Analyses of PDE-regulated phosphoproteomes reveal unique and specific cAMP-signaling modules in T cells

Specific functions for different cyclic nucleotide phosphodiesterases (PDEs) have not yet been identified in most cell types. Conventional approaches to study PDE function typically rely on measurements of global cAMP, general increases in cAMP-dependent protein kinase (PKA), or the activity of exch...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 30; pp. E6240 - E6249
Main Authors Beltejar, Michael-Claude G., Lau, Ho-Tak, Golkowski, Martin G., Ong, Shao-En, Beavo, Joseph A.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 25.07.2017
SeriesPNAS Plus
Subjects
3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors
3',5'-Cyclic-nucleotide phosphodiesterase
Adipocytes
Algorithms
Bioinformatics
Biological effects
Biological Sciences
Cascades
Cyclic AMP
Fluorescence resonance energy transfer
Humans
Inhibitors
Jurkat Cells
Lymphocytes
Lymphocytes T
Mass spectrometry
Mass spectroscopy
Metabolic Networks and Pathways
Molecules
Pharmacology
Phosphoproteins - metabolism
Phosphoproteomes
Phosphorylation
PNAS Plus
Protein kinase A
Proteomics
Signal transduction
Substrates
T-Lymphocytes - metabolism
phosphoproteomics
PDE
phosphodiesterase
cAMP
PKA
Online AccessGet full text
ISSN0027-8424
1091-6490
1091-6490
DOI10.1073/pnas.1703939114

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Abstract Specific functions for different cyclic nucleotide phosphodiesterases (PDEs) have not yet been identified in most cell types. Conventional approaches to study PDE function typically rely on measurements of global cAMP, general increases in cAMP-dependent protein kinase (PKA), or the activity of exchange protein activated by cAMP (EPAC). Although newer approaches using subcellularly targeted FRET reporter sensors have helped define more compartmentalized regulation of cAMP, PKA, and EPAC, they have limited ability to link this regulation to downstream effector molecules and biological functions. To address this problem, we have begun to use an unbiased mass spectrometry-based approach coupled with treatment using PDE isozyme-selective inhibitors to characterize the phosphoproteomes of the functional pools of cAMP/PKA/EPAC that are regulated by specific cAMP-PDEs (the PDE-regulated phosphoproteomes). In Jurkat cells we find multiple, distinct PDE-regulated phosphoproteomes that can be defined by their responses to different PDE inhibitors. We also find that little phosphorylation occurs unless at least two different PDEs are concurrently inhibited in these cells. Moreover, bioinformatics analyses of these phosphoproteomes provide insight into the unique functional roles, mechanisms of action, and synergistic relationships among the different PDEs that coordinate cAMP-signaling cascades in these cells. The data strongly suggest that the phosphorylation of many different substrates contributes to cAMP-dependent regulation of these cells. The findings further suggest that the approach of using selective, inhibitor-dependent phosphoproteome analysis can provide a generalized methodology for understanding the roles of different PDEs in the regulation of cyclic nucleotide signaling.
AbstractList Specific functions for different cyclic nucleotide phosphodiesterases (PDEs) have not yet been identified in most cell types. Conventional approaches to study PDE function typically rely on measurements of global cAMP, general increases in cAMP-dependent protein kinase (PKA), or the activity of exchange protein activated by cAMP (EPAC). Although newer approaches using subcellularly targeted FRET reporter sensors have helped define more compartmentalized regulation of cAMP, PKA, and EPAC, they have limited ability to link this regulation to downstream effector molecules and biological functions. To address this problem, we have begun to use an unbiased mass spectrometry-based approach coupled with treatment using PDE isozyme-selective inhibitors to characterize the phosphoproteomes of the functional pools of cAMP/PKA/EPAC that are regulated by specific cAMP-PDEs (the PDE-regulated phosphoproteomes). In Jurkat cells we find multiple, distinct PDE-regulated phosphoproteomes that can be defined by their responses to different PDE inhibitors. We also find that little phosphorylation occurs unless at least two different PDEs are concurrently inhibited in these cells. Moreover, bioinformatics analyses of these phosphoproteomes provide insight into the unique functional roles, mechanisms of action, and synergistic relationships among the different PDEs that coordinate cAMP-signaling cascades in these cells. The data strongly suggest that the phosphorylation of many different substrates contributes to