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The Hsp90‐binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo
Open accessAbstract
Hsp90 is required for the normal activity of steroid receptors, and in steroid receptor complexes it is typically bound to one of the immunophilin-related co-chaperones: the peptidylprolyl isomerases FKBP51, FKBP52 or CyP40, or the protein phosphatase PP5. The physiological roles of the immunophilins in regulating steroid receptor function have not been well defined, and so we examined in vivo the influences of immunophilins on hormone-dependent gene activation in the Saccharomyces cerevisiae model for glucocorticoid receptor (GR) function. 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. 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.
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“Previous studies in yeast demonstrated that FKBP52 binding to Hsp90 is required for regulation of AR activity [7].”
From The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling (2015) · cites this paper as [7]
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“In contrast, FKBP52 enhances GR, PR, and AR responsiveness to cognate hormone (28).”
From FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells (2010) · cites this paper as [28]
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“While FKBP52 is known to functionally interact with AR, GR and PR [6–8], β-catenin only interacts strongly with AR, but not GR and PR [20].”
From The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling (2015) · cites this paper as [7]
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In the citing paper
“FKBP51 inhibits GR ligand binding, nuclear translocation and transcriptional activity, while FKBP52 potentiates each of these fundamental GR activities22–32.”
From Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the glucocorticoid receptor (2023) · cites this paper as [23]
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“unlike FKBP52, FKBP51 does not enhance GR ligand binding in vitro, consistent with in vivo studies23,27,29.”
From Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the glucocorticoid receptor (2023) · cites this paper as [23]
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“Thus, the relative concentrations of FKBP51 and FKBP52 in the cell dictate the level of GR activity in vivo23,28,55.”
From Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the glucocorticoid receptor (2023) · cites this paper as [23]
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“The co-expression of FKBP52 (K354A), which completely lacks Hsp90 binding [7], with β-catenin (S33A) also resulted in the synergistic up-regulation of AR-mediated luciferase reporter expression comparable to that observed with wild type FKBP52 both in the presence and absence of hormone (Fig 5B).”
From The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling (2015) · cites this paper as [7]
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“However, FKBP51 does not potentiate GR ligand binding in any of these conditions, unlike FKBP52, recapitulating in vivo findings23,29.”
From Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the glucocorticoid receptor (2023) · cites this paper as [23]
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“strongly suggesting FKBP52 potentiates the GR ligand binding affinity beyond the minimal chaperone mixture, consistent with reports in vivo23.”
From Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the glucocorticoid receptor (2023) · cites this paper as [23]
In the citing paper
“FKBP52 is a positive regulator of glucocorticoid receptor (GR) [5], progesterone receptor (PR) [6], and androgen receptor (AR) [7], but not estrogen receptor (ER) or mineralocorticoid receptor (MR) [5].”
From FKBP51 and FKBP52 in signaling and disease (2011) · cites this paper as [5]
In the citing paper
“The fact that FKBP52 regulation has been localized to the receptor ligand binding domain (LBD) [5, 15] suggests that the FK1 interaction partner is the receptor LBD.”
From FKBP51 and FKBP52 in signaling and disease (2011) · cites this paper as [5]
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“The FK1 domain facilitates binding to the immunosuppressive drug FK506, confers PPIase activity [3], and is the primary regulatory domain for SHRs [5].”
From FKBP51 and FKBP52 in signaling and disease (2011) · cites this paper as [5]
In the citing paper
“The FKBPs compete for binding to the SHR complex and, as a result, overexpression of FKBP51 decreases receptor regulation by FKBP52 [5]”
From FKBP51 and FKBP52 in signaling and disease (2011) · cites this paper as [5]
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“The FK1 domain is deemed critical for receptor potentiation by FKBP52 [5], but its enzymatic activity is not required for this potentiation. Domain integrity in and around the PPIase pocket is essential [9].”
From FKBP51 and FKBP52 in signaling and disease (2011) · cites this paper as [5]
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Citations
Cites
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Self-citationSteroid Receptor Interactions with Heat Shock Protein and Immunophilin Chaperones
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Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)‐domain co‐chaperones
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Chaperone Function of Hsp90-Associated Proteins
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Cited by
Sorted by citations
HSP90 at the hub of protein homeostasis: emerging mechanistic insights
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“These functions seem to be dispensable for client activation in at least one case (that of FKBP52 -dependent potentiation of glucocorticoid receptor functio”
BackgroundPathways of chaperone-mediated protein folding in the cytosol
Young, J. C., Agashe, V. R., Siegers, K., & Hartl, F. U. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1492 · Cited by 1,121
“pl?Q02790">FKB4 ), which is an immunophilin with peptidyl-prolyl cis – trans isomerase activity and a TPR-clamp domain, replaces HOP on HSP90 at this stage and enhances receptor foldin”
BackgroundZhao, R., Davey, M., Hsu, Y.-C., Kaplanek, P., Tong, A., Parsons, A. B., Krogan, N., Cagney, G., Mai, D., Greenblatt, J., et al. (2005) · Cell · doi:10.1016/j.cell.2004.12.024 · Cited by 819
“For the GR maturation assay, the trains were transformed with a plasmid expressing GR nder the control of a constitutive promoter along with reporter plasmid in which the expression of lacZ reorter gene was placed under the control of a GResponse element (GRE) (Riggs et al., 2003).”
