The Emerging Role of TPR-Domain Immunophilins in the Mechanism of Action of Steroid Receptors

Mazaira, Gisela Ileana; Lagadari, Mariana; Erlejman, Alejandra G.; Galigniana, Mario D.

doi:10.11131/2014/101094

Cited by 8 publications

(6 citation statements)

References 182 publications

(216 reference statements)

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“…Upon steroid binding, they rapidly accumulate in the nucleus. Other receptors such as the estrogen receptor (ER) are constitutively nuclear even in the absence of steroid, but they are not statically confined to a cell compartment, but are continuously shuttling between cytoplasm and nucleus [44,45,46,47]. Classically, the driving force for soluble protein movement throughout the cytoplasm was always assumed to occur by simple diffusion, and steroid receptors were not the exception.…”

Section: Immunophilins Play a Key Role In Protein Traffickingmentioning

confidence: 99%

Biological Actions of the Hsp90-binding Immunophilins FKBP51 and FKBP52

et al. 2019

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Immunophilins are a family of proteins whose signature domain is the peptidylprolyl-isomerase domain. High molecular weight immunophilins are characterized by the additional presence of tetratricopeptide-repeats (TPR) through which they bind to the 90-kDa heat-shock protein (Hsp90), and via this chaperone, immunophilins contribute to the regulation of the biological functions of several client-proteins. Among these Hsp90-binding immunophilins, there are two highly homologous members named FKBP51 and FKBP52 (FK506-binding protein of 51-kDa and 52-kDa, respectively) that were first characterized as components of the Hsp90-based heterocomplex associated to steroid receptors. Afterwards, they emerged as likely contributors to a variety of other hormone-dependent diseases, stress-related pathologies, psychiatric disorders, cancer, and other syndromes characterized by misfolded proteins. The differential biological actions of these immunophilins have been assigned to the structurally similar, but functionally divergent enzymatic domain. Nonetheless, they also require the complementary input of the TPR domain, most likely due to their dependence with the association to Hsp90 as a functional unit. FKBP51 and FKBP52 regulate a variety of biological processes such as steroid receptor action, transcriptional activity, protein conformation, protein trafficking, cell differentiation, apoptosis, cancer progression, telomerase activity, cytoskeleton architecture, etc. In this article we discuss the biology of these events and some mechanistic aspects.

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Section: Immunophilins Play a Key Role In Protein Traffickingmentioning

confidence: 99%

Biological Actions of the Hsp90-binding Immunophilins FKBP51 and FKBP52

et al. 2019

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“…In previous studies, we demonstrated that TPR-domain immunophilins affect the subcellular localization of steroid receptors (Galigniana, 2012;Galigniana et al, 2010bGaligniana et al, , 2001Mazaira et al, 2014). Thus, it was shown that FKBP52 is required for the nuclear accumulation of the receptor thanks to a dynein-dependent cytoplasmic mechanism, whereas FKBP51 increases the cytoplasmic pool of the receptor and decreases its nuclear pool.…”

Section: Discussionmentioning

confidence: 95%

Nucleocytoplasmic shuttling of the glucocorticoid receptor is influenced by tetratricopeptide repeat-containing proteins

Mazaira

Echeverria

Galigniana

2020

Journal of Cell Science

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It has been demonstrated that tetratricopeptide repeats (TPR)-domain proteins regulate the subcellular localization of the glucocorticoid receptor (GR). This study analyses the influence of the TPR-domain of high molecular weight immunophilins in the retrograde transport mechanism and the nuclear retention of GR. The overexpression of the TPR peptide prevents the efficient nuclear accumulation of the GR by interfering the formation of complexes with the dynein-associated immunophilin FKBP52, the adaptor transporter importin-β1, the nuclear pore-associated glycoprotein Nup62, and nuclear matrix-associated structures. It is also demonstrated that the nuclear import of GR is impaired whereas the GR nuclear export is favoured. Interestingly, the exportin1/CRM1 inhibitor leptomycin-B abolishes the action of TPR peptide overexpression, although the drug cannot inhibit the GR nuclear export itself. This indicates the existence of a TPR-domain-dependent mechanism for the export of nuclear proteins. The findings of this study suggest that the expression balance of those TPR-domain proteins bound to the GR•Hsp90 complex may determine the subcellular localization and nucleocytoplasmic properties of the receptor, and thereby its pleiotropic biological properties in different tissues or cell types.

