Estradiol (E2) elicits Src phosphorylation in the mouse neocortex: The initial event in E2 activation of the MAPK cascade?

In neocortical explants, E2 activates various signaling components of the M APK cascade, including E-Raf and MAPK kinase-dependent ERK, suggesting a po ssible role in the differentiative actions of E2 in the brain. To further c haracterize the signaling pathways activated by E2, we determined whether c -Src, a member of the Src family of nonreceptor tyrosine kinases and an imp ortant modulator of both the MAPK cascade and neuronal differentiation, may play a role in E2 signaling. The present studies show for the first time i n the brain that E2 elicits phosphorylation of c-Src on three functionally critical tyrosine residues (Y220, Y423, and Y534), and that this phosphoryl ation occurs despite disruption of Ella (in ER knockout mice). PP2, a Src f amily kinase inhibitor, suppressed not only E2-induced phosphorylation of c -Src, but ERK phosphorylation as well, suggesting that c-Src may be an upst ream regulator of E2 signaling. E2-induced phosphorylation of c-Src is asso ciated with increased tyrosine phosphorylation of She, increased associatio n of She with Grb2, and induction of Ras, but not Rap1, activation. Togethe r, these data provide evidence that E2 activates a novel c-Src-dependent si gnal transduction pathway in the developing brain.