MethodThe Aryl Hydrocarbon Receptor Complex and the Control of Gene Expression
Beischlag, T. V., Morales, J. L., Hollingshead, B. D., & Perdew, G. H. (2008) · Critical Reviews™ in Eukaryotic Gene Expression · doi:10.1615/critreveukargeneexpr.v18.i3.20 · Cited by 727
“Interestingly, although they are closely related proteins, FKBP51 acts as a repressor of the GR, whereas the presence of FKBP52 in the GR complex enhances receptor transcriptional activity.(165,166) Also, it has been suggested that hormone binding to the GR stimulates the switching of the binding status of receptor fr…”
BackgroundWochnik, G. M., Rüegg, J., Abel, G. A., Schmidt, U., Holsboer, F., & Rein, T. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m407498200 · Cited by 638
A General Introduction to Glucocorticoid Biology
Timmermans, S., Souffriau, J., & Libert, C. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01545 · Cited by 619
“After GC-binding the GRchaperone complex again reorganizes (FKBP51 is replaced by FKBP52) and a GR conformational change is induced, leading to the exposure of the GR’s 2 nuclear localization signals (103).”
BackgroundHsp70 and Hsp90—a relay team for protein folding
Wegele, H., Müller, L., & Büchner, J. (2004) · Springer eBooks · doi:10.1007/s10254-003-0021-1 · Cited by 609
The Hsp90 chaperone machinery: Conformational dynamics and regulation by co-chaperones
Li, J., Soroka, J., & Buchner, J. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.09.003 · Cited by 498
Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility
Gjerstad, J. K., Lightman, S. L., & Spiga, F. (2018) · Stress · doi:10.1080/10253890.2018.1470238 · Cited by 437
“In their inactive state, GR and MR are predominately found in the cytosol, bound to chaperone proteins including the heat shock proteins hsp90, hsp70 and hsp23, and to immunophilins belonging to the FK506 binding-protein family, including FKBP51 and FKBP52 (encoded by the fkbp5 and fkbp4 genes, respectively; (Echeverr…”
BackgroundInfluentialThe glucocorticoid responses are shaped by molecular chaperones
Grad, I., & Picard, D. (2007) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2007.05.018 · Cited by 423
Self-citationStructure, Function and Regulation of the Hsp90 Machinery
Büchner, J., & Li, J. (2013) · Biomedical Journal · doi:10.4103/2319-4170.113230 · Cited by 433
“For example, Cyp40 is most abundant in estrogen receptor (ER) complexes([51]) and Fkbp52 mediates potentiation of GR through increasing GR hormone‐binding affinity.([34]) Interestingly, the potentiation effects do not strictly depend on the PPIase ac‐ tivity of Fkbp52 as PPIase‐deficient mutants are also able to poten…”
BackgroundMore than folding: localized functions of cytosolic chaperones
Young, J. C., Barral, J. M., & Hartl, F. U. (2003) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2003.08.009 · Cited by 372
“Recent work with S. cerevisiae, using heterologously expressed glucocorticoid receptor, suggests that this interaction might not be necessary for nuclear transport [ 51 ], but dynein binding might still increase the transport efficiency in mammalian cells.”
BackgroundJackson, S. (2012) · Topics in current chemistry · doi:10.1007/128_2012_356 · Cited by 347
“In general, FKBP52 is a positive regulator of SR action (with the possible exception of the ER) [259–262], whilst FKBP51 tends to have inhibitory effects despite being structurally very similar (again there is an exception here with AR where it is stimulatory) [263].”
BackgroundConformational dynamics of the molecular chaperone Hsp90
Krukenberg, K. A., Street, T. O., Lavery, L. A., & Agard, D. A. (2011) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583510000314 · Cited by 308
“For example, the immunophilin FKBP52 is found in complex with Hsp90, GR/PR, and p23 in vivo ; FKBP52 also increases the hormone-binding ability of GR and is essential for the correct activation of PR in vivo (Chadli et al. 2008; Riggs et al. 2003).”
