Defects of Protein Phosphatase 2A Causes Corticosteroid Insensitivity in Severe Asthma

Kobayashi, Yoshiki; Mercado, Nicolas; Barnes, Peter J.; Ito, Kazuhiro

doi:10.1371/journal.pone.0027627

Cited by 75 publications

(99 citation statements)

References 31 publications

(41 reference statements)

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“…may also be at play in GR. In fact, recent work has shown that phosphorylation of the AF1 region of the NTD can also be used to tune the activity of GR (52), thus demonstrating that many of the same thermodynamic strategies utilized for signal propagation in folded proteins can also be applied to ID proteins. How classical and ID domain-mediated allosteric strategies combine to explain the complex regulation of GR controlled genes is an intriguing and as yet unanswered question.…”

Section: Discussionmentioning

confidence: 99%

Thermodynamic Dissection of the Intrinsically Disordered N-terminal Domain of Human Glucocorticoid Receptor

Motlagh

Chakuroff

et al. 2012

Journal of Biological Chemistry

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Background: Glucocorticoid receptor (GR) translational isoforms with different lengths in the intrinsically disordered (ID) N-terminal domain (NTD) have different activities. Results: The folded conformations of the NTDs are thermodynamically globular-like proteins with stabilities that correlate with transcriptional activity. Conclusion: Stability of the ID NTD is a functional regulator of GR. Significance: Activity modulation through ID stability tuning is a new regulatory paradigm.

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Section: Discussionmentioning

confidence: 99%

Thermodynamic Dissection of the Intrinsically Disordered N-terminal Domain of Human Glucocorticoid Receptor

Motlagh

Chakuroff

et al. 2012

Journal of Biological Chemistry

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“…Noteworthy transcripts in these categories/pathways included casein kinase 1, epsilon (CSNK1E) (64), mitogenactivated protein kinase 6 (MAPK6; a.k.a. ERK3) (65), mechanistic target of rapamycin (serine/threonine kinase) (MTOR) (66), oncostatin M (OSM) (67,68), TLR6 (69), mucin 20 (MUC20) (70,71), MAD homolog 1 (SMAD1) (72, 73), (74,75), claudin 3 (CLDN3), CLDN4, CLDN5, CLDN7 (76)(77)(78), and lethal giant larvae homolog 2 (Drosphila) (LLGL2) (79,80).…”

Section: Transcriptomic Analysismentioning

confidence: 99%

Secreted Phosphoprotein 1 Is a Determinant of Lung Function Development in Mice

Ganguly

Martin

Concel

et al. 2014

Am J Respir Cell Mol Biol

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Secreted phosphoprotein 1 (Spp1) is located within quantitative trait loci associated with lung function that was previously identified by contrasting C3H/HeJ and JF1/Msf mouse strains that have extremely divergent lung function. JF1/Msf mice with diminished lung function had reduced lung SPP1 transcript and protein during the peak stage of alveologenesis (postnatal day [P]14-P28) as compared with C3H/ HeJ mice. In addition to a previously identified genetic variant that altered runt-related transcription factor 2 (RUNX2) binding in the Spp1 promoter, we identified another promoter variant in a putative RUNX2 binding site that increased the DNA protein binding. SPP1 induced dose-dependent mouse lung epithelial-15 cell proliferation. Spp1(2/2) mice have decreased specific total lung capacity/body weight, higher specific compliance, and increased mean airspace chord length (L m ) compared with Spp1(1/1) mice. Microarray analysis revealed enriched gene ontogeny categories, with numerous genes associated with lung development and/or respiratory disease. Insulin-like growth factor 1, Hedgehog-interacting protein, winglessrelated mouse mammary tumor virus integration site 5A, and NOTCH1 transcripts decreased in the lung of P14 Spp1 (2/2) mice as determined by quantitative RT-PCR analysis. SPP1 promotes pneumocyte growth, and mice lacking SPP1 have smaller, more compliant lungs with enlarged airspace (i.e., increased L m ). Microarray analysis suggests a dysregulation of key lung developmental transcripts in gene-targeted Spp1 (2/2) mice, particularly during the peak phase of alveologenesis. In addition to its known roles in lung disease, this study supports SPP1 as a determinant of lung development in mice.

