Transcription Factor GATA-4 Is Activated by Phosphorylation of Serine 261 via the cAMP/Protein Kinase A Signaling Pathway in Gonadal Cells

Gonadal gene expression is regulated by pituitary hormones acting through the cAMP/protein kinase A (PKA) signal transduction pathway. The downstream molecular effectors of these signals, however, have yet to be fully understood. We have recently shown that cAMP stimulation of gonadal cells leads to phosphorylation of the transcription factor GATA-4, a key regulator of gonadal gene expression, thus suggesting that this factor might be a novel target for the cAMP/PKA signaling pathway. We now show that the rapid phosphorylation of GATA-4 induced by cAMP in vivo can be blocked by a PKA-specific inhibitor but not by mitogen-activated protein kinase inhibitors, indicating that GATA-4 is predominantly phosphorylated by PKA in response to cAMP in gonadal cells. In addition, using in vitro kinase assays, we show that PKA phosphorylation of GATA-4 occurs predominantly on an evolutionarily conserved serine residue located at position 261. Phosphorylation of GATA-4 Ser261 by PKA enhances its transcriptional activity on different gonadal promoters, an effect that was markedly reduced with a S261A mutant. Moreover, the S261A mutant blunted cAMP-induced promoter activity in gonadal cells. Finally, PKA-dependent phosphorylation of GATA-4 also led to enhanced recruitment of the CREB-binding protein coactivator. This recruitment and transcriptional cooperation were dramatically impaired with the S261A mutant. Thus, our results identify GATA-4 as a novel downstream effector of cAMP/PKA signaling in gonadal cells, where phosphorylation of Ser261 and recruitment of CREB-binding protein likely represent a key mechanism for conveying the cAMP responsiveness of gonadal genes that lack classical cAMP regulatory elements. Gonadal gene expression is regulated by pituitary hormones acting through the cAMP/protein kinase A (PKA) signal transduction pathway. The downstream molecular effectors of these signals, however, have yet to be fully understood. We have recently shown that cAMP stimulation of gonadal cells leads to phosphorylation of the transcription factor GATA-4, a key regulator of gonadal gene expression, thus suggesting that this factor might be a novel target for the cAMP/PKA signaling pathway. We now show that the rapid phosphorylation of GATA-4 induced by cAMP in vivo can be blocked by a PKA-specific inhibitor but not by mitogen-activated protein kinase inhibitors, indicating that GATA-4 is predominantly phosphorylated by PKA in response to cAMP in gonadal cells. In addition, using in vitro kinase assays, we show that PKA phosphorylation of GATA-4 occurs predominantly on an evolutionarily conserved serine residue located at position 261. Phosphorylation of GATA-4 Ser261 by PKA enhances its transcriptional activity on different gonadal promoters, an effect that was markedly reduced with a S261A mutant. Moreover, the S261A mutant blunted cAMP-induced promoter activity in gonadal cells. Finally, PKA-dependent phosphorylation of GATA-4 also led to enhanced recruitment of the CREB-binding protein coactivator. This recruitment and transcriptional cooperation were dramatically impaired with the S261A mutant. Thus, our results identify GATA-4 as a novel downstream effector of cAMP/PKA signaling in gonadal cells, where phosphorylation of Ser261 and recruitment of CREB-binding protein likely represent a key mechanism for conveying the cAMP responsiveness of gonadal genes that lack classical cAMP regulatory elements. Gene expression in the gonads is under the influence of the pituitary trophic hormones luteinizing hormone and follicle-stimulating hormone. Binding of these hormones to their G-coupled receptors activates adenylate cyclase leading to increased cAMP production. In the classical cAMP signaling pathway, cAMP associates with the regulatory subunits