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 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.
Feng
W
W
Metabolic Research Unit, University of California, San Francisco, California 94143, USA.
Webb
P
P
Nguyen
P
P
Liu
X
X
Li
J
J
Karin
M
M
Kushner
P J
PJ
D050882:CREB-Binding Protein; D004357:Drug Synergism; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D051958:Nuclear Receptor Coactivator 2; D056918:Nuclear Receptor Coactivators; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics / Q000494:pharmacology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology*; D020218:Response Elements; D012694:Serine; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014443:Tyrosine; D014819:Vitellogenins / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; C498001:NCOA2 protein, human; C455500:NCOA7 protein, human; D009687:Nuclear Proteins; D051958:Nuclear Receptor Coactivator 2; D056918:Nuclear Receptor Coactivators; D011506:Proteins; D011960:Receptors, Estrogen; D015534:Trans-Activators; D014157:Transcription Factors; D014819:Vitellogenins; D013629:Tamoxifen; D014443:Tyrosine; D012694:Serine; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D011505:Protein-Tyrosine Kinases; D015688:Oncogene Protein pp60(v-src); D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases