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Molecular and Cellular Biology, March 2007, p. 1904-1913, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.01732-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Phosphorylation of MNAR Promotes Estrogen Activation of Phosphatidylinositol 3-Kinase{triangledown}

James G. Greger,1 Natalie Fursov,1 Neil Cooch,1 Sean McLarney,1 Leonard P. Freedman,1 Dean P. Edwards,2 and Boris J. Cheskis1*

Department of Women's Health and Musculoskeletal Biology, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426,1 Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, Texas 770302

Received 13 September 2006/ Returned for modification 13 November 2006/ Accepted 15 December 2006

Estrogen actions are mediated by a complex interface of direct control of gene expression (the so-called "genomic action") and by regulation of cell signaling/phosphorylation cascades, referred to as the "nongenomic," or extranuclear, action. We have previously described the identification of MNAR (modulator of nongenomic action of estrogen receptor) as a novel scaffold protein that regulates estrogen receptor alpha (ER{alpha}) activation of cSrc. In this study, we have investigated the role of MNAR in 17ß-estradiol (E2)-induced activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Consistent with our previous results, a direct correlation was established between MNAR expression levels and E2-induced activation of PI3 and Akt kinases. Endogenous MNAR, ER{alpha}, cSrc, and p85, the regulatory subunit of PI3 kinase, interacted in MCF7 cells treated with E2. The interaction between p85 and MNAR required activation of cSrc and MNAR phosphorylation on Tyr 920. Consequently, the mutation of this tyrosine to alanine (Y920A) abrogated the interaction between MNAR and p85 and the E2-induced activation of the PI3K/Akt pathway, which was required for the E2-induced protection of MCF7 cells from apoptosis. Nonetheless, the Y920A mutant potentiated the E2-induced activation of the Src/MAPK pathway and MCF7 cell proliferation, as observed with the wild-type MNAR. These results provide new and important insights into the molecular mechanisms of E2-induced regulation of cell proliferation and apoptosis.

* Corresponding author. Mailing address: Women's Health and Musculoskeletal Biology, Wyeth Research, Nuclear Receptors, 500 Arcola Road, Collegeville, PA 19426. Phone: (484) 865-2702. Fax: (484) 865-9367. E-mail: cheskib{at}wyeth.com.

{triangledown} Published ahead of print on 28 December 2006.

Molecular and Cellular Biology, March 2007, p. 1904-1913, Vol. 27, No. 5
0270-7306/07/$08.00+0     doi:10.1128/MCB.01732-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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