Disease relevance of Fkbp4

• To gain insight into the structure and function of the immunophilin FKBP-52, a mouse FKBP-52 was overexpressed in Spodoptera frugiperda insect cells (Sf9 cells) with the baculovirus expression system [1].
• Production of mouse p59 using recombinant vaccinia viruses resulted in a protein with the expected size of 59 kDa that can interact with the recombinant glucocorticoid receptor, as shown by co-immunoprecipitation experiments [2].
• Early decrease of the immunophilin FKBP 52 in the spinal cord of a transgenic model for amyotrophic lateral sclerosis [3].
• No apparent difference in the FKBP52 expression was detected in healthy controls, mild or severe hypospadias patients [4].
• Fractionation of differentiating murine teratocarcinoma F9 cells and extraction of the nuclear/microsomal pellets with ethidium bromide led to the purification and microsequencing of the protein mCyP-S1, a novel cyclosporin A-sensitive peptidyl-prolyl cis-trans isomerase (PPIase). mCyP-S1 is a new member of the cyclophilin class of proteins [5].

High impact information on Fkbp4

• In addition, they raise doubts about whether PPIase has a direct function in lymphocyte signal transduction [6].
• First, we address whether the major cytosolic protein for CsA, cyclophilin, is directly involved in mediating the immunosuppressive activity of this drug, and, in particular, whether inhibition of this protein's peptidyl-prolyl cis-trans isomerase (PPIase) activity results in inhibition of murine T cell activation [6].
• Deficiency of Src family kinases p59/61hck and p58c-fgr results in defective adhesion-dependent neutrophil functions [7].
• The immunophilin FKBP52 serves as a cochaperone for steroid hormone nuclear receptors to govern appropriate hormone action in target tissues [8].
• This immunophilin has unique spatiotemporal expression in the uterus during implantation, and females missing the Fkbp52 gene have complete implantation failure due to lack of attainment of uterine receptivity [8].

Biological context of Fkbp4

• Using the proteomics approach of difference gel electrophoresis, we have identified an immunophilin FKBP52 (FK506 binding protein 4) as one of the Hoxa10-mediated signaling molecules in the uterus [9].
• Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation [8].
• A virtual combinatorial library composed of diverse combinations of two substituted groups was constructed using Project Library, followed by an automated screening of the library against the ligand binding site on FKBP52 using DOCK [10].
• However, FKBP52 and AR are similarly coexpressed in testis even though testis morphology and spermatogenesis in 52KO males are usually normal [11].
• The 59 kDa FK506-binding protein, a 90 kDa heat shock protein binding immunophilin (FKBP59-HBI), is associated with the nucleus, the cytoskeleton and mitotic apparatus [12].

Anatomical context of Fkbp4

• Furthermore, FKBP52 shows differential cell-specific expression in the uterus in response to progesterone and/or estrogen consistent with its expression patterns during the periimplantation period [9].
• We found that FKBP52, a cochaperone protein known to influence steroid hormone receptor functions, is down-regulated in stromal cells of Hoxa10-/- mice [9].
• A cDNA encoding the homologue of the rabbit immunophilin p59 was cloned from a mouse NIH-3T3 cell line library [2].
• Second, we ask whether the nephrotoxicity observed with CsA is related to inhibition of PPIase-dependent pathways in cells other than lymphocytes [6].
• Interestingly, during mitosis FKBP59-HBI segregated from the region of the chromosomes; it mainly localized with the mitotic apparatus (centrosome, spindle and interzone separating the chromosomes), the cleavage furrow and the midbodies during cytokinesis [12].

Associations of Fkbp4 with chemical compounds

• FKBP52 (-/-) females are sterile due to a complete failure of implantation, a process that requires estrogen (ER) and progesterone receptors (PR) [13].
• These studies corroborate the fact that tyrosine phosphorylation of the cellular FKBP52 protein strongly influences AAV transduction efficiency, which may have important implications in the optimal use of AAV vectors in human gene therapy [14].
• FKBP52 can be phosphorylated at both tyrosine and serine/threonine residues, but only the phosphorylated forms of FKBP52 interact with the D sequence [14].
• However, when mice were pretreated with cyclophosphamide, p65 primed for a strong DTH response to a level similar to that induced by p59 in mice either pretreated or not treated with cyclophosphamide [15].
• Intracellular distribution of a cytoplasmic progesterone receptor mutant and of immunophilins cyclophilin 40 and FKBP59: effects of cyclosporin A, of various metabolic inhibitors and of several culture conditions [16].

Regulatory relationships of Fkbp4

• Anti-ATF-2 immunoprecipitates from control and DADLE-treated splenocytes showed a dominant 59kDa phosphorylated band and a 71kDa band [17].
• Fkbp51 expression was down-regulated in Fkbp52-deficient males but only in affected tissues, providing further evidence of tissue-specific loss of AR activity and suggesting that Fkbp51 is an AR target gene essential to penile and prostate development [18].

Other interactions of Fkbp4

• More importantly, FKBP52 shows differential uterine cell-specific expression during the periimplantation period [9].
• While FKBP52 had no effect on PPARalpha activity, p23 greatly enhanced constitutive and Wy14 643 induced PPRE-reporter activity [19].
• We demonstrate that the FKBP46 does not form a complex with the FKBP52 but rather with the highly basic nuclear protein TP2 [20].
• Recently, we identified a 59-kDa nuclear phosphoprotein that is associated with a recombinant mouse FKBP-52 (Alnemri, E. S., Fernandes-Alnemri, T., Nelki, D. S., Dudley, K., DuBois, G. C., and Litwack, G. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 6839-6843) [20].
• FKBP52 is a steroid receptor-associated immunophilin that binds via a tetratricopeptide repeat (TPR) domain to hsp90 [21].

Analytical, diagnostic and therapeutic context of Fkbp4

• Sequence analysis of one identified clone showed it to be identical to the Drosophila homolog of human FK506-binding protein, FKBP52 (previously known as FKBP59) [22].
• Two polyclonal antipeptide antibodies directed against the C-terminal end (amino acids 441-458) (Ab 173) or the sequence 182-201 (Ab 790) of the FKBP59-HBI were used in light and confocal laser immunofluorescence [12].
• Ribonuclease protection assay and Western blot analysis revealed that p59 is the predominant C9 isoform in rat VP [23].
• Northern blot analysis demonstrated that the three clones, p59 (A), p2 (B1) and p16 (B2) hybridized to mRNA species 9.8, 6.0, and 8.0 kb in length, respectively [24].
• Effects of immunosuppressive peptidyl-prolyl cis-trans isomerase (PPIase) inhibitors, cyclosporin A, FK506, ascomycin and rapamycin, on hair growth initiation in mouse: immunosuppression is not required for new hair growth [25].

References