The extent of uterine Gab-1-pY is dependent on the stage of the mouse estrous cycle, with the greatest level of tyrosine phosphorylation observed during late diestrus/early proestrus, suggesting that a kinase acting on the Gab-1 substrate is regulated by ovarian steroid hormones. Consistent with such a role for ovarian steroid hormones, alone or treatment of ovariectomized adult mice stimulated uterine Gab-1-pY. Additionally, ovarian steroid treatment resulted in the formation of Gab-1 signaling complexes containing p85 and/or SHP2, indicating that E2 and P stimulate active signaling cascades that utilize Gab-1. Furthermore, EGF treatment resulted in Gab-1-pY, which may be indicative of a possible role for EGFR signaling in uterine Gab-1 activation. The phosphorylation of uterine Gab-1 in response to steroid hormones and EGF was recapitulated in vitro in uterine endometrial cancer cells by EGFR ligands, as well as by HGF (data not shown). HGF/Met signaling has been demonstrated to promote proliferation, migration, and lumen formation of human endometrial cells in vitro (15), providing another suitable candidate for a mediator of E2-and/or P-stimulated Gab-1 activation. Elucidation of the different signaling pathways through which the ovarian steroid hormones exert their effects on the uterus will serve to provide investigators with new pathways to target in the development of endocrine and anti-hormone therapies.
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