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FKBP4  -  FK506 binding protein 4, 59kDa

Homo sapiens

Synonyms: 51 kDa FK506-binding protein, 52 kDa FK506-binding protein, 52 kDa FKBP, 59 kDa immunophilin, FK506-binding protein 4, ...
 
 
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Disease relevance of FKBP4

  • We amplified a murine cDNA fragment, used it to select a human FKBP52 (hFKBP52) cDNA clone, and then used the clone to deduce the hFKBP52 sequence (calculated M(r) 51,810) and to express hFKBP52 in Escherichia coli [1].
  • The use of cycloheximide to inhibit protein synthesis revealed that in comparison to MCF-7 cells cultured at 37 degrees C, those exposed to heat stress (42 degrees C for 3 hours) displayed an elevated rate of degradation of both CyP40 and FKBP52 proteins [2].
  • No sequence variants in the FKBP4 gene have implicated in hypospadias in our study [3].
  • Taken together, our present findings suggest that FKBP52 is a component of the copper efflux machinery, and in so, may also promote neuroprotection from copper toxicity [4].
  • Adeno-associated virus type 2-mediated gene transfer: role of cellular FKBP52 protein in transgene expression [5].
 

Psychiatry related information on FKBP4

 

High impact information on FKBP4

  • These results reveal a complex role for p52 as regulator of cell proliferation and p53 transcriptional activity [6].
  • Regulation of p53 tumour suppressor target gene expression by the p52 NF-kappaB subunit [6].
  • The mechanism for potentiation is an increase in GR hormone-binding affinity that requires both the Hsp90-binding ability and the prolyl isomerase activity of FKBP52 [7].
  • FKBP52 selectively potentiates hormone-dependent reporter gene activation by as much as 20-fold at limiting hormone concentrations, and this potentiation is readily blocked by co-expression of the closely related FKBP51 [7].
  • The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo [7].
 

Chemical compound and disease context of FKBP4

  • In human neuroblastoma SH-SY5Y cells, the neurotrophic action of FK506 (10 pM to 10 nM) is completely prevented by the addition of a monoclonal antibody (50-100 nM) to the immunophilin FKBP-52 (also known as FKBP-59 or heat shock protein 56), a component of mature steroid receptor complexes [8].
  • Studies were therefore initiated to investigate the influence of estradiol on CyP40 and FKBP52 expression in MCF-7 breast cancer cells [9].
  • The analysis revealed that the 52 kDa FK506 binding protein, Rho G-protein dissociation inhibitor (RhoGDI), and glyoxalase I are found to be uniquely overexpressed in invasive human ovarian cancer when compared to the LMP form of this cancer [10].
 

Biological context of FKBP4

  • This region contains a CAAT motif sequence and consensus binding sites for Sp1, heat-shock factor, and MYC-MAX, which are conserved in the rabbit FKBP4 promoter and, when deleted, dramatically reduced promoter activity in T-47D cells [11].
  • The immunophilin FKBP4 (FKBP52/FKBP59) maps to the distal short arm of human chromosome 12 [12].
  • Recombinant hFKBP52 has peptidyl-prolyl cis-trans isomerase activity that is inhibited by FK506 and rapamycin and an FKBP12-like consensus sequence that probably defines the immunosuppressant-binding site [1].
  • The wFKBP73 interacts transiently with non-native CS and slows down its inactivation kinetics, whereas the mammalian homologue, hFKBP52 binds tightly to CS and does not affect its rate of inactivation [13].
  • Specific antibodies showed that the open reading frame encodes a heat-induced 77-kD protein, the wheat FKBP77 (wFKBP77), which exhibits 84% identity with the wFKBP73 and 42% identity with the human FKBP59 [14].
 

