Pp90rsk1 Regulates Estrogen Receptor-mediated Transcription Through Phosphorylation of Ser-167

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 1998 Apr 7

PMID 9528769

Citations 95

Authors

P B JOEL

J Smith

T W Sturgill

T L Fisher

J Blenis

D A Lannigan

Affiliations

Soon will be listed here.

Abstract

The estrogen receptor alpha (ER), a member of the steroid receptor superfamily, contains an N-terminal hormone-independent transcriptional activation function (AF-1) and a C-terminal hormone-dependent transcriptional activation function (AF-2). Here, we used in-gel kinase assays to determine that pp90rsk1 activated by either epidermal growth factor (EGF) or phorbol myristate acetate specifically phosphorylates Ser-167 within AF-1. In vitro kinase assays demonstrated that pp90rsk1 phosphorylates the N terminus of the wild-type ER but not of a mutant ER in which Ser-167 was replaced by Ala. In vivo, EGF stimulated phosphorylation of Ser-167 as well as Ser-118. Ectopic expression of active pp90rsk1 increased the level of phosphorylation of Ser-167 compared to that of either a mutant pp90rsk1, which is catalytically inactive in the N-terminal kinase domain, or to that of vector control. The ER formed a stable complex with the mutant pp90rsk1 in vivo. Transfection of the mutant pp90rsk1 depressed ER-dependent transcription of both a wild-type ER and a mutant ER that had a defective AF-2 domain (ER TAF-1). Furthermore, replacing either Ser-118 or Ser-167 with Ala in ER TAF-1 showed similar decreases in transcription levels. A double mutant in which both Ser-118 and Ser-167 were replaced with Ala demonstrated a further decrease in transcription compared to either of the single mutations. Taken together, our results strongly suggest that pp90rsk1 phosphorylates Ser-167 of the human ER in vivo and that Ser-167 aids in regulating the transcriptional activity of AF-1 in the ER.

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References

Vik T, Sweet L, Erikson R . Coinfection of insect cells with recombinant baculovirus expressing pp60v-src results in the activation of a serine-specific protein kinase pp90rsk. Proc Natl Acad Sci U S A. 1990; 87(7):2685-9. PMC: 53755. DOI: 10.1073/pnas.87.7.2685. View

Barik S . Site-directed mutagenesis by double polymerase chain reaction : megaprimer method. Methods Mol Biol. 2011; 15:277-86. DOI: 10.1385/0-89603-244-2:277. View

Reese J, Katzenellenbogen B . Differential DNA-binding abilities of estrogen receptor occupied with two classes of antiestrogens: studies using human estrogen receptor overexpressed in mammalian cells. Nucleic Acids Res. 1991; 19(23):6595-602. PMC: 329226. DOI: 10.1093/nar/19.23.6595. View

Dauvois S, Danielian P, White R, Parker M . Antiestrogen ICI 164,384 reduces cellular estrogen receptor content by increasing its turnover. Proc Natl Acad Sci U S A. 1992; 89(9):4037-41. PMC: 525627. DOI: 10.1073/pnas.89.9.4037. View

Nguyen T, Scimeca J, Filloux C, Peraldi P, Carpentier J, Van Obberghen E . Co-regulation of the mitogen-activated protein kinase, extracellular signal-regulated kinase 1, and the 90-kDa ribosomal S6 kinase in PC12 cells. Distinct effects of the neurotrophic factor, nerve growth factor, and the mitogenic factor, epidermal.... J Biol Chem. 1993; 268(13):9803-10. View

Blenis J . Signal transduction via the MAP kinases: proceed at your own RSK. Proc Natl Acad Sci U S A. 1993; 90(13):5889-92. PMC: 46831. DOI: 10.1073/pnas.90.13.5889. View

Chen R, Abate C, Blenis J . Phosphorylation of the c-Fos transrepression domain by mitogen-activated protein kinase and 90-kDa ribosomal S6 kinase. Proc Natl Acad Sci U S A. 1993; 90(23):10952-6. PMC: 47899. DOI: 10.1073/pnas.90.23.10952. View

Le Goff P, Montano M, Schodin D, Katzenellenbogen B . Phosphorylation of the human estrogen receptor. Identification of hormone-regulated sites and examination of their influence on transcriptional activity. J Biol Chem. 1994; 269(6):4458-66. View

Moller D, Xia C, Tang W, Zhu A, Jakubowski M . Human rsk isoforms: cloning and characterization of tissue-specific expression. Am J Physiol. 1994; 266(2 Pt 1):C351-9. DOI: 10.1152/ajpcell.1994.266.2.C351. View

10.

Tzukerman M, Esty A, Danielian P, Parker M, Stein R, Pike J . Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions. Mol Endocrinol. 1994; 8(1):21-30. DOI: 10.1210/mend.8.1.8152428. View

11.

Pumiglia K, Chow Y, Fabian J, Morrison D, Decker S, Jove R . Raf-1 N-terminal sequences necessary for Ras-Raf interaction and signal transduction. Mol Cell Biol. 1995; 15(1):398-406. PMC: 231979. DOI: 10.1128/MCB.15.1.398. View

12.

Eldar-Finkelman H, Seger R, Vandenheede J, KREBS E . Inactivation of glycogen synthase kinase-3 by epidermal growth factor is mediated by mitogen-activated protein kinase/p90 ribosomal protein S6 kinase signaling pathway in NIH/3T3 cells. J Biol Chem. 1995; 270(3):987-90. DOI: 10.1074/jbc.270.3.987. View

13.

Arnold S, Obourn J, Jaffe H, Notides A . Serine 167 is the major estradiol-induced phosphorylation site on the human estrogen receptor. Mol Endocrinol. 1994; 8(9):1208-14. DOI: 10.1210/mend.8.9.7838153. View

14.

Richards S, Lounsbury K, Macara I . The C terminus of the nuclear RAN/TC4 GTPase stabilizes the GDP-bound state and mediates interactions with RCC1, RAN-GAP, and HTF9A/RANBP1. J Biol Chem. 1995; 270(24):14405-11. DOI: 10.1074/jbc.270.24.14405. View

15.

Bjorbaek C, Zhao Y, Moller D . Divergent functional roles for p90rsk kinase domains. J Biol Chem. 1995; 270(32):18848-52. DOI: 10.1074/jbc.270.32.18848. View

16.

JOEL P, Traish A, Lannigan D . Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Mol Endocrinol. 1995; 9(8):1041-52. DOI: 10.1210/mend.9.8.7476978. View

17.

Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H . Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. 1995; 270(5241):1491-4. DOI: 10.1126/science.270.5241.1491. View

18.

Mangelsdorf D, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K . The nuclear receptor superfamily: the second decade. Cell. 1995; 83(6):835-9. PMC: 6159888. DOI: 10.1016/0092-8674(95)90199-x. View

19.

Fisher T, Blenis J . Evidence for two catalytically active kinase domains in pp90rsk. Mol Cell Biol. 1996; 16(3):1212-9. PMC: 231103. DOI: 10.1128/MCB.16.3.1212. View

20.

Tora L, Mullick A, Metzger D, Ponglikitmongkol M, Park I, Chambon P . The cloned human oestrogen receptor contains a mutation which alters its hormone binding properties. EMBO J. 1989; 8(7):1981-6. PMC: 401066. DOI: 10.1002/j.1460-2075.1989.tb03604.x. View