BackgroundIsing, M., Depping, A., Siebertz, A., Lucae, S., Unschuld, P. G., Kloiber, S. M., Horstmann, S., Uhr, M., Müller‐Myhsok, B., & Holsboer, F. (2008) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2008.06332.x · Cited by 320
“binding protein 52 (FKBP52 or FKBP4), a positive regulator of GR signalling (Riggs et al., 2003; Wochnik et al., 2005).”
BackgroundStructure, Function, and Regulation of the Hsp90 MachineryPreprint
Biebl, M. M., & Büchner, J. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a034017 · Cited by 315
“Despite 47% sequence homology, Cpr6 and Cpr7 seem to have very different functions, which also holds true for FKBP51 and FKBP52 for which even opposing effects on glucocorticoid receptor (GR) activity have been shown (Hutchison et al. 1993; Smith and Toft 1993; Smith et al. 1993; Duina et al. 1996, 1998; Mayr et al. 2…”
BackgroundEvolution and function of diverse Hsp90 homologs and cochaperone proteins
Johnson, J. L. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.09.020 · Cited by 283
Role of hsp90 and the hsp90-binding immunophilins in signalling protein movement
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Touma, C., Gassen, N. C., Herrmann, L., Cheung‐Flynn, J., Büll, D., Ionescu, I. A., Heinzmann, J.-M., Knapman, A., Siebertz, A., Depping, A., et al. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.07.023 · Cited by 280
Self-citationFKBP51 and FKBP52 in signaling and disease
Storer, C. L., Dickey, C. A., Galigniana, M. D., Rein, T., & Cox, M. B. (2011) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2011.08.001 · Cited by 266
“The FK1 domain facilitates binding to the immunosuppressive drug FK506, confers PPIase activity [3], and is the primary regulatory domain for SHRs [5].”
InfluentialHartmann, K., Koenen, M., Schauer, S., Wittig-Blaich, S., Ahmad, M., Baschant, U., & Tuckermann, J. P. (2016) · Physiological Reviews · doi:10.1152/physrev.00011.2015 · Cited by 251
Versatile TPR domains accommodate different modes of target protein recognition and function
Allan, R. K., & Ratajczak, T. (2010) · Cell Stress and Chaperones · doi:10.1007/s12192-010-0248-0 · Cited by 245
Self-citationChaperoning of Glucocorticoid Receptors
Pratt, W. B., Morishima, Y., Murphy, M. N., & Harrell, M. (2005) · Springer eBooks · doi:10.1007/3-540-29717-0_5 · Cited by 247
“This action is specific to the GR, as opposed to the estrogen receptor, and is specific to FKBP52 vs other hsp90bound immunophilins (Riggs et al. 2003).”
BackgroundAsymmetric Activation of the Hsp90 Dimer by Its Cochaperone Aha1
Retzlaff, M., Hagn, F., Mitschke, L., Heßling, M., Gugel, F., Kessler, H., Richter, K., & Büchner, J. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.01.006 · Cited by 244
“In eukaryotes, accessory factors (so-called cochaperones) have been identified, which regulate the ATP turnover, induce structural changes in Hsp90, or are involved in the substrate activation process (Forafonov et al., 2008; Johnson et al., 1994, 1996; Pirkl and Buchner, 2001; Riggs et al., 2003; Siligardi et al., 20…”
BackgroundProteomic data from human cell cultures refine mechanisms of chaperone-mediated protein homeostasis
Finka, A., & Goloubinoff, P. (2013) · Cell Stress and Chaperones · doi:10.1007/s12192-013-0413-3 · Cited by 218
“The PPIs, some of which known to collaborate closely with Hsp90 (Riggs et al. 2003), were present in significant amounts in the cytoplasm and ER, where Hsp90 was also abundant, in contrast to mitochondria.”
BackgroundMolecular chaperones, essential partners of steroid hormone receptors for activity and mobility
Echeverría, P. C., & Picard, D. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2009.11.012 · Cited by 225
“receptor function [39] are Hsp90-dependent.”
Self-citationOn the Trail of the Glucocorticoid Receptor: Into the Nucleus and Back
Vandevyver, S., Dejager, L., & Libert, C. (2011) · Traffic · doi:10.1111/j.1600-0854.2011.01288.x · Cited by 222
“FKBP52 increases the affinity of GR for hormone by interacting with hsp90 and by exerting its peptidylprolyl isomerase (PPI) activity (32).”
