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

Weijun Feng, Paul Webb, Phuong Nguyen, Xiaohong Liu, Jiandong Li, Michael Karin, Peter J. Kushner

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120 Scopus citations


Estrogen receptor (ER) is activated either by ligand or by signals from tyrosine kinase-linked cell surface receptors. We investigated whether the nonreceptor Src tyrosine kinase could affect ER activity. Expression of constitutively active Src or stimulation of the endogenous Src/JNK pathway enhances transcriptional activation by the estrogen-ER complex and strongly stimulates 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, and does so through its tyrosine kinase activity. This effect of Src is mediated 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 activated ERK stimulates AF-1 by phosphorylation at S118, Src action through activated JNK neither leads to phosphorylation of S118 nor requires S118 for its action. We therefore suggest that the Src/JNK pathway enhances AF-1 activity by modification of ER AF-1-associated proteins. Src potentiates activation functions in CREB-binding protein (CBP) and glucocorticoid receptor interacting protein 1 (GRIP1), and we discuss the possibility that the Src/JNK pathway enhances the activity of these co-activators, which are known to mediate AF-1 action.

Original languageEnglish (US)
Pages (from-to)32-45
Number of pages14
JournalMolecular Endocrinology
Issue number1
StatePublished - 2001

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology


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