of the protein kinase A (PKA) 1The abbreviations used are: PKA, protein kinase A; CREB, cAMP-responsive element-binding protein; CBP, CREB-binding protein; C/EBP, CCAAT/enhancer-binding protein; MAPK, mitogen-activated protein kinase; GST, glutathione S-transferase; db-cAMP, dibutyryl cAMP; ERK, extracellular signal-regulated kinase; FL, full-length; MEK, MAPK/ERK kinase; AD, activation domain; DBD, DNA-binding domain. holoenzyme, allowing dissociation of its catalytic subunits, which then translocate to the nucleus and phosphorylate target proteins (1Daniel P.B. Walker W.H. Habener J.F. Annu. Rev. Nutr. 1998; 18: 353-383Crossref PubMed Scopus (216) Google Scholar, 2Montminy M. Annu. Rev. Biochem. 1997; 66: 807-822Crossref PubMed Scopus (860) Google Scholar). The best studied target of PKA is the transcription factor cAMP-responsive element-binding protein (CREB), which binds as a dimer to the 8-bp palindromic sequence CRE found in the regulatory region of some cAMP-regulated genes. Phosphorylation of CREB Ser133 by PKA allows recruitment of the coactivator CREB-binding protein (CBP), which contacts the transcriptional machinery leading to increased gene transcription (3Mayr B. Montminy M. Nat. Rev. Mol. Cell. Biol. 2001; 2: 599-609Crossref PubMed Scopus (2084) Google Scholar). In the gonads, however, several cAMP-regulated genes, such as steroidogenic acute regulatory protein (Star), steroid 17α-hydroxylase (Cyp17), P450scc (Cyp11A1), inhibin α (Inha), and aromatase (Cyp19), lack consensus CRE elements. Therefore, transcription factors in addition to CREB must be acting as downstream effectors of cAMP signaling in gonadal cells. There are several factors that have been shown to be activated by cAMP in gonadal cells. These include stimulatory protein 1 (Sp1), upstream stimulatory factor, estrogen receptor α/β, activating protein 1 (AP-1), CCAAT/enhancer-binding protein (C/EBP) β, and Nur77/NR4A1 (4Nalbant D. Williams S.C. Stocco D.M. Khan S.A. Endocrinology. 1998; 139: 272-279Crossref PubMed Scopus (75) Google Scholar, 5Christenson L.K. Johnson P.F. McAllister J.M. Strauss III, J.F. J. Biol. Chem. 1999; 274: 26591-26598Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 6Richards J.S. Mol. Endocrinol. 2001; 15: 209-218Crossref PubMed Scopus (342) Google Scholar, 7Silverman E. Eimerl S. Orly J. J. Biol. Chem. 1999; 274: 17987-17996Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 8Song K.H. Park J.I. Lee M.O. Soh J. Lee K. Choi H.S. Endocrinology. 2001; 142: 5116-5123Crossref PubMed Scopus (92) Google Scholar). Although these transcription factors have been shown to contribute to the hormonal regulation of gonadal genes, most are ubiquitously expressed and respond to several stimuli other than cAMP. Moreover, not all cAMP-responsive gonadal promoters lacking CRE elements have binding sites for these factors. In the gonads, the orphan nuclear receptor steroidogenic factor 1 (SF-1/NR5A1) has been proposed to be a candidate factor downstream of cAMP/PKA. In support of this hypothesis, SF-1-binding sites are found in several hormonally regulated genes. Indeed, a role for SF-1 in the cAMP-dependent stimulation of several gonadal genes has been described (9Parker K.L. Rice D.A. Lala D.S. Ikeda Y. Luo X. Wong M. Bakke M. Zhao L. Frigeri C. Hanley N.A. Stallings N. Schimmer B.P. Recent Prog. Horm. Res. 2002; 57: 19-36Crossref PubMed Scopus (305) Google Scholar). Although SF-1 can be phosphorylated by PKA in vitro (10Zhang P. Mellon S.H. Mol. Endocrinol. 