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Serine/Threonine Protein Phosphatases 1 and 2A in Lung Endothelial Barrier Regulation

Vascular barrier dysfunction is characterized by increased permeability and inflammation of endothelial cells (ECs), which are prominent features of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and sepsis, and a major complication of the SARS-CoV-2 infection and COVID-19. Fun...

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Autores principales: Patil, Rahul S., Kovacs-Kasa, Anita, Gorshkov, Boris A., Fulton, David J. R., Su, Yunchao, Batori, Robert K., Verin, Alexander D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10296329/
https://www.ncbi.nlm.nih.gov/pubmed/37371733
http://dx.doi.org/10.3390/biomedicines11061638
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author Patil, Rahul S.
Kovacs-Kasa, Anita
Gorshkov, Boris A.
Fulton, David J. R.
Su, Yunchao
Batori, Robert K.
Verin, Alexander D.
author_facet Patil, Rahul S.
Kovacs-Kasa, Anita
Gorshkov, Boris A.
Fulton, David J. R.
Su, Yunchao
Batori, Robert K.
Verin, Alexander D.
author_sort Patil, Rahul S.
collection PubMed
description Vascular barrier dysfunction is characterized by increased permeability and inflammation of endothelial cells (ECs), which are prominent features of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and sepsis, and a major complication of the SARS-CoV-2 infection and COVID-19. Functional impairment of the EC barrier and accompanying inflammation arises due to microbial toxins and from white blood cells of the lung as part of a defensive action against pathogens, ischemia-reperfusion or blood product transfusions, and aspiration syndromes-based injury. A loss of barrier function results in the excessive movement of fluid and macromolecules from the vasculature into the interstitium and alveolae resulting in pulmonary edema and collapse of the architecture and function of the lungs, and eventually culminates in respiratory failure. Therefore, EC barrier integrity, which is heavily dependent on cytoskeletal elements (mainly actin filaments, microtubules (MTs), cell-matrix focal adhesions, and intercellular junctions) to maintain cellular contacts, is a critical requirement for the preservation of lung function. EC cytoskeletal remodeling is regulated, at least in part, by Ser/Thr phosphorylation/dephosphorylation of key cytoskeletal proteins. While a large body of literature describes the role of phosphorylation of cytoskeletal proteins on Ser/Thr residues in the context of EC barrier regulation, the role of Ser/Thr dephosphorylation catalyzed by Ser/Thr protein phosphatases (PPases) in EC barrier regulation is less documented. Ser/Thr PPases have been proposed to act as a counter-regulatory mechanism that preserves the EC barrier and opposes EC contraction. Despite the importance of PPases, our knowledge of the catalytic and regulatory subunits involved, as well as their cellular targets, is limited and under-appreciated. Therefore, the goal of this review is to discuss the role of Ser/Thr PPases in the regulation of lung EC cytoskeleton and permeability with special emphasis on the role of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) as major mammalian Ser/Thr PPases. Importantly, we integrate the role of PPases with the structural dynamics of the cytoskeleton and signaling cascades that regulate endothelial cell permeability and inflammation.
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spelling pubmed-102963292023-06-28 Serine/Threonine Protein Phosphatases 1 and 2A in Lung Endothelial Barrier Regulation Patil, Rahul S. Kovacs-Kasa, Anita Gorshkov, Boris A. Fulton, David J. R. Su, Yunchao Batori, Robert K. Verin, Alexander D. Biomedicines Review Vascular barrier dysfunction is characterized by increased permeability and inflammation of endothelial cells (ECs), which are prominent features of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and sepsis, and a major complication of the SARS-CoV-2 infection and COVID-19. Functional impairment of the EC barrier and accompanying inflammation arises due to microbial toxins and from white blood cells of the lung as part of a defensive action against pathogens, ischemia-reperfusion or blood product transfusions, and aspiration syndromes-based injury. A loss of barrier function results in the excessive movement of fluid and macromolecules from the vasculature into the interstitium and alveolae resulting in pulmonary edema and collapse of the architecture and function of the lungs, and eventually culminates in respiratory failure. Therefore, EC barrier integrity, which is heavily dependent on cytoskeletal elements (mainly actin filaments, microtubules (MTs), cell-matrix focal adhesions, and intercellular junctions) to maintain cellular contacts, is a critical requirement for the preservation of lung function. EC cytoskeletal remodeling is regulated, at least in part, by Ser/Thr phosphorylation/dephosphorylation of key cytoskeletal proteins. While a large body of literature describes the role of phosphorylation of cytoskeletal proteins on Ser/Thr residues in the context of EC barrier regulation, the role of Ser/Thr dephosphorylation catalyzed by Ser/Thr protein phosphatases (PPases) in EC barrier regulation is less documented. Ser/Thr PPases have been proposed to act as a counter-regulatory mechanism that preserves the EC barrier and opposes EC contraction. Despite the importance of PPases, our knowledge of the catalytic and regulatory subunits involved, as well as their cellular targets, is limited and under-appreciated. Therefore, the goal of this review is to discuss the role of Ser/Thr PPases in the regulation of lung EC cytoskeleton and permeability with special emphasis on the role of protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) as major mammalian Ser/Thr PPases. Importantly, we integrate the role of PPases with the structural dynamics of the cytoskeleton and signaling cascades that regulate endothelial cell permeability and inflammation. MDPI 2023-06-05 /pmc/articles/PMC10296329/ /pubmed/37371733 http://dx.doi.org/10.3390/biomedicines11061638 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Patil, Rahul S.
Kovacs-Kasa, Anita
Gorshkov, Boris A.
Fulton, David J. R.
Su, Yunchao
Batori, Robert K.
Verin, Alexander D.
Serine/Threonine Protein Phosphatases 1 and 2A in Lung Endothelial Barrier Regulation
title Serine/Threonine Protein Phosphatases 1 and 2A in Lung Endothelial Barrier Regulation
title_full Serine/Threonine Protein Phosphatases 1 and 2A in Lung Endothelial Barrier Regulation
title_fullStr Serine/Threonine Protein Phosphatases 1 and 2A in Lung Endothelial Barrier Regulation
title_full_unstemmed Serine/Threonine Protein Phosphatases 1 and 2A in Lung Endothelial Barrier Regulation
title_short Serine/Threonine Protein Phosphatases 1 and 2A in Lung Endothelial Barrier Regulation
title_sort serine/threonine protein phosphatases 1 and 2a in lung endothelial barrier regulation
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10296329/
https://www.ncbi.nlm.nih.gov/pubmed/37371733
http://dx.doi.org/10.3390/biomedicines11061638
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