BackgroundPhysiological role for the cochaperone FKBP52 in androgen receptor signaling
Cheung-Flynn, J., Prapapanich, V., Cox, M. B., Riggs, D. L., Suarez-Quian, C., & Smith, D. F. (2005) · Molecular Endocrinology · doi:10.1210/me.2005-0071 · Cited by 212
“Furthermore, a double point mutation (52-FD67DV) in the PPIase active site (20) also blocks potentiation, suggesting that the PPIase domain is required for enhancing AR function.”
BackgroundMethodResultInfluentialSelf-citationHartmann, J., Wagner, K. V., Liebl, C., Scharf, S. H., Wang, X.-D., Wolf, M., Hausch, F., Rein, T., Schmidt, U., Touma, C., et al. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.07.041 · Cited by 224
“Once FKBP5 is bound to the GR complex via hsp90, the receptor’s affinity for cortisol is decreased (Riggs et al., 2003; Wochnik et al., 2005).”
BackgroundSelf-citationIntronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids
Hubler, T. R., & Scammell, J. G. (2004) · Cell Stress & Chaperones · doi:10.1379/csc-32r.1 · Cited by 201
“In addition to modulating steroid receptor function (Denny et al 2000; Galigniana et al 2001; Hubler et al 2003; Riggs et al 2003), the large molecular weight FKBPs have been shown to play a role in a number of biochemical processes including regulation of transient receptor potential–like calcium…”
BackgroundWang, Q., Shelton, R. C., & Dwivedi, Y. (2018) · Journal of Affective Disorders · doi:10.1016/j.jad.2017.08.066 · Cited by 201
“FKBP51 binds to and inhibits GR, which is a critical mechanism for GR desensitization (Rein, 2016; Riggs et al., 2003; Wochnik et al., 2005).”
BackgroundFolding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone
Liu, B., Yang, Y., Qiu, Z., Staron, M., Hong, F., Li, Y., Wu, S., Li, Y., Hao, B., Bona, R., et al. (2010) · Nature Communications · doi:10.1038/ncomms1070 · Cited by 186
Chaperoning steroid hormone action
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Self-citationHSP90AB1: Helping the good and the bad
Haase, M., & Fitze, G. (2016) · Gene · doi:10.1016/j.gene.2015.08.063 · Cited by 179
“FKBP52 facilitates hormone binding (Riggs et al. 2003).”
Davies, T. H., Ning, Y.-M., & Sánchez, E. R. (2005) · Biochemistry · doi:10.1021/bi048503v · Cited by 180
“But it has been shown by the Pratt and Smith laboratories (29, 30 ) that FKBP52 can also contact the GR at the hormone-binding domain, which FKBP51 may or may not be able to do.”
MethodMolecular mechanisms regulating glucocorticoid sensitivity and resistance
Gross, K. L., Lu, N. Z., & Cidlowski, J. A. (2008) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2008.10.001 · Cited by 180
“The relative levels of FKBP51 and FKBP52 have been shown to be important determinants of cellular sensitivity to glucocorticoids in various systems (Reynolds et al., 1999; Denny et al., 2000; Scammell et al., 2001; Scammell et al., 2002; Riggs et al., 2003).”
BackgroundSmith, D. F., & Toft, D. O. (2008) · Molecular Endocrinology · doi:10.1210/me.2008-0089 · Cited by 173
Self-citationFKBP Ligands—Where We Are and Where to Go?
Kolos, J. M., Voll, A. M., Bauder, M., & Hausch, F. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01425 · Cited by 158
“FKBP51 The FK506-binding protein 51 (FKBP51), encoded by the FKBP5 gene, acts as a cochaperone for the heat shock protein 90 (Hsp90) (Riggs et al., 2003) and is best known for the negative regulation of glucocorticoid and progesterone receptors (Pratt and Toft, 1997; Cioffi et al.”
BackgroundFries, G. R., Gassen, N. C., & Rein, T. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122614 · Cited by 170
“The FK1 domain is the primary determi ant for the divergent actions of FKBP51 and FKBP52 on GR [7,9].”
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Cyclophilin 40 facilitates HSP90‐mediated RISC assembly in plants
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“For example, FKBP52 potentiates glucocorticoid signalling by increasing hormone-binding affinity, while FKBP51 anta-gonizes the FKBP52 function (Riggs et al , 2003).”
Allan, R. K., Mok, D., Ward, B. K., & Ratajczak, T. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m512406200 · Cited by 160
Self-citationNi, L., Yang, C.-S., Gioeli, D., Frierson, H., Toft, D. O., & Paschal, B. M. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01891-08 · Cited by 155
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“In our initial characterization of potentiation by FKBP52 (25), we presented evidence that supported a role for PPIase activity in receptor potentiation.”