1996; 10: 147-158Crossref PubMed Scopus (162) Google Scholar), SF-1 is constitutively phosphorylated in vivo by the mitogen-activated protein kinase (MAPK) pathway, and its phosphorylation levels are not affected by cAMP treatment (11Hammer G.D. Krylova I. Zhang Y. Darimont B.D. Simpson K. Weigel N.L. Ingraham H.A. Mol. Cell. 1999; 3: 521-526Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar). Unfortunately, the absence of adrenals and gonads in SF-1 knockout mice (12Luo X. Ikeda Y. Parker K.L. Cell. 1994; 77: 481-490Abstract Full Text PDF PubMed Scopus (1397) Google Scholar, 13Sadovsky Y. Crawford P.A. Woodson K.G. Polish J.A. Clements M.A. Tourtellotte L.M. Simburger K. Milbrandt J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10939-10943Crossref PubMed Scopus (395) Google Scholar, 14Shinoda K. Lei H. Yoshii H. Nomura M. Nagano M. Shiba H. Sasaki H. Osawa Y. Ninomiya Y. Niwa O. Dev. Dyn. 1995; 204: 22-29Crossref PubMed Scopus (313) Google Scholar) precludes a definitive answer to the role of this factor in these tissues. However, in other steroidogenic tissues normally expressing SF-1, such as the placenta and skin, expression of the cAMP-regulated genes Cyp11A1 and Cyp17 was normal in SF-1–/– mice (13Sadovsky Y. Crawford P.A. Woodson K.G. Polish J.A. Clements M.A. Tourtellotte L.M. Simburger K. Milbrandt J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 10939-10943Crossref PubMed Scopus (395) Google Scholar, 15Keeney D.S. Ikeda Y. Waterman M.R. Parker K.L. Mol. Endocrinol. 1995; 9: 1091-1098PubMed Google Scholar, 16Patel M.V. McKay I.A. Burrin J.M. J. Invest. Dermatol. 2001; 117: 1559-1565Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). Therefore, SF-1 might not be the predominant downstream effector of cAMP signaling in gonadal cells. In addition to SF-1 regulatory elements, many cAMP-regulated gonadal promoters also contain GATA motifs for the binding of members of the GATA family of transcription factors. There are six vertebrate GATA factors (named GATA-1 to GATA-6). Four of these are expressed in the mammalian gonads: GATA-1, GATA-2, GATA-4, and GATA-6 (17Viger R.S. Mertineit C. Trasler J.M. Nemer M. Development. 1998; 125: 2665-2675Crossref PubMed Google Scholar, 18Heikinheimo M. Ermolaeva M. Bielinska M. Rahnman N.A. Narita N. Huhtaniemi I.T. Tapanainen J.S. Wilson D.B. Endocrinology. 1997; 138: 3505-3514Crossref PubMed Scopus (164) Google Scholar, 19Ito E. Toki T. Ishihara H. Ohtani H. Gu L. Yokoyama M. Engel J.D. Yamamoto M. Nature. 1993; 362: 466-468Crossref PubMed Scopus (258) Google Scholar, I. N. J. Bielinska M. Tapanainen J.S. Huhtaniemi I.T. Wilson D.B. M. Endocrinology. 1999; PubMed Google Scholar, S.A. S.C. Biol. 2001; PubMed Scopus Google Scholar, R.S. Endocrinology. 2002; PubMed Scopus Google Scholar, P. L. A. Dev. 2002; PubMed Scopus Google Scholar, K. Ohtani H. H. E. Y. Engel J.D. Yamamoto M. Development. 1994; PubMed Google Scholar). In GATA-4 is expressed the of gonadal and is found in and cells and cells of the (17Viger R.S. Mertineit C. Trasler J.M. Nemer M. Development. 1998; 125: 2665-2675Crossref PubMed Google Scholar). the of these cells is under hormonal GATA-4 represent a key effector of hormonal signaling in gonadal cells. In with GATA-4 has been shown to several cAMP-dependent gonadal promoters inhibin and aromatase R.S. Endocrinology. 2001; 142: PubMed Scopus Google Scholar). In addition, we have recently shown that cAMP stimulation of gonadal cells leads to phosphorylation of GATA-4 R.S. Endocrinology. 2002; PubMed Scopus Google Scholar). Although PKA was a likely the activated by cAMP in gonadal cells and for GATA-4 We now that GATA-4 is a key effector of cAMP signaling in gonadal cells. cells, we show that GATA-4 is phosphorylated in response to cAMP stimulation predominantly through PKA and not the signal transduction pathway. cAMP-induced phosphorylation occurs on an evolutionarily conserved residue of the GATA-4 we a novel mechanism activation of GATA-4 by PKA target genes an enhanced recruitment of the transcriptional coactivator. for the aromatase and inhibin α promoters have been described R.S. Endocrinology. 2001; 142: PubMed Scopus Google Scholar). The steroid 17α-hydroxylase promoter was by The was by of the GATA the promoter upstream of the promoter R.S. Mol. Endocrinol. 1999; PubMed Scopus Google Scholar). GATA-4 expression and have been R.S. Endocrinology. 