The Hormonal Response of Estrogen Receptor β Is Decreased by the Phosphatidylinositol 3-Kinase/Akt Pathway via a Phosphorylation-dependent Release of CREB-binding Protein

The hormonal response of estrogen receptors (ER) α and ERβ is controlled by a number of cofactors, including the general transcriptional coactivator CREB-binding protein (CBP). Growing evidence suggests that specific kinase signaling events also modulate the formation and activity of the ER coactivation complex. Here we show that ERβ activity and target gene expression are decreased upon activation of ErbB2/ErbB3 receptors despite the presence of CBP. This inhibition of ERβ involved activation of the phosphatidylinositol 3-kinase/Akt pathway, abrogating the potential of CBP to facilitate ERβ response to estrogen. Such reduced activity was associated with an impaired ability of ERβ to recruit CBP upon activation of Akt. Mutation of serine 255, an Akt consensus site contained in the hinge region of ERβ, prevented the release of CBP and rendered ERβ transcriptionally more responsive to CBP coactivation, suggesting that Ser-255 may serve as a regulatory site to restrain ERβ activity in Akt-activated cells. In contrast, we found that CBP intrinsic activity was increased by Akt through threonine 1872, a consensus site for Akt in the cysteine- and histidine-rich 3 domain of CBP, indicating that such enhanced transcriptional potential of CBP did not serve to activate ERβ. Interestingly, nuclear receptors sharing a conserved Akt consensus site with ERβ also exhibit a reduced ability to be coactivated by CBP, whereas others missing that site were able to benefit from the activation of CBP by Akt. These results therefore outline a regulatory mechanism by which the phosphatidylinositol 3-kinase/Akt pathway may discriminate nuclear receptor response through coactivator transcriptional competence. The hormonal response of estrogen receptors (ER) α and ERβ is controlled by a number of cofactors, including the general transcriptional coactivator CREB-binding protein (CBP). Growing evidence suggests that specific kinase signaling events also modulate the formation and activity of the ER coactivation complex. Here we show that ERβ activity and target gene expression are decreased upon activation of ErbB2/ErbB3 receptors despite the presence of CBP. This inhibition of ERβ involved activation of the phosphatidylinositol 3-kinase/Akt pathway, abrogating the potential of CBP to facilitate ERβ response to estrogen. Such reduced activity was associated with an impaired ability of ERβ to recruit CBP upon activation of Akt. Mutation of serine 255, an Akt consensus site contained in the hinge region of ERβ, prevented the release of CBP and rendered ERβ transcriptionally more responsive to CBP coactivation, suggesting that Ser-255 may serve as a regulatory site to restrain ERβ activity in Akt-activated cells. In contrast, we found that CBP intrinsic activity was increased by Akt through threonine 1872, a consensus site for Akt in the cysteine- and histidine-rich 3 domain of CBP, indicating that such enhanced transcriptional potential of CBP did not serve to activate ERβ. Interestingly, nuclear receptors sharing a conserved Akt consensus site with ERβ also exhibit a reduced ability to be coactivated by CBP, whereas others missing that site were able to benefit from the activation of CBP by Akt. These results therefore outline a regulatory mechanism by which the phosphatidylinositol 3-kinase/Akt pathway may discriminate nuclear receptor response through coactivator transcriptional competence. Estrogen mediates many aspects in growth, development, and reproduction, through its interaction with estrogen receptors ER 2The abbreviations used are: ER, estrogen receptor; PI3K, phosphatidylinositol 3-kinase; CBP, CREB binding protein; C/H3, cysteine- and histidine-rich 3; SRC, steroid receptor coactivator; ERR, estrogen-related receptor; GR, glucocorticoid receptor; PR, progesterone receptor; PPAR, peroxisome proliferator-activated receptor; EGFR, epidermal growth factor receptor; ERE, estrogen response element; CREB, cAMP-response element-binding protein; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; WT, wild type; YFP, yellow fluorescent protein; CFP, cyan fluorescent protein; HA, hemagglutinin; GST, glutathione S-transferase; RT, reverse transcription; FBS, fetal bovine serum; DMEM, Dulbecco’s modified Eagle’s medium; EGF, epidermal growth