Anatomical context of FKBP4

  • Approximately 3.5 kb of 5'-flanking DNA of FKBP4 was subcloned into a luciferase reporter vector and was found to exhibit robust activity in T-47D, MCF7, and COS-7 cells [11].
  • In HeLa cell extracts, a 55-kDa FK506-binding protein, distinct from FKBP52, cross-reacts with anti-p54 antibody FF1 [15].
  • Approximately one-half of the GR.hsp90 heterocomplexes in L cell cytosol contains an immunophilin with high affinity FK506 binding activity, such as FKBP51 or FKBP52, and approximately 35% contains PP5 [16].
  • CONCLUSION: FKBP52 is likely to play a role in growth and development of the male genitalia, since it is expressed in the genital skin of prepubertal boys; however alterations in the sequence and in the expression of the FKBP4 gene are not a common cause of non-syndromic hypospadias [3].
  • Inhibition of movement by the FKBP52 PPIase domain is abrogated in cells treated with colcemid to eliminate microtubules prior to steroid addition [17].
 

Associations of FKBP4 with chemical compounds

  • 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 [1].
  • The interaction between FKBP52 and Atox1 was observed in both glutathione S-transferase pull-down experiments and when proteins were ectopically expressed in human embryonic kidney (HEK) 293T cells and was sensitive to FK506 [4].
  • The purified protein could be phosphorylated at both tyrosine and serine or threonine residues, and only the phosphorylated forms of FKBP52 were shown to interact with the AAV single-stranded D-sequence probe [5].
  • Serine- or threonine-phosphorylated FKBP52 caused approximately 40% inhibition, whereas dephosphorylated FKBP52 had no effect on AAV second-strand DNA synthesis [5].
  • The interaction of the immunophilin domain of FKBP59 (FKBP59-I) with immunosuppressant drugs was investigated by steady-state and time-resolved fluorescence of tryptophan [18].
 

Physical interactions of FKBP4

  • FAP48 was identified and cloned thanks to its interaction with FK506-binding proteins (FKBPs) such as FKBP52 and FKBP12, which belong to the large family of immunophilins that bind the macrolide immunosuppressant drugs FK506 and rapamycin [19].
  • The purpose of the present study was to determine if mammalian FKBP12 or FKBP52 interact with TRPC channel proteins [20].
  • We have identified a human gene encoding a 48-kDa protein that specifically interacts with the peptidyl prolyl isomerase FK506-binding protein 59 (FKBP59) and also with the well known FKBP12 [21].
  • The Hsp56 component of steroid receptor complexes binds to immobilized FK506 and shows homology to FKBP-12 and FKBP-13 [22].
  • Hsp56 is known to bind to hsp90, but its potential site, or sites, of interaction with the receptor are undefined [23].
 

Regulatory relationships of FKBP4

  • FKBP52 is a widely expressed FK506-binding immunophilin that possesses peptidylprolyl isomerase activity and a tetratricopeptide repeat involved in protein-protein interaction [11].
  • The immunophilin FKBP52 inhibits the activity of the epithelial Ca2+ channel TRPV5 [24].
 

Other interactions of FKBP4

  • Whereas the binding of calcineurin to FKBP12 is potentiated by FK506, the specific association of PAHX and FKBP52 is maintained in the presence of FK506 [25].
  • This observation suggests that PAHX is a serious candidate for studying the cellular signaling pathway(s) involving FKBP52 in the presence of immunosuppressant drugs [25].
  • Elevated levels of FKBP52 per se showed no effect but mitigated the inhibition of the receptor induced by FKBP51 [26].
  • The unliganded mineralocorticoid receptor is associated with heat shock proteins 70 and 90 and the immunophilin FKBP-52 [27].
  • We show here that p50, but not p54, cross-reacts with a rabbit antiserum prepared against human FKBP52 [15].
 

