 (AF-1) by Src/JNK through a serine 118-independent pathway

Estrogen receptor (ER) is activated either by ligand or by signals from tyr osine kinase-linked cell surface receptors. We investigated whether the non receptor Src tyrosine kinase could affect 88 activity. Expression of consti tutively active Src or stimulation of the endogenous Src/JNK pathway enhanc es transcriptional activation by the estrogen-ER complex and strongly stimu lates the otherwise weak activation by the unliganded ER and the tamoxifen- ER complex. Src affects ER activation function 1 (AF-1), and not ER AF-2, a nd does so through its tyrosine kinase activity. This effect of Src is medi ated partly through a Raf/mitogen-activated ERK kinase/extracellular signal -regulated kinase (Raf/MEK/ERK) signaling cascade and partly through a MEKK /JNKK/JNK cascade. Although, as previously shown, Src action through activa ted ERK stimulates AF-1 by phosphorylation at S118, Src action through acti vated JNK neither leads to phosphorylation of S118 nor requires S118 for it s action. We therefore suggest that the Src/JNK pathway enhances AF-1 activ ity by modification of ER AF-1-associated proteins. Src potentiates activat ion functions in CREB-binding protein (CBP) and glucocorticoid receptor int eracting protein 1 (GRIP1), and we discuss the possibility that the Src/JNK pathway enhances the activity of these coactivators, which are known to me diate AF-1 action.