factor; E2, estradiol; PBS, phosphate-buffered saline; AF, activation function; CatD1, cathepsin D1.2The abbreviations used are: ER, estrogen receptor; PI3K, phosphatidylinositol 3-kinase; CBP, CREB binding protein; C/H3, cysteine- and histidine-rich 3; SRC, steroid receptor coactivator; ERR, estrogen-related receptor; GR, glucocorticoid receptor; PR, progesterone receptor; PPAR, peroxisome proliferator-activated receptor; EGFR, epidermal growth factor receptor; ERE, estrogen response element; CREB, cAMP-response element-binding protein; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; WT, wild type; YFP, yellow fluorescent protein; CFP, cyan fluorescent protein; HA, hemagglutinin; GST, glutathione S-transferase; RT, reverse transcription; FBS, fetal bovine serum; DMEM, Dulbecco’s modified Eagle’s medium; EGF, epidermal growth factor; E2, estradiol; PBS, phosphate-buffered saline; AF, activation function; CatD1, cathepsin D1. α and ERβ. Although encoded by unique genes, the two ERs share the functional domains characteristic of the nuclear hormone receptor family (1.Mangelsdorf D.J. Thummel C. Beato M. Herrlich P. Schütz G. Umesono K. Blumberg B. Kastner P. Mark M. Chambon P. Evans R.M. Cell. 1995; 83: 835-839Abstract Full Text PDF PubMed Scopus (6043) Google Scholar). These consist of an N-terminal region (also termed AB region), which confers ligand-independent activation of ERs through its activation function (AF)-1, a highly conserved DNA-binding domain (C) that allows specific binding to genomic response elements, a flexible hinge region (D) that includes signals for nuclear localization and the binding of heat shock proteins, and finally a C-terminal region (EF) that contains the ligand binding domain, and the AF-2 function that mediates hormone-dependent activation. Increasing evidence suggests that, beside hormonal activation, ER function can be modulated by phosphorylation-dependent mechanisms, involving a wide variety of protein kinases that mostly target the AF-1 domain (2.Pearce S.T. Jordan V.C. Crit. Rev. Oncol. Hematol. 2004; 50: 3-22Crossref PubMed Scopus (250) Google Scholar, 3.Sanchez M. Tremblay of Scholar). In of AF-1 by in response to was to in the of ligand Chambon P. 1995; PubMed Scopus Google Scholar, G. PubMed Scopus Google Scholar). of by was to AF-1 activity Cell. PubMed Scopus Google Scholar). of phosphatidylinositol and kinase also to and its ligand-independent activation, an to the in P. Full Text Full Text PDF PubMed Scopus Google Scholar). Although of ERβ not in ERβ as a potential target for kinases that modulate its was found that the ability of and the to activate ERβ from the of and the AF-1 domain to of and CBP Tremblay Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). the activation of ERβ by the was to of ERβ in a the were not Full Text Full Text PDF PubMed Scopus Google Scholar). we that activation of and which to the receptor kinase by growth factor in a in the growth and activity of and ERβ in M. C. Tremblay PubMed Scopus Google Scholar). transcriptional of ERβ by was upon ERβ AF-1 a for in ERβ AF-1 and AF-2 the of estrogen receptor activity by is and receptor activation evidence suggesting that nuclear receptor may also serve as of the ER and growth factor signaling of to modulate intrinsic in nuclear receptor Rev. PubMed Scopus Google Scholar). are in in the that of of expression as as activity can to in nuclear receptor The transcriptional CREB-binding protein and are highly conserved proteins, and evidence to be In of functional of to a in M. D.J. 1995; PubMed Scopus Google Scholar). ability in including nuclear with the of is to transcriptional events Google Scholar). of the for was that of CBP its interaction with including CREB, and Full Text Full Text PDF PubMed Scopus Google Scholar, 2004; PubMed Scopus Google Scholar). that of ERβ also the of CBP to the ligand-independent activation of ERβ in response to growth PubMed Scopus Google Scholar). such in the signaling by CBP, is that events may for the of CBP. Here we a mechanism by which ErbB2/ErbB3 and signaling the activity of ERβ by its ability to recruit and CBP as a The by Akt was also found for nuclear for which a conserved Akt site may also in a to ERβ. In contrast, nuclear receptors that not share such increased to CBP and benefit from the enhanced intrinsic activity of CBP by Akt. of for ERβ, CBP, its and and and Tremblay Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, M. C. Tremblay PubMed Scopus Google