Analytical, diagnostic and therapeutic context of FKBP4

References

  1. 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. Peattie, D.A., Harding, M.W., Fleming, M.A., DeCenzo, M.T., Lippke, J.A., Livingston, D.J., Benasutti, M. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  2. Human cyclophilin 40 is a heat shock protein that exhibits altered intracellular localization following heat shock. Mark, P.J., Ward, B.K., Kumar, P., Lahooti, H., Minchin, R.F., Ratajczak, T. Cell Stress Chaperones (2001) [Pubmed]
  3. Studies of a co-chaperone of the androgen receptor, FKBP52, as candidate for hypospadias. Beleza-Meireles, A., Barbaro, M., Wedell, A., Töhönen, V., Nordenskjöld, A. Reprod. Biol. Endocrinol. (2007) [Pubmed]
  4. A novel role for the immunophilin FKBP52 in copper transport. Sanokawa-Akakura, R., Dai, H., Akakura, S., Weinstein, D., Fajardo, J.E., Lang, S.E., Wadsworth, S., Siekierka, J., Birge, R.B. J. Biol. Chem. (2004) [Pubmed]
  5. Adeno-associated virus type 2-mediated gene transfer: role of cellular FKBP52 protein in transgene expression. Qing, K., Hansen, J., Weigel-Kelley, K.A., Tan, M., Zhou, S., Srivastava, A. J. Virol. (2001) [Pubmed]
  6. Regulation of p53 tumour suppressor target gene expression by the p52 NF-kappaB subunit. Schumm, K., Rocha, S., Caamano, J., Perkins, N.D. EMBO J. (2006) [Pubmed]
  7. The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo. Riggs, D.L., Roberts, P.J., Chirillo, S.C., Cheung-Flynn, J., Prapapanich, V., Ratajczak, T., Gaber, R., Picard, D., Smith, D.F. EMBO J. (2003) [Pubmed]
  8. Immunophilin FK506-binding protein 52 (not FK506-binding protein 12) mediates the neurotrophic action of FK506. Gold, B.G., Densmore, V., Shou, W., Matzuk, M.M., Gordon, H.S. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  9. Estradiol-regulated expression of the immunophilins cyclophilin 40 and FKBP52 in MCF-7 breast cancer cells. Kumar, P., Mark, P.J., Ward, B.K., Minchin, R.F., Ratajczak, T. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  10. Proteomic analysis and identification of new biomarkers and therapeutic targets for invasive ovarian cancer. Jones, M.B., Krutzsch, H., Shu, H., Zhao, Y., Liotta, L.A., Kohn, E.C., Petricoin, E.F. Proteomics (2002) [Pubmed]
  11. Organization of the human FK506-binding immunophilin FKBP52 protein gene (FKBP4). Scammell, J.G., Hubler, T.R., Denny, W.B., Valentine, D.L. Genomics (2003) [Pubmed]
  12. The immunophilin FKBP4 (FKBP52/FKBP59) maps to the distal short arm of human chromosome 12. Bermingham, N.A., Rauf, S., Katsanis, N., Martin, J.E., Hunter, A.J., Fisher, E.M. Mamm. Genome (1998) [Pubmed]
  13. Wheat FKBP73 functions in vitro as a molecular chaperone independently of its peptidyl prolyl cis-trans isomerase activity. Kurek, I., Pirkl, F., Fischer, E., Buchner, J., Breiman, A. Planta (2002) [Pubmed]
  14. The wheat peptidyl prolyl cis-trans-isomerase FKBP77 is heat induced and developmentally regulated. Kurek, I., Aviezer, K., Erel, N., Herman, E., Breiman, A. Plant Physiol. (1999) [Pubmed]
  15. FKBP54, a novel FK506-binding protein in avian progesterone receptor complexes and HeLa extracts. Smith, D.F., Albers, M.W., Schreiber, S.L., Leach, K.L., Deibel, M.R. J. Biol. Chem. (1993) [Pubmed]
  16. Protein phosphatase 5 is a major component of glucocorticoid receptor.hsp90 complexes with properties of an FK506-binding immunophilin. Silverstein, A.M., Galigniana, M.D., Chen, M.S., Owens-Grillo, J.K., Chinkers, M., Pratt, W.B. J. Biol. Chem. (1997) [Pubmed]