2001; 142: PubMed Scopus Google Scholar, R.S. Endocrinology. 2002; PubMed Scopus Google Scholar, R.S. Mol. Endocrinol. 1999; PubMed Scopus Google Scholar, R.S. Biol. 2001; PubMed Scopus Google Scholar, R.S. Mol. Endocrinol. 2001; 15: PubMed Scopus Google Scholar). The GATA-4 S261A mutant was by of GATA-4 using the and the of is The was by the activation upstream of A of the to was by and a expression to its of proteins were by of GATA-4 in with using the proteins were in the and using a glutathione and and cells were in with The cells were in M. Endocrinology. PubMed Scopus Google Scholar). cells were in using the R.S. Endocrinology. 2001; 142: PubMed Scopus Google Scholar). cells were in and using the In of and of an expression expression for GATA-4 GATA-4 S261A were with of in and was used as an was The the cells were with dibutyryl cAMP for and then and using the The represent the of at in and were by the described by E. P. Res. PubMed Scopus Google Scholar). GATA proteins were by cells with expression for the different GATA-4 In of nuclear were by and to of the GATA-4 protein was using a GATA-4 GATA-4 proteins were using an and a was used as of in GATA-4 cells were in using The the cells were and in for was and the cells were for an The cells were then with different signaling and for The cells were for by The cAMP treatment is the of that have for the of GATA phosphorylation in using in vivo phosphorylation increased GATA binding as Zhang J.M. A. J. PubMed Scopus Google Scholar, M. L. J.D. S. Nemer M. Dev. 2001; 15: PubMed Scopus Google Scholar, T. K. S. T. H. T. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J.D. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). the cells were and in of 1 and of the and GATA-4 was by with of GATA-4 for at A of protein was then and was for an at were in in at for by and to GATA-4 protein was by In Phosphorylation vitro kinase were using 1 of the different proteins and of PKA catalytic for at in a of 1 of in the of of The were by and the for at the proteins were to and by The protein was by of the vitro were as described R.S. Endocrinology. 2002; PubMed Scopus Google Scholar). A of the protein was using the in vitro The protein was in vitro phosphorylated as described but with was by in of binding R.S. Endocrinology. 2002; PubMed Scopus Google Scholar) with GATA-4 through the cAMP/PKA in results in our using an a residue that the GATA-4 transcription factor was phosphorylated in response to cAMP stimulation of cells R.S. Endocrinology. 2002; PubMed Scopus Google Scholar). Although our results that PKA might be for GATA-4 the signaling and kinase not been the phosphorylation of GATA-4 and identify the signaling were in and the is in shown in GATA-4 is constitutively phosphorylated in these cells in the absence of GATA-4 phosphorylation however, were increased than treatment This a in GATA-4 protein levels which is with that hormonal stimulation of cells has effect on GATA-4 and protein levels E. Eimerl S. Orly J. J. Biol. Chem. 1999; 274: 17987-17996Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, R.S. Endocrinology. 2002; PubMed Scopus Google Scholar, Endocrinology. PubMed Scopus Google Scholar, D. Endocrinology. 2002; PubMed Scopus Google Scholar). GATA-4 has recently been shown to be phosphorylated at through the and in cells M. L. J.D. S. Nemer M. Dev. 2001; 15: PubMed Scopus Google Scholar, J.D. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar) and cAMP is also to the J.S. Mol. Endocrinol. 