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“…Altered PP2A activity plays a key role in cancer (3), neurodegenerative diseases (4), and innate immune responses (5). In the lung, PP2A is a key modulator of inflammatory responses in asthma (6) and chronic obstructive pulmonary disease (COPD) (5). Despite its importance in these and other biological processes, the mechanisms by which PP2A is regulated within the lung remains to be determined.…”

mentioning

confidence: 99%

The Glutathione Peroxidase 1–Protein Tyrosine Phosphatase 1B–Protein Phosphatase 2A Axis. A Key Determinant of Airway Inflammation and Alveolar Destruction

Geraghty

Hardigan

Wallace

et al. 2013

Am J Respir Cell Mol Biol

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Protein phosphatase-2A (PP2A) is a primary serine-threonine phosphatase that modulates inflammatory responses in asthma and chronic obstructive pulmonary disease (COPD). Despite its importance, the mechanisms that regulate lung PP2A activity remain to be determined. The redox-sensitive enzyme protein tyrosine phosphatase-1B (PTP1B) activates PP2A by dephosphorylating the catalytic subunit of the protein at tyrosine 307. This study aimed to identify how the interaction between the intracellular antioxidant glutathione peroxidase-1 (GPx-1) and PTP1B affected lung PP2A activity and airway inflammation. Experiments using gene silencing techniques in mouse lung or human small airway epithelial cells determined that knocking down PTP1B expression blocked GPx-1's activation of PP2A and negated the anti-inflammatory effects of GPx-1 protein in the lung. Similarly, the expression of human GPx-1 in transgenic mice significantly increased PP2A and PTP1B activities and prevented chronic cigarette smoke-induced airway inflammation and alveolar destruction. GPx-1 knockout mice, however, exhibited an exaggerated emphysema phenotype, correlating with a nonresponsive PP2A pathway. Importantly, GPx-1-PTP1B-PP2A signaling becomes inactivated in advanced lung disease. Indeed, PTP1B protein was oxidized in the lungs of subjects with advanced emphysema, and cigarette smoke did not increase GPx-1 or PTP1B activity within epithelial cells isolated from subjects with COPD, unlike samples of healthy lung epithelial cells. In conclusion, these findings establish that the GPx-1-PTP1B-PP2A axis plays a critical role in countering the inflammatory and proteolytic responses that result in lung-tissue destruction in response to cigarette smoke exposure.Keywords: phosphorylation; inflammation; oxidation; kinase Protein phosphatase-2A (PP2A) is the major serine-threonine eukaryotic phosphatase (1), and accounts for up to 1% of total cellular protein (2). Altered PP2A activity plays a key role in cancer (3), neurodegenerative diseases (4), and innate immune responses (5). In the lung, PP2A is a key modulator of inflammatory responses in asthma (6) and chronic obstructive pulmonary disease (COPD) (5). Despite its importance in these and other biological processes, the mechanisms by which PP2A is regulated within the lung remains to be determined. Increasing evidence indicates that PP2A activity is sensitive to the redox status of the cell (7). Indeed, deficiencies in PP2A activity during Alzheimer disease (8) and chronic lymphocytic leukemia (9) are associated with enhanced oxidative stress and impaired antioxidant defenses (10,11). Despite the established links between oxidative stress and altered PP2A activity, the biological pathways by which redox factors modulate PP2A activity to influence disease development are not yet known.Increased oxidative injury has been detected in the lungs of patients with COPD, and animal studies demonstrate that inflammation in this disease can be regulated by the redox status of the lung (12, 13). COPD is the th...

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Defects of Protein Phosphatase 2A Causes Corticosteroid Insensitivity in Severe Asthma

Cited by 75 publications

References 31 publications

Thermodynamic Dissection of the Intrinsically Disordered N-terminal Domain of Human Glucocorticoid Receptor

Thermodynamic Dissection of the Intrinsically Disordered N-terminal Domain of Human Glucocorticoid Receptor

Secreted Phosphoprotein 1 Is a Determinant of Lung Function Development in Mice

The Glutathione Peroxidase 1–Protein Tyrosine Phosphatase 1B–Protein Phosphatase 2A Axis. A Key Determinant of Airway Inflammation and Alveolar Destruction

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