BackgroundMethodInfluentialSelf-citationThirumalaikumar, V. P., Górka, M., Schulz, K., Masclaux‐Daubresse, C., Sampathkumar, A., Skirycz, A., Vierstra, R. D., & Balazadeh, S. (2020) · Autophagy · doi:10.1080/15548627.2020.1820778 · Cited by 154
“1 interacts with ROF1/ AFKBP62 (rotamase FKBP 1), a plant homolog of mammalian FKBP4/FKBP52, and regulates responses to HS [22,23].”
BackgroundGaligniana, M. D., Erlejman, A. G., Monte, M., Gomez-Sanchez, C., & Piwien-Pilipuk, G. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01190-09 · Cited by 152
“(50) collides with the proposed relevance of TPR proteins”
BackgroundHsp90-binding immunophilins link p53 to dynein during p53 transport to the nucleus
Galigniana, M. D., Harrell, J. M., O'Hagen, H. M., Ljungman, M., & Pratt, W. B. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m402223200 · Cited by 150
Tetratricopeptide repeat cochaperones in steroid receptor complexes
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“In the yeast model where FKBP52 was shown to specifically enhance GR activity, dynein was excluded as a mediator of GR potentiation (Riggs et al 2003).”
BackgroundMethodInfluentialSelf-citationConstantly Updated Knowledge of Hsp90
Terasawa, K. (2005) · The Journal of Biochemistry · doi:10.1093/jb/mvi056 · Cited by 151
MicroRNA mediators of early life stress vulnerability to depression and suicidal behavior
Allen, L., & Dwivedi, Y. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0597-8 · Cited by 152
Hsp90 and FKBP51: complex regulators of psychiatric diseases
Criado‐Marrero, M., Rein, T., Binder, E. B., Porter, J. T., Koren, J., & Blair, L. J. (2017) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2016.0532 · Cited by 152
Molecular mechanism of glucocorticoid resistance in inflammatory bowel disease
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A role for FKBP52 in tau protein function
Chambraud, B., Sardin, E., Giustiniani, J., Dounane, O., Schumacher, M., Goedert, M., & Baulieu, E.-E. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914957107 · Cited by 140
Bell, A., Monaghan, P., & Page, A. P. (2005) · International Journal for Parasitology · doi:10.1016/j.ijpara.2005.11.003 · Cited by 139
Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function
Balsevich, G., Häusl, A. S., Meyer, C. W., Karamihalev, S., Feng, X., Pöhlmann, M. L., Dournes, C., Uribe-Marino, A., Santarelli, S., Labermaier, C., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01783-y · Cited by 134
Mahon, P. B., Zandi, P. P., Potash, J. B., Nestadt, G., & Wand, G. S. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2956-x · Cited by 140
“When cortisol binds to the GR, FKBP5 is replaced by a positive regulator of GR signaling, FKBP4, and the complex is shuttled into the nucleus for transcriptional regulatory activity (Riggs et al. 2003; Wochnik et al. 2005).”
De Leon, J. T., Iwai, A., Feau, C., Garcia, Y., Balsiger, H. A., Storer, C. L., Suro, R. M., Garza, K. M., Lee, S., Sang Kim, Y., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105160108 · Cited by 132
“Analysis of the AR LBD crystal structure revealed that these residues comprise a surface region that overlaps with the recently described AR BF3 surface (11) (Fig.”
BackgroundMethodInfluentialSelf-citationThe Middle Domain of Hsp90 Acts as a Discriminator between Different Types of Client Proteins
Hawle, P., Siepmann, M., Harst, A., Siderius, M., Reusch, H. P., & Obermann, W. M. J. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.02188-05 · Cited by 127
“In order to examine different client protein handling by Hsp90 further, steady-state levels of client proteins v-Src and GR were monitored and quantified in yeast cells by Western blotting using specific antibodies (Fig. 6; Table 2) (19, 28 ).”
MethodInfluentialFunctional Specificity of Co-Chaperone Interactions with Hsp90 Client Proteins
Riggs, D., Cox, M., Cheung-Flynn, J., Prapapanich, V., Carrigan, P., & Smith, D. F. (2004) · Critical reviews in biochemistry and molecular biology · doi:10.1080/10409230490892513 · Cited by 141
“Because FKBP52 does not enhance ER function, chimeric receptors with swapped functional domains were used to localize potentiation to the ligand binding domain of GR (Riggs et al., 2003).”