2001; 15: 209-218Crossref PubMed Scopus (342) Google Scholar), we used different to identify which signaling is for GATA-4 phosphorylation in gonadal cells. shown in cAMP-induced GATA-4 phosphorylation was by a PKA but not by which are of the and The effect of was not to a of GATA-4 phosphorylation treatment in the absence of cAMP in a in phosphorylation levels Thus, PKA to be the predominant kinase for cAMP-induced GATA-4 phosphorylation in cells. the we the GATA-4 sequence for PKA phosphorylation PKA consensus phosphorylation that the is at position the of the DNA-binding This region is conserved the and GATA-4 proteins the of this to in vitro kinase were using proteins PKA phosphorylated a GATA-4 protein the consensus PKA lacking this region and not be phosphorylated by Therefore, the PKA target on GATA-4 are located and with of Ser261 a that Ser261 impaired phosphorylation by protein the absence of phosphorylation with proteins lacking Ser261 was not to of The likely represent different of the Thus, these results that Ser261 is a predominant of the GATA-4 protein by the cAMP/PKA signaling in cells. The phosphorylation with the S261A and however, that might also be phosphorylation sites in the of the GATA-4 Phosphorylation GATA-4 cAMP/PKA phosphorylation of GATA-4 a role in gonadal gene expression, then phosphorylation of GATA-4 might its on target gonadal Indeed, we have recently that PKA activates GATA-4 transcriptional activity on the promoter R.S. Endocrinology. 2002; PubMed Scopus Google Scholar). shown in we now that in addition to PKA enhances the activation of several gonadal promoters and inhibin The stimulatory effect of PKA most likely occurs through phosphorylation of GATA-4 PKA effect on promoter This stimulation was also on GATA-4 binding to of the GATA elements in the target promoters by GATA-4 and by PKA not Therefore, phosphorylation of GATA-4 activates its transcriptional activity on a of promoters that are in gonadal cells. PKA-dependent of GATA-4 the of Ser261 for and GATA-4 transcriptional the GATA-4 proteins were used in with its role in phosphorylation of GATA-4 Ser261 markedly reduced its activation by PKA This was not to in expression, nuclear of the different GATA-4 the and S261A GATA-4 proteins were expressed at levels The of GATA-4 S261A by PKA is likely to phosphorylation located in the region of the GATA-4 protein the GATA-4 protein phosphorylation at which is a target of the and in cells M. L. J.D. S. Nemer M. Dev. 2001; 15: PubMed Scopus Google Scholar, J.D. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). Therefore, that the PKA of GATA-4 transcriptional activity be through the pathway. Although a constitutively of MAPK/ERK kinase 1 GATA-4 transcriptional activity this was the of GATA-4 the target was In PKA the activity of this This effect was not to in the of GATA-4 protein the and GATA-4 were expressed at levels Moreover, the of PKA and were not to in GATA-4 expression the GATA-4 protein levels were not by kinase Therefore, GATA-4 to contain at phosphorylation sites of which Ser261 is for the transcriptional by the GATA-4 Ser261 blunted transcriptional in cells, we the effect of this on cAMP-induced promoter activity in cells of cells with activated the promoter cAMP was not affected by expressed GATA-4 the and This however, was blunted by of the GATA-4 S261A mutant which with GATA-4 protein for Thus, these results that phosphorylation of GATA-4 Ser261 is to activation of and cAMP-dependent gonadal promoters in response to hormonal GATA-4 and on Gonadal transcriptional coactivator is an regulator of gene expression through its to and with several transcription factors such as CREB in response to cAMP/PKA signaling (3Mayr B. Montminy M. Nat. Rev. Mol. Cell. Biol. 2001; 2: 599-609Crossref PubMed Scopus (2084) Google Scholar). has also been to in vitro with the of GATA-4 J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), we GATA-4 with on a of gonadal promoters and this cooperation protein phosphorylation by PKA cooperation GATA-4 and was in the absence of PKA on the and inhibin α promoters In the of PKA, however, was on all promoters In addition, the PKA-dependent cooperation was also on a of a of the consensus GATA the promoter to the promoter this effect was of in GATA-4 protein levels Thus, GATA-4 binding