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Proc Natl Acad Sci U S A. Aug 15, 1993; 90(16): 7769–7773.
PMCID: PMC47224

The 25-kDa FK506-binding protein is localized in the nucleus and associates with casein kinase II and nucleolin.

Abstract

FK506-binding proteins (FKBPs) have been identified as the cellular receptors of the immunosuppressive drugs FK506 and rapamycin. Recently, we cloned a 25-kDa FKBP family member (FKBP25) and found that FKBP25 contains a nuclear localization sequence and several potential casein kinase II phosphorylation sites. It has been previously shown that phosphorylation of proteins by casein kinase II can enhance their nuclear localization. Here we demonstrate that FKBP25 is localized to the nucleus and that a glutathione S-transferase fusion protein of FKBP25 (GST-FKBP25) can be phosphorylated by casein kinase II. Also a stable FKBP25/casein kinase II complex was formed when the GST-FKBP25 fusion protein was incubated either with purified casein kinase II or with cell lysates. Furthermore, when GST-FKBP25 was incubated with nuclear lysates, nucleolin, a major nuclear substrate of casein kinase II, was found associated with the GST-FKBP25/casein kinase II complex. Casein kinase II phosphorylation of several cytosolic and nuclear substrates, including nucleolin, appears to be important for the regulation of cell growth. The interaction of FKBP25 with casein kinase II may regulate these functions.