BackgroundMethodInfluentialSelf-citationFK506-Binding Proteins and Their Diverse Functions
Tong, M., & Jiang, Y. (2015) · Current Molecular Pharmacology · doi:10.2174/1874467208666150519113541 · Cited by 135
“It competes with FKBP52 for binding with steroid receptors, consequently, antagonizes the positive effect of FKBP52 on these receptors [96, 121].”
BackgroundGenetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks
Sarapas, C., Cai, G., Bierer, L. M., Golier, J. A., Galea, S., Ising, M., Rein, T., Schmeidler, J., Müller-Myhsok, B., Uhr, M., et al. (2011) · Disease Markers · doi:10.1155/2011/328054 · Cited by 143
Yang, Z., Wolf, I. M., Chen, H., Periyasamy, S., Chen, Z., Yong, W., Shi, S., Zhao, W., Xu, J., Srivastava, A., et al. (2006) · Molecular Endocrinology · doi:10.1210/me.2006-0024 · Cited by 119
“Transfection of FKBP52 into Saccharomyces cerevisiae (21) or overexpression in mammalian cells (22) caused potentiation of GR-mediated reporter gene expression that correlated with an increase in GR hormone-binding function.”
BackgroundHähle, A., Merz, S., Meyners, C., & Hausch, F. (2019) · Biomolecules · doi:10.3390/biom9010035 · Cited by 119
“GR via Hsp90 [58] SUMOylation dependent [22] FKBP52 competitive [70] PR b [58] d [58]”
BackgroundZhang, X., Clark, A. F., & Yorio, T. (2008) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.07-1279 · Cited by 116
Plant immunophilins: functional versatility beyond protein maturation
Romano, P. G. N., Gray, J. E., Horton, P., & Luan, S. (2005) · New Phytologist · doi:10.1111/j.1469-8137.2005.01373.x · Cited by 109
Independent Regulation of Hsp70 and Hsp90 Chaperones by Hsp70/Hsp90-organizing Protein Sti1 (Hop1)
Song, Y., & Masison, D. C. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505420200 · Cited by 112
Tranguch, S., Wang, H., Daikoku, T., Xie, H., Smith, D. F., & Dey, S. K. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31622 · Cited by 121
Self-citationGallo, L. I., Lagadari, M., Piwien‐Pilipuk, G., & Galigniana, M. D. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.256610 · Cited by 110
Davies, T. H., & Sánchez, E. R. (2004) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2004.03.013 · Cited by 109
Periyasamy, S., Hinds, T., Shemshedini, L., Shou, W., & Sanchez, E. R. (2010) · Oncogene · doi:10.1038/onc.2009.458 · Cited by 108
“Yet, it is clear that the PPIase domain (rather than catalytic activity) is critical to FKBP52 actions on GR and PR (Riggs et al., 2003; Tranguch et al., 2005; Wochnik et al., 2005).”
BackgroundGassen, N. C., Fries, G. R., Zannas, A. S., Hartmann, J., Zschocke, J., Hafner, K., Carrillo‐Roa, T., Steinbacher, J., Preißinger, S. N., Hoeijmakers, L., et al. (2015) · Science Signaling · doi:10.1126/scisignal.aac7695 · Cited by 109
Pharmacological Inhibition of the Psychiatric Risk Factor FKBP51 Has Anxiolytic Properties
Hartmann, J., Wagner, K. V., Gaali, S., Kirschner, A., Kozany, C., Ruhter, G., Dedic, N., Hausl, A. S., Hoeijmakers, L., Westerholz, S., et al. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.4024-14.2015 · Cited by 109
“FKBP51 is an imunophilin best known to alter glucocorticoid receptor (GR) sensitivity (Riggs et al., 2003; Binder et al., 2004).”
BackgroundBrooks, N. A., Wilcox, G., Walker, K. Z., Ashton, J., Cox, M. B., & Stojanovska, L. (2008) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0b013e3181732953 · Cited by 106
“The wells were then treated with the chemiluminescent substrate, incubated for 2 hours at room temperature, and measured on a microplate luminometer (Luminoskan Ascent, LabSystems) as described previously.(26,27)”
MethodDifferential Impact of Tetratricopeptide Repeat Proteins on the Steroid Hormone Receptors
Schülke, J.-P., Wochnik, G. M., Lang‐Rollin, I., Gassen, N. C., Knapp, R., Berning, B., Yassouridis, A., & Rein, T. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011717 · Cited by 109
“The immunophilin and peptidylprolyl isomerase (PPIase) Cyp40 has also been identified in SR-heterocomplexes, but its role regarding SR-function is still unclear [18].”