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“…). Because the PPIase domain of FKBP52, but not the PPIase domain of FKBP51, is able to interact with dynein/dynactin, the motor protein complex is also recruited to steroid receptors and powers the active cytoplasmic transport to the nucleus along cytoskeletal tracks …”

Section: Hsp90‐binding Immunophilins and Transcription Factorsmentioning

confidence: 99%

“…In nontransformed isoforms, the stoichiometry of the receptor•(Hsp90) 2 complex shows one molecule of Hsp70, one molecule of p23 and a TPRdomain cochaperone bound to the TPR acceptor site of the Hsp90 dimer. 12,13 During the early steps of heterocomplex assembly, the TPR protein Hop/p60/Sti1 is required for bringing together Hsp90 and Hsp70, but after the formation of the complex and its subsequent transference to the aporeceptor, Hop/p60/Sti1 is released and a TPR-domain immunophilin occupies the TPR acceptor site on the Hsp90 dimer. FKBP51 is the immunophilin present in the mature and transcriptionally inactive receptor and is exchanged by FKBP52 upon steroid binding ( Fig.…”

Section: Hsp90-binding Immunophilins and Transcription Factorsmentioning

confidence: 99%

“…Because the PPIase domain of FKBP52, but not the PPIase domain of FKBP51, is able to interact with dynein/dynactin, 14,15 the motor protein complex is also recruited to steroid receptors and powers the active cytoplasmic transport to the nucleus along cytoskeletal tracks. 12,13 Hsp90 is mostly localized in the cytoplasm of unstressed cells and a small fraction is nuclear. In early times there was a controversy related to the fact that Hsp90 could not exist associated to the nuclear pool of steroid receptors.…”

Section: Hsp90-binding Immunophilins and Transcription Factorsmentioning

confidence: 99%

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Biological relevance of Hsp90‐binding immunophilins in cancer development and treatment

Mazaira

Camisay

Leo

et al. 2015

Intl Journal of Cancer

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Immunophilins are a family of intracellular receptors for immunosuppressive drugs. Those immunophilins that are related to immunosuppression are the smallest proteins of the family, i.e., FKBP12 and CyPA, whereas the other members of the family have higher molecular weight because the show additional domains to the drug-binding site. Among these extra domains, the TPR-domain is perhaps the most relevant because it permits the interaction of high molecular weight immunophilins with the 90-kDa heat-shock protein, Hsp90. This essential molecular chaperone regulates the biological function of several proteinkinases, oncogenes, protein phosphatases, transcription factors and cofactors . Hsp90-binding immunophilins where first characterized due to their association with steroid receptors. They regulate the cytoplasmic transport and the subcellular localization of these and other Hsp90 client proteins, as well as transcriptional activity, cell proliferation, cell differentiation and apoptosis. Hsp90-binding immunophilins are frequently overexpressed in several types of cancers and play a key role in cell survival. In this article we analyze the most important biological actions of the best characterized Hsp90-binding immunophilins in both steroid receptor function and cancer development and discuss the potential use of these immunophilins for therapeutic purposes as potential targets of specific small molecules.

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The Emerging Role of TPR-Domain Immunophilins in the Mechanism of Action of Steroid Receptors

Cited by 8 publications

References 182 publications

Biological Actions of the Hsp90-binding Immunophilins FKBP51 and FKBP52

Biological Actions of the Hsp90-binding Immunophilins FKBP51 and FKBP52

Nucleocytoplasmic shuttling of the glucocorticoid receptor is influenced by tetratricopeptide repeat-containing proteins

Biological relevance of Hsp90‐binding immunophilins in cancer development and treatment

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