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Proc Natl Acad Sci U S A. Apr 16, 1996; 93(8): 3519–3524.

Human vitamin D receptor phosphorylation by casein kinase II at Ser-208 potentiates transcriptional activation.


The potential functional significance of human 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] receptor (hVDR) phosphorylation at Ser-208 was evaluated by cotransfecting COS-7 kidney cells with hVDR constructs and the catalytic subunit of human casein kinase 11 (CK-11). Under these conditions, hVDR is intensely phosphorylated in a reaction that depends on both CK-II and the presence of Ser-208. The resulting hyperphosphorylated receptor is unaltered in its kinetics for binding the 1,25(OH)2D3 ligand, its partitioning into the nucleus, and its ability to associate with a vitamin D responsive element. Replacement of Ser-208 with glycine or alanine indicates that phosphorylation of hVDR at Ser-208 is not obligatory for 1,25(OH)2D3 action, but coexpression of wild-type hVDR and CK-11 elicits a dose-dependent enhancement of 1,25(OH)2D3-stimulated transcription of a vitamin D responsive element reporter construct. This enhancement by CK-II is abolished by mutating Ser-208 to glycine or alanine and does not occur with glucocorticoid receptor-mediated transcription. Therefore, phosphorylation of hVDR by CK-11 at Ser-208 specifically modulates its transcriptional capacity, suggesting that this covalent modification alters the conformation of VDR to potentiate its interaction with the machinery for DNA transcription.