Scholar). ERβ to the AB and were by and with the binding The ERβ Ser-255 to and the CBP to were by were by The expression for the was a from and Akt and kinase Akt were by and P. and were in Dulbecco’s modified Eagle’s with fetal bovine The were in a with were in with FBS, and were the as M. C. Tremblay PubMed Scopus Google Scholar). were with of which of of receptor expression of of and Akt expression and of CBP the was and were with for were in and was a the of were in from and were as to the activity of and for the of and Akt was as with M. C. Tremblay PubMed Scopus Google Scholar). were with for in PBS, and in and were to and to for were with in with a Akt a and signals by The was used to the of ERβ, that were with ERβ and by an were in and as were with an and protein were in by and by an were also with an for of CBP in of and were in and with expression for and ERβ as M. C. Tremblay PubMed Scopus Google and were in the presence of to and were for expression of ERβ by and for response by with cells. was from and was as K. Tremblay PubMed Scopus Google Scholar). The was from In and of wild and ERβ were as Tremblay D.J. PubMed Scopus Google Scholar). in were in kinase and and for to the were in kinase and in PBS, and was and were with to for were in a to in with were as the expression and were with and in The were and in with of and a ErbB2/ErbB3 the and of ERβ by of the epidermal growth factor receptor a of the receptor kinase is to and ERβ transcriptional activation Chambon P. 1995; PubMed Scopus Google Scholar, Tremblay Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). we that activation of the ErbB2/ErbB3 to a decreased transcriptional activity of ERβ M. C. Tremblay PubMed Scopus Google Scholar). the ability of CBP to and the activation of ERβ by a growth factor such as PubMed Scopus Google we CBP modulate ERβ activity in response to ErbB2/ErbB3 activation. were with an and an ERβ with CBP a in ERβ activity and a in the presence of hormone M. C. Tremblay PubMed Scopus Google the activation of the ErbB2/ErbB3 by growth factor which in a reduced activation of ERβ by estrogen. Such impaired response was also a of which to the found in the PubMed Scopus Google Scholar). CBP ERβ in is to the inhibition of the hormonal response of ERβ the ErbB2/ErbB3 is not is also by the presence of CBP, the transcriptional activity of ERβ was decreased in a and This inhibition was more in the of the family the activation of a variety of kinase activation of the ErbB2/ErbB3 to with the pathway, through the intrinsic ability of that the regulatory of P. Cell. PubMed Google Scholar, PubMed Scopus Google Scholar). the of ErbB2/ErbB3 activation the Akt pathway, the activity of Akt was by a Although of with did not to activation of indicating that expression of is not an in Akt was in ErbB2/ErbB3 and with the in the presence of also increased of Akt. of the the of ERβ to in the of CBP through the C-terminal of that ErbB2/ErbB3 activation by ERβ activity and its coactivation by CBP by the activity of Akt was by expression of a and of of the was to activate Akt in which was enhanced were with a for as by P. Full Text Full Text PDF PubMed Google not we found that the activation of ERβ in the presence of CBP, which with was impaired to a response in Akt-activated in in response to Akt activation the of CBP the response of ERβ to estrogen with CBP. These results that expression of CBP not the inhibition of ERβ by the pathway, therefore the results in cells. The of ERβ by Akt in the presence of CBP was in a of Akt suggesting that the of ERβ through Akt to the of ERβ activity was not a of its protein the in activation of the Akt pathway to an of ERβ in cells. was also in the presence of the of ERβ were with an in ER in response to hormone as PubMed Scopus Google Scholar). These results that the inhibition in ERβ activity to Akt activation is not to a in ERβ protein CBP is to estrogen receptors through its AF-1 and AF-2 PubMed Scopus Google Scholar, M. Full Text Full Text PDF PubMed Scopus Google Scholar). In an to the functional domain ERβ for its impaired ability to be coactivated by CBP in response to we used of of ERβ for which domain that in Akt-activated the activation of a to ERβ a was enhanced by CBP, a with cells. The N-terminal domain of ERβ is to serine that are conserved the for kinases of the and of specific was to for such as CBP to be and to ERβ AF-1 activity Tremblay Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). of