  17. Evidence that the peptidylprolyl isomerase domain of the hsp90-binding immunophilin FKBP52 is involved in both dynein interaction and glucocorticoid receptor movement to the nucleus. Galigniana, M.D., Radanyi, C., Renoir, J.M., Housley, P.R., Pratt, W.B. J. Biol. Chem. (2001) [Pubmed]
  18. Immunosuppressor binding to the immunophilin FKBP59 affects the local structural dynamics of a surface beta-strand: time-resolved fluorescence study. Rouviere, N., Vincent, M., Craescu, C.T., Gallay, J. Biochemistry (1997) [Pubmed]
  19. The FKBP-associated protein FAP48 is an antiproliferative molecule and a player in T cell activation that increases IL2 synthesis. Krummrei, U., Baulieu, E.E., Chambraud, B. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  20. Association of immunophilins with mammalian TRPC channels. Sinkins, W.G., Goel, M., Estacion, M., Schilling, W.P. J. Biol. Chem. (2004) [Pubmed]
  21. FAP48, a new protein that forms specific complexes with both immunophilins FKBP59 and FKBP12. Prevention by the immunosuppressant drugs FK506 and rapamycin. Chambraud, B., Radanyi, C., Camonis, J.H., Shazand, K., Rajkowski, K., Baulieu, E.E. J. Biol. Chem. (1996) [Pubmed]
  22. The Hsp56 component of steroid receptor complexes binds to immobilized FK506 and shows homology to FKBP-12 and FKBP-13. Yem, A.W., Tomasselli, A.G., Heinrikson, R.L., Zurcher-Neely, H., Ruff, V.A., Johnson, R.A., Deibel, M.R. J. Biol. Chem. (1992) [Pubmed]
  23. The hsp56 immunophilin component of steroid receptor heterocomplexes: could this be the elusive nuclear localization signal-binding protein? Pratt, W.B., Czar, M.J., Stancato, L.F., Owens, J.K. J. Steroid Biochem. Mol. Biol. (1993) [Pubmed]
  24. The immunophilin FKBP52 inhibits the activity of the epithelial Ca2+ channel TRPV5. Gkika, D., Topala, C.N., Hoenderop, J.G., Bindels, R.J. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  25. Immunophilins, Refsum disease, and lupus nephritis: the peroxisomal enzyme phytanoyl-COA alpha-hydroxylase is a new FKBP-associated protein. Chambraud, B., Radanyi, C., Camonis, J.H., Rajkowski, K., Schumacher, M., Baulieu, E.E. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  26. FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. Wochnik, G.M., Rüegg, J., Abel, G.A., Schmidt, U., Holsboer, F., Rein, T. J. Biol. Chem. (2005) [Pubmed]
  27. The unliganded mineralocorticoid receptor is associated with heat shock proteins 70 and 90 and the immunophilin FKBP-52. Bruner, K.L., Derfoul, A., Robertson, N.M., Guerriero, G., Fernandes-Alnemri, T., Alnemri, E.S., Litwack, G. Receptors & signal transduction. (1997) [Pubmed]
  28. Crystallization and preliminary crystallographic studies of the C-terminal domain of human FKBP52. Wu, B., Li, P., Shu, C., Shen, B., Rao, Z. Acta Crystallogr. D Biol. Crystallogr. (2003) [Pubmed]
  29. Three-step purification of a fragment of the large immunophilin FKBP52. Pirkl, F. J. Chromatogr. B Biomed. Sci. Appl. (2000) [Pubmed]
  30. Neuroimmunophilin ligands: evaluation of their therapeutic potential for the treatment of neurological disorders. Gold, B.G. Expert opinion on investigational drugs. (2000) [Pubmed]
  31. Cloning and characterization of p52, the fifth subunit of the core of the transcription/DNA repair factor TFIIH. Marinoni, J.C., Roy, R., Vermeulen, W., Miniou, P., Lutz, Y., Weeda, G., Seroz, T., Gomez, D.M., Hoeijmakers, J.H., Egly, J.M. EMBO J. (1997) [Pubmed]
 
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