The Glutathione Peroxidase 1–Protein Tyrosine Phosphatase 1B–Protein Phosphatase 2A Axis. A Key Determinant of Airway Inflammation and Alveolar Destruction
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 protei...
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Published in | American journal of respiratory cell and molecular biology Vol. 49; no. 5; pp. 721 - 730 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Thoracic Society
01.11.2013
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Subjects | |
Online Access | Get full text |
ISSN | 1044-1549 1535-4989 1535-4989 |
DOI | 10.1165/rcmb.2013-0026OC |
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Abstract | 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. |
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AbstractList | 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.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. 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. |
Author | Geraghty, Patrick Mirochnitchenko, Oleg Foronjy, Robert F. Hardigan, Andrew A. Thompson, Victor Thankachen, Jincy D’Armiento, Jeanine M. Wallace, Alison M. Arellanos, Leo |
Author_xml | – sequence: 1 givenname: Patrick surname: Geraghty fullname: Geraghty, Patrick organization: St. Luke’s Roosevelt Hospital Center, New York, New York – sequence: 2 givenname: Andrew A. surname: Hardigan fullname: Hardigan, Andrew A. organization: St. Luke’s Roosevelt Hospital Center, New York, New York – sequence: 3 givenname: Alison M. surname: Wallace fullname: Wallace, Alison M. organization: Columbia University, New York, New York; and – sequence: 4 givenname: Oleg surname: Mirochnitchenko fullname: Mirochnitchenko, Oleg organization: National Institutes of Health, Bethesda, Maryland – sequence: 5 givenname: Jincy surname: Thankachen fullname: Thankachen, Jincy organization: Columbia University, New York, New York; and – sequence: 6 givenname: Leo surname: Arellanos fullname: Arellanos, Leo organization: Columbia University, New York, New York; and – sequence: 7 givenname: Victor surname: Thompson fullname: Thompson, Victor organization: Columbia University, New York, New York; and – sequence: 8 givenname: Jeanine M. surname: D’Armiento fullname: D’Armiento, Jeanine M. organization: Columbia University, New York, New York; and – sequence: 9 givenname: Robert F. surname: Foronjy fullname: Foronjy, Robert F. organization: St. Luke’s Roosevelt Hospital Center, New York, New York |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23590304$$D View this record in MEDLINE/PubMed |
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SubjectTerms | Animals Case-Control Studies Cell Line Enzyme Activation Gene Knockdown Techniques Glutathione Peroxidase - deficiency Glutathione Peroxidase - genetics Glutathione Peroxidase - metabolism Humans Mice Mice, Inbred C57BL Mice, Inbred CBA Mice, Knockout Oxidation-Reduction Oxidative Stress Phosphorylation Pneumonia - enzymology Pneumonia - etiology Pneumonia - genetics Pneumonia - pathology Pneumonia - prevention & control Protein Binding Protein Phosphatase 2 - metabolism Protein Tyrosine Phosphatase, Non-Receptor Type 1 - genetics Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism Pulmonary Alveoli - enzymology Pulmonary Alveoli - pathology Pulmonary Disease, Chronic Obstructive - enzymology Pulmonary Disease, Chronic Obstructive - pathology Pulmonary Emphysema - enzymology Pulmonary Emphysema - pathology Respiratory Mucosa - enzymology Respiratory Mucosa - pathology RNA Interference Signal Transduction Smoking - adverse effects Transfection |
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Title | 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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