Alternative titles; symbols
HGNC Approved Gene Symbol: FKBP4
Cytogenetic location: 12p13.33 Genomic coordinates (GRCh38) : 12:2,794,970-2,805,423 (from NCBI)
For background information on FK506-binding proteins (FKBPs), see FKBP1A (186945).
Peattie et al. (1992) identified a novel FKBP using an FK506 affinity matrix. By database analysis, 2 murine DNA sequences were identified, and PCR primers to these were used to generate a probe for screening a human placenta cDNA library. A translation of the human cDNA sequence matched the original partial protein sequence, as well as primary sequences for other FKBPs. The predicted protein, FKBP52, has a molecular mass of 52 kD. Northern blot analysis detected FKBP52 transcripts at varying levels in all tissues examined. Peattie et al. (1992) noted that FKBP52 is apparently identical to a 56- to 59-kD protein referred to as p56, p59, or FKBP59 in the literature, and they suggested that phosphorylation of FKBP52 may account for the multiple reported isoforms.
Peattie et al. (1992) showed that FKBP52 associated with the 90-kD heat shock protein (see HSP90A; 140571) in untransformed mammalian steroid receptor complexes.
FKBP52 is a 'macro' immunophilin that shares high structural and functional homologies in its N-terminal domain with FKBP12 (FKBP1A; 186945). Unlike FKBP12, however, it does not have immunosuppressant activity when complexed with FK506. To investigate the physiologic function of FKBP52, Chambraud et al. (1999) used the yeast 2-hybrid system as an approach to find its potential protein partners and its cellular role. They detected an FKBP-associated protein, which by sequencing was identified as phytanoyl-CoA alpha-hydroxylase (PHYH; 602026), a peroxisomal enzyme. Inactivation of this enzyme is responsible for Refsum disease (266500) in humans. Chambraud et al. (1999) showed that PHYH has the physical capacity to interact with the FKBP12-like domain of FKBP52, but not with FKBP12, suggesting that it is a particular and specific target of FKBP52. Whereas the binding of calcineurin (114105) to FKBP12 is potentiated by FK506, the specific association of PHYH and FKBP52 is maintained in the presence of FK506. These observations suggested that PHYH is a serious candidate for studying the cellular signaling pathway(s) involving FKBP52 in the presence of immunosuppressant drugs.
Fusco et al. (2010) demonstrated that RET51 (see 164761) activation by both glial cell line-derived neurotrophic factor (GDNF; 600837) and NGF (162030) triggers the formation of a RET51-FKBP52 complex. Substitution of tyrosine-905 in RET51, a key residue phosphorylated by both GDNF and NGF, disrupted the RET51-FKBP52 complex. NGF and GDNF have a functional role in dopaminergic neurons, where RET51 and FKBP52 are expressed. To clarify the contribution of the RET51-FKBP52 complex in dopaminergic neurons, Fusco et al. (2010) screened both genes in 30 patients with Parkinson disease (PD; 168600), in which dopaminergic neurons are selectively lost. In 1 individual with early-onset PD, the authors found heterozygous mutations in each gene, which together were sufficient to disrupt the RET51-FKBP52 complex.
Cheung-Flynn et al. (2005) found that male and female Fkbp52 -/- mice were infertile. Male infertility in Fkbp52 -/- mice was due to compromised androgen receptor (AR; 313700) function.
Tranguch et al. (2005) found that, in contrast to female progesterone receptor (Pgr; 607311) -/- mice, female Fkbp52 -/- mice had no ovulation defect. Gross and histopathologic analysis showed that Fkbp52 -/- uteri were completely nonreceptive to blastocyst implantation. In situ hybridization analysis in wildtype mice showed that Fkbp52 and Pgr expression overlapped in uterine stroma, but Fkbp52 was also expressed in luminal and glandular epithelium. Uterine refractoriness in Fkbp52 -/- mice was not due to altered expression of Pgr, for which Fkbp52 is a cochaperone, or Fkbp51 (FKBP5; 602623). However, Pgr activity was not optimal in Fkbp52 -/- mice, suggesting that the implantation defect was due to compromised progesterone function. Northern blot and in situ hybridization analyses showed downregulated expression of progesterone-responsive genes in Fkbp52 -/- uteri. Tranguch et al. (2005) concluded that FKBP52 is a critical determinant of uterine progesterone actions in preparing the uterus for blastocyst implantation.