cAMP-dependent regulation of these cells. The findings further suggest that the approach of using selective, inhibitor-dependent phosphoproteome analysis can provide a generalized methodology for understanding the roles of different PDEs in the regulation of cyclic nucleotide signaling.Specific functions for different cyclic nucleotide phosphodiesterases (PDEs) have not yet been identified in most cell types. Conventional approaches to study PDE function typically rely on measurements of global cAMP, general increases in cAMP-dependent protein kinase (PKA), or the activity of exchange protein activated by cAMP (EPAC). Although newer approaches using subcellularly targeted FRET reporter sensors have helped define more compartmentalized regulation of cAMP, PKA, and EPAC, they have limited ability to link this regulation to downstream effector molecules and biological functions. To address this problem, we have begun to use an unbiased mass spectrometry-based approach coupled with treatment using PDE isozyme-selective inhibitors to characterize the phosphoproteomes of the functional pools of cAMP/PKA/EPAC that are regulated by specific cAMP-PDEs (the PDE-regulated phosphoproteomes). In Jurkat cells we find multiple, distinct PDE-regulated phosphoproteomes that can be defined by their responses to different PDE inhibitors. We also find that little phosphorylation occurs unless at least two different PDEs are concurrently inhibited in these cells. Moreover, bioinformatics analyses of these phosphoproteomes provide insight into the unique functional roles, mechanisms of action, and synergistic relationships among the different PDEs that coordinate cAMP-signaling cascades in these cells. The data strongly suggest that the phosphorylation of many different substrates contributes to cAMP-dependent regulation of these cells. The findings further suggest that the approach of using selective, inhibitor-dependent phosphoproteome analysis can provide a generalized methodology for understanding the roles of different PDEs in the regulation of cyclic nucleotide signaling.
SignificanceWe have coupled mass spectrometry-based phosphoproteomic analyses with treatment using various selective PDE inhibitors to characterize the PDE-regulated phosphoproteome of CD3/CD28-stimulated Jurkat cells. Predictive algorithms were used to identify likely upstream regulatory kinases, metabolic pathways, and biological processes that can be regulated by different PDEs. Here we compare the phosphoproteomes of different functional compartments subserved by combinations of individual PDE isozymes in a T-cell model. We observed unique phosphoproteomes associated with specific combinations of PDEs. These data allow one to prioritize future experiments to understand further how these pathways are regulated by specific PDEs. The results also have substantial implications for the design and use of selective PDE inhibitors in clinical practice. Specific functions for different cyclic nucleotide phosphodiesterases (PDEs) have not yet been identified in most cell types. Conventional approaches to study PDE function typically rely on measurements of global cAMP, general increases in cAMP-dependent protein kinase (PKA), or the activity of exchange protein activated by cAMP (EPAC). Although newer approaches using subcellularly targeted FRET reporter sensors have helped define more compartmentalized regulation of cAMP, PKA, and EPAC, they have limited ability to link this regulation to downstream effector molecules and biological functions. To address this problem, we have begun to use an unbiased mass spectrometry-based approach coupled with treatment using PDE isozyme-selective inhibitors to characterize the phosphoproteomes of the functional pools of cAMP/PKA/EPAC that are regulated by specific cAMP-PDEs (the PDE-regulated phosphoproteomes). In Jurkat cells we find multiple, distinct PDE-regulated phosphoproteomes that can be defined by their responses to different PDE inhibitors. We also find that little phosphorylation occurs unless at least two different PDEs are concurrently inhibited in these cells. Moreover, bioinformatics analyses of these phosphoproteomes provide insight into the unique functional roles, mechanisms of action, and synergistic relationships among the different PDEs that coordinate cAMP-signaling cascades in these cells. The data strongly suggest that the phosphorylation of many different substrates contributes to cAMP-dependent regulation of these cells. The findings further suggest that the approach of using selective, inhibitor-dependent phosphoproteome analysis can provide a generalized methodology for understanding the roles of different PDEs in the regulation of cyclic nucleotide signaling.
