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Molecular Endocrinology 15 (1): 32-45
Copyright © 2001 by The Endocrine Society

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 and Peter J. Kushner

Metabolic Research Unit (W.F., P.W., P.N., P.J.K.) and Department of Anatomy (J.L.) University of California San Francisco, California 94143
Department of Pharmacology (X.H.L., M.K.) University of California San Diego La Jolla, California 92093

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 coactivators, which are known to mediate AF-1 action.




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