to is and for the PKA-dependent transcriptional the of GATA-4 for the PKA-dependent with was The GATA-4 protein activation that its of the GATA-4 not However, of GATA-4 the DBD, blunted cooperation with These results that cooperation with at and an GATA-4 DBD, the in binding and with J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In with these a the protein to the GATA-4 PKA-dependent cooperation with phosphorylation of Ser261 is to the GATA-4 transcription factor, we phosphorylation of GATA-4 Ser261 is also for transcriptional with shown in of GATA-4 Ser261 markedly impaired transcriptional with activation with for Thus, phosphorylation of GATA-4 Ser261 is likely an mechanism for the recruitment of the coactivator to cAMP-dependent promoters GATA regulatory elements. Phosphorylation of GATA-4 Ser261 the with that transcriptional cooperation GATA-4 and phosphorylation of GATA-4 Ser261 that protein phosphorylation by PKA might also the the this in vitro were using proteins and a of the protein shown to with GATA-4 J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). by and J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), GATA-4 and in the absence of PKA phosphorylation with the transcriptional cooperation phosphorylation of the GATA-4 protein enhanced the with In was with the GATA-4 S261A mutant that be phosphorylated by PKA In gonadal cells, is that most such as increased steroidogenic gene expression in cells, are through the cAMP/PKA signaling Rev. PubMed Scopus (216) Google Scholar). In several the gonads, the downstream effector of cAMP/PKA signaling is the which binds to CRE regulatory elements leading to stimulation of target promoters (1Daniel P.B. Walker W.H. Habener J.F. Annu. Rev. Nutr. 1998; 18: 353-383Crossref PubMed Scopus (216) Google Scholar, 2Montminy M. Annu. Rev. Biochem. 1997; 66: 807-822Crossref PubMed Scopus (860) Google Scholar). cAMP-regulated gonadal genes, however, lack consensus CRE elements, which that transcription factors other than CREB are for conveying the cAMP responsiveness of genes. on its expression in of the and and on the that can several gonadal promoters D.B. Endocrinology. 2001; 142: PubMed Scopus Google Scholar), GATA-4, CREB, is likely a regulatory factor that the cAMP responsiveness of gonadal genes. Indeed, our support a role for GATA-4 as a novel downstream effector of hormonal signaling in gonadal cells. a of cAMP in Gonadal of cells that GATA-4 protein is phosphorylated by PKA in response to cAMP stimulation The consensus PKA phosphorylation that we have is conserved several This a role for this that has been In addition to GATA-4, all other vertebrate GATA proteins as as GATA factors and contain PKA phosphorylation This that phosphorylation of GATA factors might have a role in the of in different tissues and is by hormone through the cAMP/PKA pathway, which expression of several steroidogenic genes, such as and Cyp17 that lack CRE regulatory elements. Although GATA-4 is not in the transcriptional activity is also by PKA on the promoter R.S. Endocrinology. 2002; PubMed Scopus Google Scholar), is expressed S. J. M. Narita N. Wilson D.B. M. Endocrinology. 2002; PubMed Scopus Google Scholar, S. J. M. Narita N. Wilson D.B. M. Res. 2002; PubMed Scopus Google Scholar). GATA factors have been as downstream effectors of signaling in other phosphorylation of has been shown to be in the regulation of gene expression in cells Zhang J.M. A. J. PubMed Scopus Google Scholar). In cells, phosphorylation of of M. S. T. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar), and phosphorylation of GATA-1 of cells M. S.H. J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). GATA-4 is also phosphorylated in response to stimuli in the M. L. J.D. S. Nemer M. Dev. 2001; 15: PubMed Scopus Google Scholar, T. K. S. T. H. T. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J.D. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar, N. H. M. J. H. O. H. 2001; PubMed Scopus Google Scholar, S. T. H. H. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, K. S.A. J. Biochem. J. 2001; PubMed Scopus Google Scholar, T. K. H. T. M. T. S. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). Although some of cAMP GATA phosphorylation was not by PKA but activation of the and This can be by the cAMP and which a of proteins protein activated by that to and thus the H. N. Toki S. M. M. 1998; PubMed Scopus Google Scholar, J. A. Nature. 1998; PubMed Scopus Google Scholar). In the phosphorylation of GATA-4 occurs on which is a consensus phosphorylation for M. L. J.D. S. Nemer M. Dev. 2001; 15: PubMed Scopus Google Scholar, J.D. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). Although GATA-4 be phosphorylated by on by cAMP stimulation of cells, cAMP-induced phosphorylation was not blocked by This that cAMP and the is not for cAMP-induced phosphorylation of GATA-4 in these cells. GATA-4 is predominantly phosphorylated on which a consensus for PKA our this is the of signaling that phosphorylation of a GATA factor by The that GATA-4 is phosphorylated by PKA on Ser261 in cells not a role for In gonadal cells respond to stimuli that the cAMP but the of PKA J.S. Mol. Endocrinol. 2001; 15: 209-218Crossref PubMed Scopus (342) Google Scholar). In these activation of to a predominant role J.S. Mol. Endocrinol. 2001; 15: 209-218Crossref PubMed Scopus (342) Google Scholar). Therefore, signaling and might on GATA-4 to gonadal gene expression and such a mechanism has recently been described for the GATA factor which as a effector of key and phosphorylation by different Choi J. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). of in Gonadal addition to GATA-4 transcriptional activity on several target promoters, phosphorylation of GATA-4 also its to with transcription factors. GATA-4 can with SF-1 in the absence of PKA R.S. Mol. Endocrinol. 1999; PubMed Scopus Google Scholar). was enhanced by PKA not PKA is also for transcriptional GATA-4 and other transcription factors such as R.S. Endocrinology. 2002; PubMed Scopus Google Scholar) and Thus, of the transcriptional of GATA-4 and its to with other transcription factors are are not gonadal gene expression might be regulated by the phosphorylation of mechanism with Although GATA-4 can with the coactivator in the absence of phosphorylation of GATA-4 Ser261 enhanced this Moreover, on target gonadal promoters, this enhanced was for transcriptional these results are of the and In the classical cAMP/PKA pathway, cAMP a in CREB phosphorylation levels M.R. L.M. Nature. PubMed Scopus Google Scholar). This is to our in GATA-4 phosphorylation levels cAMP stimulation of cells. Thus, that phosphorylation of GATA-4, CREB, allows for a with CBP, leading to increased gene this novel mechanism our of the regulation of genes that lack classical cAMP regulatory elements. the GATA-4 protein sites and phosphorylation in response to might regulatory GATA-4, CREB can also be phosphorylated on different serine by different on the phosphorylation of CREB by the kinase and kinase recruitment and target gene activation (3Mayr B. Montminy M. Nat. Rev. Mol. Cell. Biol. 2001; 2: 599-609Crossref PubMed Scopus (2084) Google Scholar). This allows for signal through CREB leading to Although are coactivator recruitment phosphorylation of GATA-4 in response to a signaling pathway, is to that a mechanism also for In this phosphorylation of a transcriptional regulator by different in response to cAMP gene expression of coactivator this GATA-4 represent the of a transcriptional other transcription factors such as SF-1 and and the coactivator that is for the activation of different of genes in response to hormonal and signaling in the gonads and other tissues. We Montminy catalytic α and expression expression Parker expression and for used in this

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.