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PNAS 99 (23): 14783-14788

Copyright © 2002 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade

Chi-Wai Wong*, Christopher McNally, Elliot Nickbarg{dagger}, Barry S. Komm, and Boris J. Cheskis{ddagger}

Department of Cell Biology, Women's Health Research Institute, Wyeth Pharmaceuticals, 500 Arcolla Road, Collegeville, PA 19426

Accepted for publication September 18, 2002.

Received for publication June 12, 2002.

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.

* Present address: Metabolex, Inc., 3876 Bay Center Place, Hayward, CA 94545.

{dagger} Present address: NeoGenesis, Inc., 840 Memorial Drive, Cambridge, MA 02139.

{ddagger} To whom correspondence should be addressed. E-mail: cheskib{at}wyeth.com.

Communicated by Elwood V. Jensen, University of Cincinnati Medical Center, Cincinnati, OH

Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. AF547989).

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