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Estradiol (E2) Elicits Src Phosphorylation in the Mouse Neocortex: The Initial Event in E2 Activation of the MAPK Cascade?

Departments of Anatomy and Cell Biology, Obstetrics and Gynecology (I.S.N., M.S., X.G., Q.G., C.D.T.-A.), and Neurology (C.D.T.-A.) and Centers for Neurobiology and Behavior (C.D.T.-A.) and Reproductive Sciences (I.S.N., M.S., X.G., Q.G., C.D.T.-A.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Departments of Biochemistry and Child Health, University of Missouri (D.B.L.), Columbia, Missouri 65211; and Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences (K.S.K.), Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Dr. Dominique Toran-Allerand, Department of Anatomy and Cell Biology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, Black Building 1615, New York, New York 10032. E-mail: cdt2{at}columbia.edu

In neocortical explants, E2 activates various signaling components of the MAPK cascade, including B-Raf and MAPK kinase-dependent ERK, suggesting a possible role in the differentiative actions of E2 in the brain. To further characterize the signaling pathways activated by E2, we determined whether c-Src, a member of the Src family of nonreceptor tyrosine kinases and an important modulator of both the MAPK cascade and neuronal differentiation, may play a role in E2 signaling. The present studies show for the first time in the brain that E2 elicits phosphorylation of c-Src on three functionally critical tyrosine residues (Y220, Y423, and Y534), and that this phosphorylation occurs despite disruption of ER (in ER knockout mice). PP2, a Src family kinase inhibitor, suppressed not only E2-induced phosphorylation of c-Src, but ERK phosphorylation as well, suggesting that c-Src may be an upstream regulator of E2 signaling. E2-induced phosphorylation of c-Src is associated with increased tyrosine phosphorylation of Shc, increased association of Shc with Grb2, and induction of Ras, but not Rap1, activation. Together, these data provide evidence that E2 activates a novel c-Src-dependent signal transduction pathway in the developing brain.

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