Decreased adipogenesis and adipose tissue in mice with inactivated protein phosphatase 5

Jacob, Wright; Rosenzweig, Doron; Vázquez-Martin, Cristina; Duce, Suzanne L.; Cohen, Patricia T.W.

doi:10.1042/bj20140428

Cited by 10 publications

(7 citation statements)

References 50 publications

(79 reference statements)

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“…In a recent study, we investigated the influence of the nematode PPH-5 protein, the TPR-containing phosphatase homolog to human Pp5, on the phosphorylation state of glucocorticoid receptor fragments and observed its dependency on the C. elegans Hsp90 (HSP-90) 41 . We see that the dephosphorylation of GR-fragments is enhanced in the presence of HSP-90 and this activity is conserved in the vertebrate system 41,42 . Nevertheless, the role of Pp5 during the assembly of GR•Hsp90 complexes is far from clear.…”

mentioning

confidence: 73%

Glucocorticoid receptor complexes form cooperatively with the Hsp90 co-chaperones Pp5 and FKBPs

Kaziales

Barkovits

Marcus

et al. 2020

Sci Rep

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The function of steroid receptors in the cell depends on the chaperone machinery of Hsp90, as Hsp90 primes steroid receptors for hormone binding and transcriptional activation. Several conserved proteins are known to additionally participate in receptor chaperone assemblies, but the regulation of the process is not understood in detail. Also, it is unknown to what extent the contribution of these cofactors is conserved in other eukaryotes. We here examine the reconstituted C. elegans and human chaperone assemblies. We find that the nematode phosphatase PPH-5 and the prolyl isomerase FKB-6 facilitate the formation of glucocorticoid receptor (GR) complexes with Hsp90. Within these complexes, Hsp90 can perform its closing reaction more efficiently. By combining chemical crosslinking and mass spectrometry, we define contact sites within these assemblies. Compared to the nematode Hsp90 system, the human system shows less cooperative client interaction and a stricter requirement for the co-chaperone p23 to complete the closing reaction of GR•Hsp90•Pp5/Fkbp51/ Fkbp52 complexes. In both systems, hormone binding to GR is accelerated by Hsp90 alone and in the presence of its cofactors. our results show that cooperative complex formation and hormone binding patterns are, in many aspects, conserved between the nematode and human systems. Hsp90 is an ATP-driven molecular machine, highly abundant in the cytosol. It is recruited to client proteins that require energy-intense rearrangements and supports these reactions by performing nucleotide-induced conformational changes 1,2. These changes lead to the compaction of the Hsp90 dimer and the transient formation of a ring-like structure, where the N-terminal domains are dimerized in addition to the chaperone's permanent C-terminal dimerization 3. Only in the bacterial Hsp90 system are these changes performed and controlled by Hsp90 itself. In the eukaryotic systems, client-specific cofactors are present, which tailor the Hsp90 machinery into a client-specific mode and regulate the conformational changes while providing further interaction sites for the clients 4. This has been investigated for the Hsp90-dependent maturation of protein kinases with the help of the cofactor Cdc37 and for the chaperoning of steroid receptors, where a larger set of cofactors participates 5-7. Partly, these reactions have been reconstituted with recombinant proteins to identify interaction mechanisms, but mostly addressing the cofactors' interaction with Hsp90 in the absence of clients. Hsp90-containing protein complexes were first identified in the 1980s 8,9. In these studies, steroid hormone receptors, such as the glucocorticoid, mineralocorticoid or progesterone receptors, were isolated from vertebrate cells and the associated proteins were identified and studied by western blot analyses. Hsp90 and several other proteins were detected in these complexes, leading to the identification of Fkbp51, Fkbp52, Cyp40, Hop, p23, Hip and Pp5 as components of steroid hormone receptor complexes 10-14. The gluco...

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mentioning

confidence: 73%

Glucocorticoid receptor complexes form cooperatively with the Hsp90 co-chaperones Pp5 and FKBPs

Kaziales

Barkovits

Marcus

et al. 2020

Sci Rep

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“…A recent animal model study suggests a role of protein phosphatase 5 (PP5), which is supposed to be a regulator of the transcriptional activity of GR, in adipose tissue distribution. Mice knocked in with a defective form of PP5 had less VAT surrounding gonads and kidneys and smaller adipocytes, probably via a disruption of the GC-related effects on pre-adipocyte differentiation (92). GCs, via FOXO1, increase the expression of MKP3.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Metabolic comorbidities in Cushing's syndrome