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  • Harding MW, Galat A, Uehling DE, Schreiber SL. A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature. 1989 Oct 26;341(6244):758–760. [PubMed]
  • Siekierka JJ, Hung SH, Poe M, Lin CS, Sigal NH. A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature. 1989 Oct 26;341(6244):755–757. [PubMed]
  • Schreiber SL. Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science. 1991 Jan 18;251(4991):283–287. [PubMed]
  • Sigal NH, Dumont FJ. Cyclosporin A, FK-506, and rapamycin: pharmacologic probes of lymphocyte signal transduction. Annu Rev Immunol. 1992;10:519–560. [PubMed]
  • Jin YJ, Albers MW, Lane WS, Bierer BE, Schreiber SL, Burakoff SJ. Molecular cloning of a membrane-associated human FK506- and rapamycin-binding protein, FKBP-13. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6677–6681. [PMC free article] [PubMed]
  • Jin YJ, Burakoff SJ, Bierer BE. Molecular cloning of a 25-kDa high affinity rapamycin binding protein, FKBP25. J Biol Chem. 1992 Jun 5;267(16):10942–10945. [PubMed]
  • Hung DT, Schreiber SL. cDNA cloning of a human 25 kDa FK506 and rapamycin binding protein. Biochem Biophys Res Commun. 1992 Apr 30;184(2):733–738. [PubMed]
  • Peattie DA, Harding MW, Fleming MA, DeCenzo MT, Lippke JA, Livingston DJ, Benasutti M. Expression and characterization of human FKBP52, an immunophilin that associates with the 90-kDa heat shock protein and is a component of steroid receptor complexes. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10974–10978. [PMC free article] [PubMed]
  • Liu J, Farmer JD, Jr, Lane WS, Friedman J, Weissman I, Schreiber SL. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807–815. [PubMed]
  • Friedman J, Weissman I. Two cytoplasmic candidates for immunophilin action are revealed by affinity for a new cyclophilin: one in the presence and one in the absence of CsA. Cell. 1991 Aug 23;66(4):799–806. [PubMed]
  • O'Keefe SJ, Tamura J, Kincaid RL, Tocci MJ, O'Neill EA. FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature. 1992 Jun 25;357(6380):692–694. [PubMed]
  • Clipstone NA, Crabtree GR. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature. 1992 Jun 25;357(6380):695–697. [PubMed]
  • Chung J, Kuo CJ, Crabtree GR, Blenis J. Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell. 1992 Jun 26;69(7):1227–1236. [PubMed]
  • Kuo CJ, Chung J, Fiorentino DF, Flanagan WM, Blenis J, Crabtree GR. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature. 1992 Jul 2;358(6381):70–73. [PubMed]
  • Calvo V, Crews CM, Vik TA, Bierer BE. Interleukin 2 stimulation of p70 S6 kinase activity is inhibited by the immunosuppressant rapamycin. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7571–7575. [PMC free article] [PubMed]
  • Price DJ, Grove JR, Calvo V, Avruch J, Bierer BE. Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science. 1992 Aug 14;257(5072):973–977. [PubMed]
  • Sanchez ER, Faber LE, Henzel WJ, Pratt WB. The 56-59-kilodalton protein identified in untransformed steroid receptor complexes is a unique protein that exists in cytosol in a complex with both the 70- and 90-kilodalton heat shock proteins. Biochemistry. 1990 May 29;29(21):5145–5152. [PubMed]
  • Sanchez ER. Hsp56: a novel heat shock protein associated with untransformed steroid receptor complexes. J Biol Chem. 1990 Dec 25;265(36):22067–22070. [PubMed]
  • Yem AW, Tomasselli AG, Heinrikson RL, Zurcher-Neely H, Ruff VA, Johnson RA, Deibel MR., Jr The Hsp56 component of steroid receptor complexes binds to immobilized FK506 and shows homology to FKBP-12 and FKBP-13. J Biol Chem. 1992 Feb 15;267(5):2868–2871. [PubMed]
  • Renoir JM, Radanyi C, Jung-Testas I, Faber LE, Baulieu EE. The nonactivated progesterone receptor is a nuclear heterooligomer. J Biol Chem. 1990 Aug 25;265(24):14402–14406. [PubMed]
  • Lebeau MC, Massol N, Herrick J, Faber LE, Renoir JM, Radanyi C, Baulieu EE. P59, an hsp 90-binding protein. Cloning and sequencing of its cDNA and preparation of a peptide-directed polyclonal antibody. J Biol Chem. 1992 Mar 5;267(7):4281–4284. [PubMed]
  • Tai PK, Albers MW, Chang H, Faber LE, Schreiber SL. Association of a 59-kilodalton immunophilin with the glucocorticoid receptor complex. Science. 1992 May 29;256(5061):1315–1318. [PubMed]
  • Jayaraman T, Brillantes AM, Timerman AP, Fleischer S, Erdjument-Bromage H, Tempst P, Marks AR. FK506 binding protein associated with the calcium release channel (ryanodine receptor). J Biol Chem. 1992 May 15;267(14):9474–9477. [PubMed]
  • Hockenbery D, Nuñez G, Milliman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334–336. [PubMed]
  • Pinna LA. Casein kinase 2: an 'eminence grise' in cellular regulation? Biochim Biophys Acta. 1990 Sep 24;1054(3):267–284. [PubMed]
  • Rihs HP, Jans DA, Fan H, Peters R. The rate of nuclear cytoplasmic protein transport is determined by the casein kinase II site flanking the nuclear localization sequence of the SV40 T-antigen. EMBO J. 1991 Mar;10(3):633–639. [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]
  • Feige JJ, Pirollet F, Cochet C, Chambaz EM. Selective inhibition of a cyclic nucleotide-independent protein kinase (G-type casein kinase) by naturally occurring glycosaminoglycans. FEBS Lett. 1980 Nov 17;121(1):139–142. [PubMed]
  • Lapeyre B, Bourbon H, Amalric F. Nucleolin, the major nucleolar protein of growing eukaryotic cells: an unusual protein structure revealed by the nucleotide sequence. Proc Natl Acad Sci U S A. 1987 Mar;84(6):1472–1476. [PMC free article] [PubMed]
  • Chen CM, Chiang SY, Yeh NH. Increased stability of nucleolin in proliferating cells by inhibition of its self-cleaving activity. J Biol Chem. 1991 Apr 25;266(12):7754–7758. [PubMed]
  • Orrick LR, Olson MO, Busch H. Comparison of nucleolar proteins of normal rat liver and Novikoff hepatoma ascites cells by two-dimensional polyacrylamide gel electrophoresis. Proc Natl Acad Sci U S A. 1973 May;70(5):1316–1320. [PMC free article] [PubMed]
  • Caizergues-Ferrer M, Belenguer P, Lapeyre B, Amalric F, Wallace MO, Olson MO. Phosphorylation of nucleolin by a nucleolar type NII protein kinase. Biochemistry. 1987 Dec 1;26(24):7876–7883. [PubMed]
  • Lüscher B, Kuenzel EA, Krebs EG, Eisenman RN. Myc oncoproteins are phosphorylated by casein kinase II. EMBO J. 1989 Apr;8(4):1111–1119. [PMC free article] [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]
  • Lee CQ, Yun YD, Hoeffler JP, Habener JF. Cyclic-AMP-responsive transcriptional activation of CREB-327 involves interdependent phosphorylated subdomains. EMBO J. 1990 Dec;9(13):4455–4465. [PMC free article] [PubMed]
  • Meek DW, Simon S, Kikkawa U, Eckhart W. The p53 tumour suppressor protein is phosphorylated at serine 389 by casein kinase II. EMBO J. 1990 Oct;9(10):3253–3260. [PMC free article] [PubMed]
  • Lin A, Frost J, Deng T, Smeal T, al-Alawi N, Kikkawa U, Hunter T, Brenner D, Karin M. Casein kinase II is a negative regulator of c-Jun DNA binding and AP-1 activity. Cell. 1992 Sep 4;70(5):777–789. [PubMed]
  • Jordan G. At the heart of the nucleolus. Nature. 1987 Oct 8;329(6139):489–490. [PubMed]
  • Peter M, Nakagawa J, Dorée M, Labbé JC, Nigg EA. Identification of major nucleolar proteins as candidate mitotic substrates of cdc2 kinase. Cell. 1990 Mar 9;60(5):791–801. [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]
  • Nigg EA. Mechanisms of signal transduction to the cell nucleus. Adv Cancer Res. 1990;55:271–310. [PubMed]
  • Freskgård PO, Bergenhem N, Jonsson BH, Svensson M, Carlsson U. Isomerase and chaperone activity of prolyl isomerase in the folding of carbonic anhydrase. Science. 1992 Oct 16;258(5081):466–468. [PubMed]
  • Ellis RJ, van der Vies SM. Molecular chaperones. Annu Rev Biochem. 1991;60:321–347. [PubMed]
  • Ellis J. Protein folding. Cytosolic chaperonin confirmed. Nature. 1992 Jul 16;358(6383):191–191. [PubMed]
  • Miyata Y, Yahara I. The 90-kDa heat shock protein, HSP90, binds and protects casein kinase II from self-aggregation and enhances its kinase activity. J Biol Chem. 1992 Apr 5;267(10):7042–7047. [PubMed]

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