Tranguch et al. (2007) demonstrated implantation failure in female Fkbp52-null C57BL6/129 and CD1 mice. Progesterone supplementation rescued implantation and decidualization in CD1, but not C57BL6/129, Fkbp52-null females. Experimentally-induced decidualization in the absence of blastocysts failed in Fkbp52-null females on either background even with progesterone supplementation, suggesting that embryonic signaling complements uterine signaling for this event. In Fkbp52-null CD1 females, administration of progesterone at higher than normal pregnancy levels was sufficient for implantation but failed to maintain pregnancy to full term; elevating progesterone levels further resulted in successful term pregnancy with normal litter size. Tranguch et al. (2007) concluded that the requirement for FKBP52 in uterine progesterone/PGR signaling is a function of genetic disparity and is pregnancy-stage specific.
Chen et al. (2010) stated that male mice with targeted ablation of Fkbp52 develop hypospadias. They found that Fkbp52 expression was enriched in the ventral aspect of the developing mouse urethral epithelium at embryonic day 18.5, when the final urethra normally forms via closure of the enveloping epithelial layers. Scanning electron microscopy revealed that Fkbp52 -/- males had reduced elevation of prepucial swelling, leading to a defect in urethral seam formation. In situ hybridization and immunohistochemical analysis suggested that Fkbp52 mutants had a normal urethral epithelium signaling center and epithelial differentiation, but Fkbp52 mutant ventral epithelial cells had a reduced apoptotic cell index at the site of fusion and a defect in genital mesenchymal cell migration in vitro. Supplementation of gestating females with excess testosterone partially rescued the phenotype. Chromatin immunoprecipitation analysis revealed normal occupancy of Ar at Ar-responsive gene promoters, but reduced Ar activity at genes controlling sexual dimorphism and cell growth was observed. Chen et al. (2010) concluded that Fkbp52 functions downstream of Ar in urethra morphogenesis.
Chambraud, B., Radanyi, C., Camonis, J. H., Rajkowski, K., Schumacher, M., Baulieu, E.-E. Immunophilins, Refsum disease, and lupus nephritis: the peroxisomal enzyme phytanoyl-CoA alpha-hydroxylase is a new FKBP-associated protein. Proc. Nat. Acad. Sci. 96: 2104-2109, 1999. [PubMed: 10051602] [Full Text: https://doi.org/10.1073/pnas.96.5.2104]
Chen, H., Yong, W., Hinds, T. D., Jr., Yang, Z., Zhou, Y., Sanchez, E. R., Shou, W. Fkbp52 regulates androgen receptor transactivation activity and male urethra morphogenesis. J. Biol. Chem. 285: 27776-27784, 2010. [PubMed: 20605780] [Full Text: https://doi.org/10.1074/jbc.M110.156091]
Cheung-Flynn, J., Prapapanich, V., Cox, M. B., Riggs, D. L., Suarez-Quian, C., Smith, D. F. Physiological role for the cochaperone FKBP52 in androgen receptor signaling. Molec. Endocr. 19: 1654-1666, 2005. [PubMed: 15831525] [Full Text: https://doi.org/10.1210/me.2005-0071]
Fusco, D., Vargiolu, M., Vidone, M., Mariani, E., Pennisi, L. F., Bonora, E., Capellari, S, Dirnberger, D., Baumeister, R., Martinelli, P., Romeo, G. The RET51/FKBP52 complex and its involvement in Parkinson disease. Hum. Molec. Genet. 19: 2804-2816, 2010. [PubMed: 20442138] [Full Text: https://doi.org/10.1093/hmg/ddq181]
Peattie, D. A., Harding, M. W., Fleming, M. A., DeCenzo, M. T., Lippke, J. A., Livingston, D. J., 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. Nat. Acad. Sci. 89: 10974-10978, 1992. [PubMed: 1279700] [Full Text: https://doi.org/10.1073/pnas.89.22.10974]
Tranguch, S., Cheung-Flynn, J., Daikoku, T., Prapapanich, V., Cox, M. B., Xie, H., Wang, H., Das, S. K., Smith, D. F., Dey, S. K. Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation. Proc. Nat. Acad. Sci. 102: 14326-14331, 2005. [PubMed: 16176985] [Full Text: https://doi.org/10.1073/pnas.0505775102]
Tranguch, S., Wang, H., Daikoku, T., Xie, H., Smith, D. F., Dey, S. K. FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific. J. Clin. Invest. 117: 1824-1834, 2007. [PubMed: 17571166] [Full Text: https://doi.org/10.1172/JCI31622]