We have coupled mass spectrometry-based phosphoproteomic analyses with treatment using various selective PDE inhibitors to characterize the PDE-regulated phosphoproteome of CD3/CD28-stimulated Jurkat cells. Predictive algorithms were used to identify likely upstream regulatory kinases, metabolic pathways, and biological processes that can be regulated by different PDEs. Here we compare the phosphoproteomes of different functional compartments subserved by combinations of individual PDE isozymes in a T-cell model. We observed unique phosphoproteomes associated with specific combinations of PDEs. These data allow one to prioritize future experiments to understand further how these pathways are regulated by specific PDEs. The results also have substantial implications for the design and use of selective PDE inhibitors in clinical practice. Specific functions for different cyclic nucleotide phosphodiesterases (PDEs) have not yet been identified in most cell types. Conventional approaches to study PDE function typically rely on measurements of global cAMP, general increases in cAMP-dependent protein kinase (PKA), or the activity of exchange protein activated by cAMP (EPAC). Although newer approaches using subcellularly targeted FRET reporter sensors have helped define more compartmentalized regulation of cAMP, PKA, and EPAC, they have limited ability to link this regulation to downstream effector molecules and biological functions. To address this problem, we have begun to use an unbiased mass spectrometry-based approach coupled with treatment using PDE isozyme-selective inhibitors to characterize the phosphoproteomes of the functional pools of cAMP/PKA/EPAC that are regulated by specific cAMP-PDEs (the PDE-regulated phosphoproteomes). In Jurkat cells we find multiple, distinct PDE-regulated phosphoproteomes that can be defined by their responses to different PDE inhibitors. We also find that little phosphorylation occurs unless at least two different PDEs are concurrently inhibited in these cells. Moreover, bioinformatics analyses of these phosphoproteomes provide insight into the unique functional roles, mechanisms of action, and synergistic relationships among the different PDEs that coordinate cAMP-signaling cascades in these cells. The data strongly suggest that the phosphorylation of many different substrates contributes to cAMP-dependent regulation of these cells. The findings further suggest that the approach of using selective, inhibitor-dependent phosphoproteome analysis can provide a generalized methodology for understanding the roles of different PDEs in the regulation of cyclic nucleotide signaling.
We have coupled mass spectrometry-based phosphoproteomic analyses with treatment using various selective PDE inhibitors to characterize the PDE-regulated phosphoproteome of CD3/CD28-stimulated Jurkat cells. Predictive algorithms were used to identify likely upstream regulatory kinases, metabolic pathways, and biological processes that can be regulated by different PDEs. Here we compare the phosphoproteomes of different functional compartments subserved by combinations of individual PDE isozymes in a T-cell model. We observed unique phosphoproteomes associated with specific combinations of PDEs. These data allow one to prioritize future experiments to understand further how these pathways are regulated by specific PDEs. The results also have substantial implications for the design and use of selective PDE inhibitors in clinical practice. Specific functions for different cyclic nucleotide phosphodiesterases (PDEs) have not yet been identified in most cell types. Conventional approaches to study PDE function typically rely on measurements of global cAMP, general increases in cAMP-dependent protein kinase (PKA), or the activity of exchange protein activated by cAMP (EPAC). Although newer approaches using subcellularly targeted FRET reporter sensors have helped define more compartmentalized regulation of cAMP, PKA, and EPAC, they have limited ability to link this regulation to downstream effector molecules and biological functions. To address this problem, we have begun to use an unbiased mass spectrometry-based approach coupled with treatment using PDE isozyme-selective inhibitors to characterize the phosphoproteomes of the functional pools of cAMP/PKA/EPAC that are regulated by specific cAMP-PDEs (the PDE-regulated phosphoproteomes). In Jurkat cells we find multiple, distinct PDE-regulated phosphoproteomes that can be defined by their responses to different PDE inhibitors. We also find that little phosphorylation occurs unless at least two different PDEs are concurrently inhibited in these cells. Moreover, bioinformatics analyses of these phosphoproteomes provide insight into the unique functional roles, mechanisms of action, and synergistic relationships among the different PDEs that coordinate cAMP-signaling cascades in these cells. The data strongly suggest that the phosphorylation of many different substrates contributes to cAMP-dependent regulation of these cells. The findings further suggest that the approach of using selective, inhibitor-dependent phosphoproteome analysis can provide a generalized methodology for understanding the roles of different PDEs in the regulation of cyclic nucleotide signaling.