BackgroundInfluentialMultidomain Peptidyl Prolyl cis/trans Isomerases
Schiene‐Fischer, C. (2014) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2014.11.012 · Cited by 103
Martinez, G. J., Appleton, M., Kipp, Z. A., Loria, A. S., Min, B., & Hinds, T. D. (2023) · Physiological Reviews · doi:10.1152/physrev.00021.2023 · Cited by 115
Cheung-Flynn, J., Roberts, P. J., Riggs, D. L., & Smith, D. F. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300955200 · Cited by 96
Self-citationThe prospect of FKBP51 as a drug target
Schmidt, M. V., Paez‐Pereda, M., Holsboer, F., & Hausch, F. (2012) · ChemMedChem · doi:10.1002/cmdc.201200137 · Cited by 99
Gallo, L. I., Ghini, A. A., Piwien Pilipuk, G., & Galigniana, M. D. (2007) · Biochemistry · doi:10.1021/bi701372c · Cited by 99
Annett, S., Moore, G., & Robson, T. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107623 · Cited by 104
Involvement of Arabidopsis ROF2 (FKBP65) in thermotolerance
Meiri, D., Tazat, K., Cohen-Peer, R., Pisanty, O., Aviezer-Hagai, K., Avni, A., & Breiman, A. (2009) · Plant Molecular Biology · doi:10.1007/s11103-009-9561-3 · Cited by 99
“Following this exchange, FKBP52 has been shown to promote translocation of the receptor to the nucleus whereas FKBP51 has an inhibitory effect by maintaining the complex in the cytoplasm ( Riggs et al. 2003; Gallo et al. 2007).”
Protein Kinase CK2 in Health and Disease: CK2: The kinase controlling the Hsp90 chaperone machinery
Miyata, Y. (2009) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-009-9152-0 · Cited by 98
Aviezer-Hagai, K., Skovorodnikova, J., Galigniana, M. D., Pisanty, O., Maayan, E., Bocovza, S., Efrat, Y., von Koskull‐Döring, P., Ohad, N., & Breiman, A. (2006) · Plant Molecular Biology · doi:10.1007/s11103-006-9085-z · Cited by 99
“It acts as the central platform for distinct multichaperone complexes as the steroid receptor complex, with additional cofactors, including p23 (Pirkl and Buchner 2001; Riggs et al. 2003).”
BackgroundNF-κB Transcriptional Activity Is Modulated by FK506-binding Proteins FKBP51 and FKBP52
Erlejman, A. G., Leo, S. A. D., Mazaira, G. I., Molinari, A. M., Camisay, M. F., Fontana, V. A., Cox, M. B., Piwien‐Pilipuk, G., & Galigniana, M. D. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.582882 · Cited by 98
Chaperoning steroidal physiology: Lessons from mouse genetic models of Hsp90 and its cochaperones
Sánchez, E. R. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.11.006 · Cited by 98
Biological Actions of the Hsp90-binding Immunophilins FKBP51 and FKBP52
Zgajnar, N. R., Leo, S. A. D., Lotufo, C. M., Erlejman, A. G., Piwien‐Pilipuk, G., & Galigniana, M. D. (2019) · Biomolecules · doi:10.3390/biom9020052 · Cited by 95
“) [107] Hepatocarcinoma ↓ ↑ [112,113] Colorectal carcinoma ↑ ↑ [110,176] Lymphoma ↑ ↑ [162,177] Nervous System Neurodifferentiation ↓ ↑ [178] Neuroregeneration ↓ ↑ [179] Astrocytoma ↑ ↑ [180–182] Myoblast differentiation ↑(*) ↓ [183] Adipogenesis ↑ ↓ [141] Steroid receptors GR ↓ ↑ [18,86] MR ↓ N [56,184] PR ↓ ↑ [185,1…”
BackgroundGolden, T. A., Swingle, M. R., & Honkanen, R. E. (2008) · Cancer and Metastasis Reviews · doi:10.1007/s10555-008-9125-z · Cited by 93
“The binding of FKBP52 augments glucocorticoid signaling [26, 43], whereas FKBP51 suppresses GR-signaling [44].”
BackgroundFKBP51 – a selective modulator of glucocorticoid and androgen sensitivity
Stechschulte, L. A., & Sanchez, E. R. (2011) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2011.04.012 · Cited by 92
“In contrast to FKBP51, the better-studied FKBP52 serves to promote the molecular activities of both GR and AR [23,27,28].”