the potential ERβ AB region to a consensus Akt suggesting that the enhanced activity of ERβ AF-1 by CBP in response to Akt from kinase by Akt CBP the of the C-terminal region of ERβ in the with a a reduced hormone-dependent activity to Akt activation in the presence of CBP, the response with ERβ These results that the of Akt of ERβ is through a region contained in the C-terminal of ERβ, which in the of the receptor to the the AF-1 in the ERβ to ErbB2/ErbB3 of the C-terminal of ERβ a consensus in the hinge region of ERβ that to the for the kinase Akt Ser-255 is a target for we used to the serine an and an in kinase that of Ser-255 the of ERβ by Akt with wild indicating that Ser-255 can be by Akt. 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This also to for which coactivation was in response to Akt. the receptors that not share with ERβ we found that PR, and peroxisome proliferator-activated receptor were by CBP in Akt-activated in the presence of ligand CBP, which to with the binding protein CREB, also CREB activation to Akt. the impaired ability of CBP to ERβ in response to Akt can be to receptors that share an with the ERβ for receptors that not that to benefit from the enhanced intrinsic activity of CBP in response to activation of the Increasing evidence suggests that ligand activation, nuclear receptors are responsive to kinase signaling mechanisms, and for in may a to the transcriptional (2.Pearce S.T. Jordan V.C. Crit. Rev. Oncol. Hematol. 2004; 50: 3-22Crossref PubMed Scopus (250) Google Scholar, 3.Sanchez M. Tremblay of Scholar). the that signaling can also transcriptional of estrogen receptors to are controlled M. C. Tremblay PubMed Scopus Google Scholar, C. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). Here we show that activation of ErbB2/ErbB3 receptors and the pathway can the transcriptional response of ERβ to estrogen and its coactivation by CBP. The mechanism ERβ inhibition which upon its by Akt CBP from with ERβ, therefore abrogating ERβ of with its is the of receptors in of growth and M. PubMed Scopus Google Scholar). signaling by ErbB2/ErbB3 associated with potential in a number of and the of with as a factor in Rev. PubMed Scopus Google Scholar, G. PubMed Scopus Google Scholar). the response of ERβ to ErbB2/ErbB3 activation is not and the of ERβ in found that the transcriptional response of ERβ to estrogen was upon activation of ErbB2/ErbB3 with ligand the from the These results to therefore genes, as with the of and were associated with increased activation of Akt. the coactivator CBP to and response of ERβ, to activation of ERβ in Akt-activated cells. 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In the of the and were as for which the of with coactivator C. PubMed Scopus Google Scholar). results therefore a mechanism by which ErbB2/ErbB3 and Akt signaling ERβ activity through a phosphorylation-dependent release of coactivator CBP. are general to many and evidence suggests that of the mechanism that function Google Scholar). Interestingly, of by Akt was to activity and its transcriptional potential Cell. PubMed Scopus Google Scholar). the site CBP, we that is to CBP enhanced transcriptional in response to Akt activation. ERβ was not able to benefit from activity as to the suggesting that of ERβ Ser-255 may in the response of ERβ to Akt. of Ser-255 impaired CBP to ERβ and did not for coactivation, therefore potential of CBP to activate ERβ. mechanism was in the inhibition of gene expression by that the of in the domain of by Akt prevented to with M. Full Text Full Text PDF PubMed Scopus Google Scholar). 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Such coactivation of ERs by CBP may a mechanism by which CBP can discriminate and in response to Akt This mechanism can in such as in which activation of Akt is as a of M. P. 1995; Google Scholar). Akt activation with in whereas the of ERβ is not Rev. PubMed Scopus Google Scholar, G. B. B. PubMed Scopus Google Scholar). therefore to that the that to Ser-255 a reduced response of ERβ to CBP are to The ER of CBP by the pathway also to and contains a consensus for Akt found the region as ERβ and was found by Akt in the presence of CBP. Although to the the not exhibit estrogen binding and are receptors a results that can be by kinase signaling such as the of in ER and target gene expression Full Text Full Text PDF PubMed Scopus Google Scholar, Jordan V.C. 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