Estrogen triggers rapid yet transient activation of the MAPKs, @entity12206 and @entity3963 . We have reported that this estrogen action requires the G protein-coupled receptor, @entity21841 , and occurs via Gbetagamma-subunit protein-dependent transactivation of the @entity470 through the release of pro-heparan-bound EGF from the cell surface. Here we investigate the mechanism by which @entity1366 activity is rapidly restored to basal levels after estrogen stimulation. Evidence is provided that attenuation of @entity1366 activity by estrogen occurs via @entity21841 -dependent stimulation of adenylyl cyclase and @entity14695 -dependent signaling that results in @entity10242 inactivation. We show that 17beta-E2 represses EGF-induced activation of the @entity8496 -to- @entity3963 pathway in @entity1 @entity0 cells that express @entity21841 , including MCF-7 and SKBR3 cells which express both or neither, ER, respectively. MDA-MB-231 cells, which express @entity1783 , but not @entity1782 , and low levels of @entity21841 protein, are unable to stimulate adenylyl cyclase or promote estrogen-mediated blockade of EGF-induced activation of @entity1366 . Pretreatment of MDA-MB-231 cells with cholera toxin, which ADP-ribosylates and activates Galphas subunit proteins, results in G protein-coupled receptor (GPCR)-independent adenylyl cyclase activity and suppression of EGF-induced @entity1366 activity. Transfection of @entity21841 into MDA-MB-231 cells restores their ability to stimulate adenylyl cyclase and attenuate EGF-induced activation of @entity1366 by estrogen. Moreover, @entity21841 -dependent, @entity14695 -mediated attenuation of EGF-induced @entity1366 activity was achieved by ER antagonists such as tamoxifen or ICI 182, 780; yet not by 17alpha-E2 or progesterone. Thus, our data delineate a novel mechanism, requiring @entity21841 and estrogen, that acts to regulate @entity1366 activity via an inhibitory signal mediated by @entity14695 . Coupled with our prior findings, these current data imply that estrogen balances @entity1366 activity through a single GPCR via two distinct G protein-dependent signaling pathways that have opposing effects on the @entity470 -to-MAPK pathway.

Estrogen action via the G protein-coupled receptor, @entity21841 : stimulation of adenylyl cyclase and XXXX -mediated attenuation of the @entity470 -to-MAPK signaling axis.

@entity1 :: ('9606', 'Species') :: ['human'] @entity1782 :: ('2099', 'Gene') :: ['ERalpha'] @entity0 :: ('MESH:D001943', 'Disease') :: ['breast carcinoma'] @entity470 :: ('1956', 'Gene') :: ['EGF receptor', 'epidermal growth factor (EGF) receptor'] @entity3963 :: ('5594', 'Gene') :: ['Erk', 'Erk-2'] @entity1783 :: ('2100', 'Gene') :: ['ERbeta'] @entity14695 :: ('820', 'Gene') :: ['cAMP'] @entity21841 :: ('2852', 'Gene') :: ['GPR30'] @entity10242 :: ('5894', 'Gene') :: ['Raf-1'] @entity12206 :: ('5595', 'Gene') :: ['extracellular signal-regulated kinase (Erk)-1'] @entity1366 :: ('5595;5594', 'Gene') :: ['Erk-1/-2'] @entity8496 :: ('22882', 'Gene') :: ['Raf']
@entity14695 :: (820,Gene) :: ['cAMP']
