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Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation
Chi-Wai Wong1, Christopher McNally, Elliot Nickbarg
1Department of Cell Biology, Women's Health Research Institute, Wyeth Pharmaceuticals, 500 Arcolla Road, Collegeville, PA 19426, USA.
Abstract:
Numerous studies have demonstrated that estrogens induce rapid and transient activation of the Src/Erk phosphorylation cascade. Activation of this cascade triggers vital cellular functions including cell proliferation and differentiation. However, the details of the molecular mechanism of this process remain to be elucidated. We have identified a previously uncharacterized nuclear receptor-interacting protein designated as modulator of nongenomic activity of estrogen receptor (MNAR). Here we show that MNAR modulates estrogen-receptor (ER) interaction with members of the Src family of tyrosine kinases, which leads to a stimulation of Src enzymatic activity and activation of Erk1 and Erk2 kinases. We also show that MNAR, through activation of the Src/Erk phosphorylation cascade, affects ER transcriptional activity and ultimately ER-mediated gene expression. These data reveal that MNAR mediates the crosstalk between two important classes of signal transducing molecules and suggest that ER "genomic" and "nongenomic" activities are interrelated.
Insights
A novel protein, modulator of nongenomic activity of estrogen receptor (MNAR), links estrogen receptor (ER) signaling to Src/Erk pathways. MNAR influences ER
Area of Science:
- Molecular Endocrinology
- Cell Signaling
Background:
- Estrogens rapidly activate the Src/Erk phosphorylation cascade, crucial for cell proliferation and differentiation.
- The precise molecular mechanisms underlying estrogen-induced Src/Erk activation remain incompletely understood.
Purpose of the Study:
- To identify and characterize novel proteins involved in estrogen receptor (ER) signaling.
- To elucidate the role of these proteins in mediating the crosstalk between ER and Src/Erk pathways.
Main Methods:
- Identification of a novel nuclear receptor-interacting protein, modulator of nongenomic activity of estrogen receptor (MNAR).
- Assays to investigate MNAR's effect on ER interaction with Src family kinases.
- Analysis of Src enzymatic activity and Erk1/Erk2 kinase activation.
- Assessment of MNAR's impact on ER transcriptional activity and gene expression.
Main Results:
- MNAR was identified as a modulator of ER interaction with Src family kinases.
- MNAR significantly stimulates Src enzymatic activity and subsequent Erk1/Erk2 activation.
- MNAR enhances ER transcriptional activity and ER-mediated gene expression via the Src/Erk cascade.
Conclusions:
- MNAR acts as a crucial mediator, linking estrogen receptor signaling to the Src/Erk phosphorylation cascade.
- These findings reveal a molecular mechanism for the crosstalk between nuclear receptors and tyrosine kinases.
- The study suggests an interrelationship between the 'genomic' and 'nongenomic' activities of the estrogen receptor.