BackgroundWestberry, J. M., Sadosky, P. W., Hubler, T. R., Gross, K. L., & Scammell, J. G. (2006) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2006.03.004 · Cited by 91
Fluorescent Probes to Characterise FK506‐Binding Proteins
Kozany, C., März, A., Kress, C., & Hausch, F. (2009) · ChemBioChem · doi:10.1002/cbic.200800806 · Cited by 91
Daikoku, T., Tranguch, S., Friedman, D., Das, S., Smith, D. F., & Dey, S. (2005) · Molecular Endocrinology · doi:10.1210/me.2004-0332 · Cited by 90
“FKBP52 can elevate the hormone-binding affinity of glucocorticoid receptor in an Hsp90- and peptidylprolyl isomerase-dependent manner; conversely, FKBP51 can reverse the action of FKBP52 and revert glucocorticoid receptor to a lower affinity (23).”
BackgroundSelf-citationStructure and function of Hip, an attenuator of the Hsp70 chaperone cycle
Li, Z., Hartl, F. U., & Bracher, A. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2608 · Cited by 87
Prolyl isomerases in gene transcription
Hanes, S. D. (2014) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2014.10.028 · Cited by 87
Molecular complexity in establishing uterine receptivity and implantation
Tranguch, S. L., Daikoku, T., Guo, Y., Wang, H., & Dey, S. K. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-5230-0 · Cited by 89
The immunophilin FKBP52 specifically binds to tubulin and prevents microtubule formation
Chambraud, B., Belabes, H., Fontaine‐Lenoir, V., Fellous, A., & Baulieu, E. E. (2007) · The FASEB Journal · doi:10.1096/fj.06-7667com · Cited by 85
“Besides its effect on steroid receptor activity (27), it has been reported that FKBP52 in the nervous system could mediate the neurotrophic and neuroprotective effects of FK506 (28–29).”
BackgroundLee, K., Thwin, A. C., Nadel, C. M., Tse, E., Gates, S. N., Gestwicki, J. E., & Southworth, D. R. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.07.023 · Cited by 76
Prolyl Isomerization and Its Catalysis in Protein Folding and Protein Function
Schmidpeter, P. A. M., & Schmid, F. X. (2015) · Journal of Molecular Biology · doi:10.1016/j.jmb.2015.01.023 · Cited by 85
“Initially, the preference for binding to FKBP51 or FKBP52 was suggested to depend on the type of hormone receptor [228, 229].”
BackgroundRegulation of steroid hormone receptor function by the 52-kDa FK506-binding protein (FKBP52)
Sivils, J. C., Storer, C. L., Galigniana, M. D., & Cox, M. B. (2011) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2011.03.010 · Cited by 81
Multiple Domains of the Co-chaperone Hop Are Important for Hsp70 Binding
Carrigan, P. E., Nelson, G. M., Roberts, P. J., Stoffer, J. B., Riggs, D. L., & Smith, D. F. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m314130200 · Cited by 80
Self-citation
Metadata
- Authors
- Riggs, D. L., Roberts, P. J., Chirillo, S. C., Cheung‐Flynn, J., Prapapanich, V., Ratajczak, T., Gaber, R., Picard, D., & Smith, D. F.
- Affiliations
- Mayo Clinic (US)
- The University of Western Australia (AU)
- Northwestern University (US)
- University of Geneva (CH)
- Corresponding author
- Smith, David F.
- Venue
- The EMBO Journal
- Published
- 2003-03-03
- Volume
- 22
- Issue
- 5
- Pages
- 1158-1167
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC150341
- OpenAlex
- W2075431153
- Semantic Scholar
- 1ac04c1350d5c46f954ac9ade4bc83458748b0ac
- Cited by
- 353
- References
- 58
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 6 · 2023: 19 · 2022: 13 · 2021: 16 · 2020: 13 · 2019: 16 · 2018: 9 · 2017: 14 · 2016: 15 · 2015: 21 · 2014: 16 · 2013: 18 · 2012: 16
- FWCI
- 6.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Science Foundation (0079249)
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK44923, R01DK044923, R01DK048218)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- FKBP52, HSP90, immunophilins, glucocorticoid receptor, glucocorticoid signaling, peptidylprolyl isomerase, FKBP51, hormone binding affinity, Saccharomyces cerevisiae, protein phosphatase 5
- MeSH terms
- Animals, Dose-Response Relationship, Drug, Gene Expression Regulation, Glucocorticoids, Humans, Models, Molecular, Protein Binding, Protein Conformation, Receptors, Glucocorticoid, Saccharomyces cerevisiae, Signal Transduction, Transcriptional Activation, Genes, Reporter, Molecular Chaperones, HSP90 Heat-Shock Proteins, Peptidylprolyl Isomerase, Tacrolimus Binding Proteins
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