Specific functions for different cyclic nucleotide phosphodiesterases (PDEs) have not yet been identified in most cell types. Conventional approaches to study PDE function typically rely on measurements of global cAMP, general increases in cAMP-dependent protein kinase (PKA), or the activity of exchange protein activated by cAMP (EPAC). Although newer approaches using subcellularly targeted FRET reporter sensors have helped define more compartmentalized regulation of cAMP, PKA, and EPAC, they have limited ability to link this regulation to downstream effector molecules and biological functions. To address this problem, we have begun to use an unbiased mass spectrometry-based approach coupled with treatment using PDE isozyme-selective inhibitors to characterize the phosphoproteomes of the functional pools of cAMP/PKA/EPAC that are regulated by specific cAMP-PDEs (the PDE-regulated phosphoproteomes). In Jurkat cells we find multiple, distinct PDE-regulated phosphoproteomes that can be defined by their responses to different PDE inhibitors. We also find that little phosphorylation occurs unless at least two different PDEs are concurrently inhibited in these cells. Moreover, bioinformatics analyses of these phosphoproteomes provide insight into the unique functional roles, mechanisms of action, and synergistic relationships among the different PDEs that coordinate cAMP-signaling cascades in these cells. The data strongly suggest that the phosphorylation of many different substrates contributes to cAMP-dependent regulation of these cells. The findings further suggest that the approach of using selective, inhibitor-dependent phosphoproteome analysis can provide a generalized methodology for understanding the roles of different PDEs in the regulation of cyclic nucleotide signaling.
Author Golkowski, Martin G.
Beavo, Joseph A.
Ong, Shao-En
Lau, Ho-Tak
Beltejar, Michael-Claude G.
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/28634298$$D View this record in MEDLINE/PubMed
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Keywords phosphoproteomics
PDE
phosphodiesterase
cAMP
PKA
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content type line 23
Reviewers: P.M.E., University of Connecticut Health Center; D.H.M., Queen's University; and K.T., University of Oslo.
Author contributions: M.-C.G.B., H.-T.L., M.G.G., S.-E.O., and J.A.B. designed research; M.-C.G.B., H.-T.L., M.G.G., and S.-E.O. performed research; M.-C.G.B., H.-T.L., M.G.G., and S.-E.O. contributed new reagents/analytic tools; M.-C.G.B., H.-T.L., M.G.G., S.-E.O., and J.A.B. analyzed data; and M.-C.G.B., H.-T.L., M.G.G., S.-E.O., and J.A.B. wrote the paper.
Contributed by Joseph A. Beavo, May 28, 2017 (sent for review March 10, 2017; reviewed by Paul M. Epstein, Donald H. Maurice, and Kjetil Tasken)
OpenAccessLink https://proxy.k.utb.cz/login?url=https://www.pnas.org/content/pnas/114/30/E6240.full.pdf
PMID 28634298
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PublicationTitle Proceedings of the National Academy of Sciences - PNAS
PublicationTitleAbbrev Proc Natl Acad Sci USA
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PublicationYear 2017
Publisher National Academy of Sciences
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Snippet Specific functions for different cyclic nucleotide phosphodiesterases (PDEs) have not yet been identified in most cell types. Conventional approaches to study...
SignificanceWe have coupled mass spectrometry-based phosphoproteomic analyses with treatment using various selective PDE inhibitors to characterize the...
We have coupled mass spectrometry-based phosphoproteomic analyses with treatment using various selective PDE inhibitors to characterize the PDE-regulated...
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SubjectTerms 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors
3',5'-Cyclic-nucleotide phosphodiesterase
Adipocytes
Algorithms
Bioinformatics
Biological effects
Biological Sciences
Cascades
Cyclic AMP
Fluorescence resonance energy transfer
Humans
Inhibitors
Jurkat Cells
Lymphocytes
Lymphocytes T
Mass spectrometry
Mass spectroscopy
Metabolic Networks and Pathways
Molecules
Pharmacology
Phosphoproteins - metabolism
Phosphoproteomes
Phosphorylation
PNAS Plus
Protein kinase A
Proteomics
Signal transduction
Substrates
T-Lymphocytes - metabolism
Title Analyses of PDE-regulated phosphoproteomes reveal unique and specific cAMP-signaling modules in T cells
URI https://www.jstor.org/stable/26486191
https://www.pnas.org/doi/10.1073/pnas.1703939114
https://www.ncbi.nlm.nih.gov/pubmed/28634298
https://www.proquest.com/docview/1946416448
https://www.proquest.com/docview/1912198203
https://pubmed.ncbi.nlm.nih.gov/PMC5544305
https://www.pnas.org/content/pnas/114/30/E6240.full.pdf
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