XAP2 inhibits glucocorticoid receptor activity in mammalian cells

Laenger, Anna; Lang-Rollin, Isabelle; Kozany, C.; Zschocke, Jürgen; Zimmermann, Nicole; Rüegg, Joëlle; Holsboer, Florian; Hausch, Felix; Rein, Theo

doi:10.1016/j.febslet.2009.03.072

Cited by 34 publications

(27 citation statements)

References 45 publications

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“…For XAP2, a moderate interaction with Hsp90 has been found before [37], [74], but there were no reports on incorporation into SR heterocomplexes. We reveal here the potential of XAP2 to interact with SR.…”

Section: Discussionmentioning

confidence: 99%

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Differential Impact of Tetratricopeptide Repeat Proteins on the Steroid Hormone Receptors

et al. 2010

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BackgroundTetratricopeptide repeat (TPR) motif containing co-chaperones of the chaperone Hsp90 are considered control modules that govern activity and specificity of this central folding platform. Steroid receptors are paradigm clients of Hsp90. The influence of some TPR proteins on selected receptors has been described, but a comprehensive analysis of the effects of TPR proteins on all steroid receptors has not been accomplished yet.Methodology and Principal FindingsWe compared the influence of the TPR proteins FK506 binding proteins 51 and 52, protein phosphatase-5, C-terminus of Hsp70 interacting protein, cyclophillin 40, hepatitis-virus-B X-associated protein-2, and tetratricopeptide repeat protein-2 on all six steroid hormone receptors in a homogeneous mammalian cell system. To be able to assess each cofactor's effect on the transcriptional activity of on each steroid receptor we employed transient transfection in a reporter gene assay. In addition, we evaluated the interactions of the TPR proteins with the receptors and components of the Hsp90 chaperone heterocomplex by coimmunoprecipitation. In the functional assays, corticosteroid and progesterone receptors displayed the most sensitive and distinct reaction to the TPR proteins. Androgen receptor's activity was moderately impaired by most cofactors, whereas the Estrogen receptors' activity was impaired by most cofactors only to a minor degree. Second, interaction studies revealed that the strongly receptor-interacting co-chaperones were all among the inhibitory proteins. Intriguingly, the TPR-proteins also differentially co-precipitated the heterochaperone complex components Hsp90, Hsp70, and p23, pointing to differences in their modes of action.Conclusion and SignificanceThe results of this comprehensive study provide important insight into chaperoning of diverse client proteins via the combinatorial action of (co)-chaperones. The differential effects of the TPR proteins on steroid receptors bear on all physiological processes related to steroid hormone activity.

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Section: Discussionmentioning

confidence: 99%

“…XAP2 has been well studied for its role in regulating the activity of the arylhydrocarbon receptor (AhR) class of nuclear receptors [36]. Recently, XAP2 was shown to inhibit GR-mediated transcription [37].…”

Section: Introductionmentioning

confidence: 99%

Differential Impact of Tetratricopeptide Repeat Proteins on the Steroid Hormone Receptors

et al. 2010

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“…As the name implies, Xap2 also functionally interacts with the hepatitis B virus protein X (Kuzhandaivelu et al 1996). Recently, Xap2 was shown to exert an inhibitory effect on both GR and ERα, but not ERβ activity, and may inhibit AR and PR as well (Cai et al 2011;Laenger et al 2009;Schulke et al 2010). In addition, Xap2 is known to have functional interactions with peroxisome proliferator activated receptor α (PPARα) (Sumanasekera et al 2003) and thyroid hormone receptor β, however, these interactions have not been extensively characterized.…”

Section: Xap2mentioning

confidence: 95%

Functions of the Hsp90-Binding FKBP Immunophilins

Guy

Garcia

Sivils

et al. 2014

Subcellular Biochemistry

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Hsp90 functionally interacts with a broad array of client proteins, but in every case examined Hsp90 is accompanied by one or more co-chaperones. One class of co-chaperone contains a tetratricopeptide repeat domain that targets the co-chaperone to the C-terminal region of Hsp90. Within this class are Hsp90-binding peptidylprolyl isomerases, most of which belong to the FK506-binding protein (FKBP) family. Despite the common association of FKBP co-chaperones with Hsp90, it is now clear that the client protein influences, and is influenced by, the particular FKBP bound to Hsp90. Examples include Xap2 in aryl hydrocarbon receptor complexes and FKBP52 in steroid receptor complexes. In this chapter, we discuss the known functional roles played by FKBP co-chaperones and, where possible, relate distinctive functions to structural differences between FKBP members.

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“…AIP was shown to bind Hsp90 and AHR primarily through the TPR and suggested to act in complex with Hsp90 to regulate ligand-triggered AHR responses [[8]-[10]]. The N-terminal FKBP-like PPI domain of AIP that we identified as the CARMA1 interaction surface does not confer enzymatic activity [[11]-[13]]. Since extensive intramolecular restructuring of the CARMA1 MAGUK region is required to initiate downstream signaling after T cell stimulation [[14]], we asked if AIP can support conformational changes involved in CBM formation.…”

Section: Resultsmentioning

confidence: 99%

AIP augments CARMA1-BCL10-MALT1 complex formation to facilitate NF-κB signaling upon T cell activation

et al. 2014

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BackgroundThe CARMA1-BCL10-MALT1 (CBM) complex bridges T cell receptor (TCR) signaling to the canonical IκB kinase (IKK)/NF-κB pathway. The CBM complex constitutes a signaling cluster of more than 1 Mio Dalton. Little is known about factors that facilitate the rapid assembly and maintenance of this dynamic higher order complex.FindingsHere, we report the novel interaction of the aryl hydrocarbon receptor (AHR) interacting protein (AIP) and the molecular scaffold protein CARMA1. In T cells, transient binding of CARMA1 and AIP enhanced formation of the CBM complex. Thereby, AIP promoted optimal IKK/NF-κB signaling and IL-2 production in response to TCR/CD28 co-stimulation.ConclusionsOur data demonstrate that AIP acts as a positive regulator of NF-κB signaling upon T cell activation.

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XAP2 inhibits glucocorticoid receptor activity in mammalian cells

Cited by 34 publications

References 45 publications

Differential Impact of Tetratricopeptide Repeat Proteins on the Steroid Hormone Receptors

Differential Impact of Tetratricopeptide Repeat Proteins on the Steroid Hormone Receptors

Functions of the Hsp90-Binding FKBP Immunophilins

AIP augments CARMA1-BCL10-MALT1 complex formation to facilitate NF-κB signaling upon T cell activation

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