Ferraú

Korbonits

2015

European Journal of Endocrinology

146

121

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Cushing's syndrome (CS) patients have increased mortality primarily due to cardiovascular events induced by glucocorticoid (GC) excess-related severe metabolic changes. Glucose metabolism abnormalities are common in CS due to increased gluconeogenesis, disruption of insulin signalling with reduced glucose uptake and disposal of glucose and altered insulin secretion, consequent to the combination of GCs effects on liver, muscle, adipose tissue and pancreas. Dyslipidaemia is a frequent feature in CS as a result of GC-induced increased lipolysis, lipid mobilisation, liponeogenesis and adipogenesis. Protein metabolism is severely affected by GC excess via complex direct and indirect stimulation of protein breakdown and inhibition of protein synthesis, which can lead to muscle loss. CS patients show changes in body composition, with fat redistribution resulting in accumulation of central adipose tissue. Metabolic changes, altered adipokine release, GC-induced heart and vasculature abnormalities, hypertension and atherosclerosis contribute to the increased cardiovascular morbidity and mortality. In paediatric CS patients, the interplay between GC and the GH/IGF1 axis affects growth and body composition, while in adults it further contributes to the metabolic derangement. GC excess has a myriad of deleterious effects and here we attempt to summarise the metabolic comorbidities related to CS and their management in the perspective of reducing the cardiovascular risk and mortality overall.

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“…MSCs were isolated from PP5 KO and WT mice following the protocol described in ref. 25 with a slight modification. MSCs were plated in a 60 mm cell culture dish at a density of 3 × 10 5 cells/ml.…”

Section: Methodsmentioning

confidence: 99%

“…PP5 contains a 34-amino acid tetratricopeptide repeat motif that mediates protein–protein interaction and also serves as an auto-inhibitory domain for phosphatase activity 22 , 23 . Genetic studies indicated that inactivation of PP5 prevented high-fat diet feeding-induced weight gain and adipogenesis 24 , 25 . Several studies have demonstrated that PP5 regulates both PPARγ and Runx2 through posttranscriptional and posttranslational mechanisms 26 – 28 .…”

Section: Introductionmentioning

confidence: 99%

Ablation of protein phosphatase 5 (PP5) leads to enhanced both bone and cartilage development in mice

et al. 2018

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This study aimed to investigate the role of protein phosphatase 5 (PP5) on bone and cartilage development using both in vivo and in vitro approaches. Six- to 8-week- old male PP5 knockout mice (KO) and their wild-type (WT) littermate controls were randomly selected for this study, and their body weights and bone (femur) lengths were measured. Micro-computed tomography scanning (Micro-CT) was performed to determine femoral bone density and micro-architecture. Mesenchymal stem cells (MSCs) isolated from bone marrow were used to examine the effects of PP5 on osteogenesis in vitro. Whole-mount Alcian blue and Alizarin red staining were used to detect cartilage formation in newborn vertebrae, limbs, and feet. Hematoxylin and eosin (H&E) staining was performed to determine growth plate thickness. Real-time PCR analysis, western blotting, and immunohistochemistry were used to detect the expression of genes and proteins in bone marrow-derived MSCs as well as in bone and cartilage tissues. The results showed PP5 KO mice exhibited significantly reduced body weight and shorter femur length compared to WT controls. The KO mice also had significantly higher volumetric bone mineral density (BMD), trabecular bone volume, and cortical thickness in the femur. The deficiency of PP5 significantly enhanced the formation of cartilage in vertebrae, limbs, and feet. In addition, KO mice possessed a wider distal femur growth plates containing significantly more chondrocytes than WT mice. Furthermore, higher expressions of several cartilage-specific genes were observed in the articular cartilage of PP5 KO mice. Immunohistochemical labeling of growth plates demonstrated that phospho-PPARγ, Runx1, and Runx2 levels were considerably higher in the KO mice. In conclusion, PP5 is a significant negative regulator on the regulation of bone and cartilage development.

show abstract

Decreased adipogenesis and adipose tissue in mice with inactivated protein phosphatase 5

Cited by 10 publications

References 50 publications

Glucocorticoid receptor complexes form cooperatively with the Hsp90 co-chaperones Pp5 and FKBPs

Glucocorticoid receptor complexes form cooperatively with the Hsp90 co-chaperones Pp5 and FKBPs

Metabolic comorbidities in Cushing's syndrome

Ablation of protein phosphatase 5 (PP5) leads to enhanced both bone and cartilage development in mice

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