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  • Cohen P. The subunit structure of rabbit-skeletal-muscle phosphorylase kinase, and the molecular basis of its activation reactions. Eur J Biochem. 1973 Apr 2;34(1):1–14. [PubMed]
  • Hausdorff WP, Caron MG, Lefkowitz RJ. Turning off the signal: desensitization of beta-adrenergic receptor function. FASEB J. 1990 Aug;4(11):2881–2889. [PubMed]
  • Ortí E, Bodwell JE, Munck A. Phosphorylation of steroid hormone receptors. Endocr Rev. 1992 Feb;13(1):105–128. [PubMed]
  • Brown TA, DeLuca HF. Phosphorylation of the 1,25-dihydroxyvitamin D3 receptor. A primary event in 1,25-dihydroxyvitamin D3 action. J Biol Chem. 1990 Jun 15;265(17):10025–10029. [PubMed]
  • Jones BB, Jurutka PW, Haussler CA, Haussler MR, Whitfield GK. Vitamin D receptor phosphorylation in transfected ROS 17/2.8 cells is localized to the N-terminal region of the hormone-binding domain. Mol Endocrinol. 1991 Aug;5(8):1137–1146. [PubMed]
  • Kuiper GG, Brinkmann AO. Steroid hormone receptor phosphorylation: is there a physiological role? Mol Cell Endocrinol. 1994 Apr;100(1-2):103–107. [PubMed]
  • Krek W, Maridor G, Nigg EA. Casein kinase II is a predominantly nuclear enzyme. J Cell Biol. 1992 Jan;116(1):43–55. [PMC free article] [PubMed]
  • Tuazon PT, Traugh JA. Casein kinase I and II--multipotential serine protein kinases: structure, function, and regulation. Adv Second Messenger Phosphoprotein Res. 1991;23:123–164. [PubMed]
  • Allende JE, Allende CC. Protein kinases. 4. Protein kinase CK2: an enzyme with multiple substrates and a puzzling regulation. FASEB J. 1995 Mar;9(5):313–323. [PubMed]
  • Glineur C, Bailly M, Ghysdael J. The c-erbA alpha-encoded thyroid hormone receptor is phosphorylated in its amino terminal domain by casein kinase II. Oncogene. 1989 Oct;4(10):1247–1254. [PubMed]
  • Arnold SF, Obourn JD, Jaffe H, Notides AC. Serine 167 is the major estradiol-induced phosphorylation site on the human estrogen receptor. Mol Endocrinol. 1994 Sep;8(9):1208–1214. [PubMed]
  • Zhang Y, Beck CA, Poletti A, Edwards DP, Weigel NL. Identification of phosphorylation sites unique to the B form of human progesterone receptor. In vitro phosphorylation by casein kinase II. J Biol Chem. 1994 Dec 9;269(49):31034–31040. [PubMed]
  • Jurutka PW, Hsieh JC, MacDonald PN, Terpening CM, Haussler CA, Haussler MR, Whitfield GK. Phosphorylation of serine 208 in the human vitamin D receptor. The predominant amino acid phosphorylated by casein kinase II, in vitro, and identification as a significant phosphorylation site in intact cells. J Biol Chem. 1993 Mar 25;268(9):6791–6799. [PubMed]
  • Hilliard GM, 4th, Cook RG, Weigel NL, Pike JW. 1,25-dihydroxyvitamin D3 modulates phosphorylation of serine 205 in the human vitamin D receptor: site-directed mutagenesis of this residue promotes alternative phosphorylation. Biochemistry. 1994 Apr 12;33(14):4300–4311. [PubMed]
  • Sugawara A, Yen PM, Apriletti JW, Ribeiro RC, Sacks DB, Baxter JD, Chin WW. Phosphorylation selectively increases triiodothyronine receptor homodimer binding to DNA. J Biol Chem. 1994 Jan 7;269(1):433–437. [PubMed]
  • Migliaccio A, Di Domenico M, Green S, de Falco A, Kajtaniak EL, Blasi F, Chambon P, Auricchio F. Phosphorylation on tyrosine of in vitro synthesized human estrogen receptor activates its hormone binding. Mol Endocrinol. 1989 Jul;3(7):1061–1069. [PubMed]
  • van Laar JH, Berrevoets CA, Trapman J, Zegers ND, Brinkmann AO. Hormone-dependent androgen receptor phosphorylation is accompanied by receptor transformation in human lymph node carcinoma of the prostate cells. J Biol Chem. 1991 Feb 25;266(6):3734–3738. [PubMed]
  • Ali S, Metzger D, Bornert JM, Chambon P. Modulation of transcriptional activation by ligand-dependent phosphorylation of the human oestrogen receptor A/B region. EMBO J. 1993 Mar;12(3):1153–1160. [PMC free article] [PubMed]
  • Rochette-Egly C, Oulad-Abdelghani M, Staub A, Pfister V, Scheuer I, Chambon P, Gaub MP. Phosphorylation of the retinoic acid receptor-alpha by protein kinase A. Mol Endocrinol. 1995 Jul;9(7):860–871. [PubMed]
  • Mason SA, Housley PR. Site-directed mutagenesis of the phosphorylation sites in the mouse glucocorticoid receptor. J Biol Chem. 1993 Oct 15;268(29):21501–21504. [PubMed]
  • Almlöf T, Wright AP, Gustafsson JA. Role of acidic and phosphorylated residues in gene activation by the glucocorticoid receptor. J Biol Chem. 1995 Jul 21;270(29):17535–17540. [PubMed]
  • Terpening CM, Haussler CA, Jurutka PW, Galligan MA, Komm BS, Haussler MR. The vitamin D-responsive element in the rat bone Gla protein gene is an imperfect direct repeat that cooperates with other cis-elements in 1,25-dihydroxyvitamin D3- mediated transcriptional activation. Mol Endocrinol. 1991 Mar;5(3):373–385. [PubMed]
  • MacDonald PN, Dowd DR, Nakajima S, Galligan MA, Reeder MC, Haussler CA, Ozato K, Haussler MR. Retinoid X receptors stimulate and 9-cis retinoic acid inhibits 1,25-dihydroxyvitamin D3-activated expression of the rat osteocalcin gene. Mol Cell Biol. 1993 Sep;13(9):5907–5917. [PMC free article] [PubMed]
  • Scheidereit C, Geisse S, Westphal HM, Beato M. The glucocorticoid receptor binds to defined nucleotide sequences near the promoter of mouse mammary tumour virus. Nature. 1983 Aug 25;304(5928):749–752. [PubMed]
  • Nakajima S, Hsieh JC, MacDonald PN, Galligan MA, Haussler CA, Whitfield GK, Haussler MR. The C-terminal region of the vitamin D receptor is essential to form a complex with a receptor auxiliary factor required for high affinity binding to the vitamin D-responsive element. Mol Endocrinol. 1994 Feb;8(2):159–172. [PubMed]
  • Hsieh JC, Jurutka PW, Nakajima S, Galligan MA, Haussler CA, Shimizu Y, Shimizu N, Whitfield GK, Haussler MR. Phosphorylation of the human vitamin D receptor by protein kinase C. Biochemical and functional evaluation of the serine 51 recognition site. J Biol Chem. 1993 Jul 15;268(20):15118–15126. [PubMed]
  • Blanco JC, Wang IM, Tsai SY, Tsai MJ, O'Malley BW, Jurutka PW, Haussler MR, Ozato K. Transcription factor TFIIB and the vitamin D receptor cooperatively activate ligand-dependent transcription. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1535–1539. [PMC free article] [PubMed]
  • MacDonald PN, Sherman DR, Dowd DR, Jefcoat SC, Jr, DeLisle RK. The vitamin D receptor interacts with general transcription factor IIB. J Biol Chem. 1995 Mar 3;270(9):4748–4752. [PubMed]
  • Gonzalez GA, Montminy MR. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 1989 Nov 17;59(4):675–680. [PubMed]
  • Manak JR, Prywes R. Mutation of serum response factor phosphorylation sites and the mechanism by which its DNA-binding activity is increased by casein kinase II. Mol Cell Biol. 1991 Jul;11(7):3652–3659. [PMC free article] [PubMed]
  • Pongubala JM, Van Beveren C, Nagulapalli S, Klemsz MJ, McKercher SR, Maki RA, Atchison ML. Effect of PU.1 phosphorylation on interaction with NF-EM5 and transcriptional activation. Science. 1993 Mar 12;259(5101):1622–1625. [PubMed]

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