From phosphoproteins to phosphoproteomes: a historical account

Venerando, Andrea; Cesaro, Luca; Pinna, Lorenzo A.

doi:10.1111/febs.14014

Cited by 32 publications

(20 citation statements)

References 90 publications

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“…If S-nitrosation participates in cellular signaling and is not simply a result of nitrosative stress, the cellular levels of protein S-nitrosation must be tightly controlled (12). In this sense, S-nitrosation is often compared to O-phosphorylation, where a kinase transfers a phosphoryl moiety to an acceptor amino acid from an ATP donor molecule, which then changes the function or activity of the enzyme target (13). Phosphatases then act to reverse the process by hydrolytically removing the phosphoryl group.…”

mentioning

confidence: 99%

Comparative and integrative metabolomics reveal that S-nitrosation inhibits physiologically relevant metabolic enzymes

Bruegger¹,

Smith²,

Wynia-Smith³

et al. 2018

Journal of Biological Chemistry

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Cysteine S-nitrosation is a reversible posttranslational modification mediated by nitric oxide (•NO)-derived agents. S-nitrosation participates in cellular signaling and is associated with several diseases such as cancer, cardiovascular diseases, and neuronal disorders. Despite the physiological importance of this nonclassical •NO signaling pathway, little is understood about how much S-nitrosation affects protein function. Moreover, identifying physiologically relevant targets of S-nitrosation is difficult because of the dynamics of transnitrosation and a limited understanding of the physiological mechanisms leading to selective protein S-nitrosation. To identify proteins whose activities are modulated by S-nitrosation, we performed a metabolomics study comparing wild-type and endothelial nitric oxide synthase (eNOS) knockout mice. We integrated our results with those of a previous proteomics study that identified physiologically relevant S-nitrosated cysteines, and we found that the activity of at least 21 metabolic enzymes might be regulated by Snitrosation. We cloned, expressed, and purified four of these enzymes and observed that S-nitrosation inhibits the metabolic enzymes 6-phosphogluconate dehydrogenase (6PGD), Δ1-pyrroline-5-carboxylate dehydrogenase (ALDH4A1), catechol-O-methyltransferase (COMT), and D-3-phosphoglycerate dehydrogenase (PHGDH). Furthermore, using sitedirected mutagenesis, we identified the predominate cysteine residue influencing the observed activity changes in each enzyme. In summary, using an integrated metabolomics approach, we have identified several physiologically relevant S-nitrosation targets, including metabolic enzymes, which are inhibited by this modification, and have found the cysteines modified by S-nitrosation in each enzyme.Nitric oxide (•NO) is an important signaling molecule in vertebrate tissue that controls physiological processes including vasodilation, neurotransmission, and platelet aggregation (1-3).•NO is biosynthesized by the three mammalian isoforms of nitric oxide synthase (NOS). Endothelial (eNOS) and neuronal NOS (nNOS) produce picomolar to nanomolar concentrations of •NO for cellular signaling, while inducible NOS (iNOS) produces •NO at cytotoxic concentrations in the low micromolar range at sites of infection (4,5). The most thoroughly characterized •NO signaling pathway involves the enzyme soluble guanylate cyclase (sGC) (6).•NO produced by NOS freely diffuses into adjacent cells where it activates sGC to increase the concentration of the secondary messenger cyclic guanosine monophosphate (cGMP) that activates downstream signaling pathways. S-nitrosation Modifies Metabolic Enzyme Function 2Another important, though less well understood, signaling mechanism involving •NO is cysteine S-nitrosation. S-nitrosation is a posttranslational modification of cysteine residues by which an S-nitrosothiol is initially formed via a oneelectron oxidation. Once formed, S-nitrosothiols can be transferred through an intermediate transnitrosating agent such as S-...

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mentioning

confidence: 99%

Comparative and integrative metabolomics reveal that S-nitrosation inhibits physiologically relevant metabolic enzymes

Bruegger¹,

Smith²,

Wynia-Smith³

et al. 2018

Journal of Biological Chemistry

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“…It is now clear that casein is not a natural substrate of CK2. The kinase committed to the phosphorylation of casein in the Golgi apparatus of the lactating mammary gland is conventionally termed genuine or Golgi casein kinase (92).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Ecto‑protein kinase CK2, the neglected form of CK2 (Review)

Montenarh

Götz

2018

biom rep

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Ecto-protein kinases, including protein kinase CK2 (former name, casein kinase 2), have been the focus of research for more than 30 years. At the beginning of the ecto-kinase research their identification was performed with substrates and inhibitors whose specificity under the current knowledge was rather limited. Since all currently known ecto-kinases, including ecto-CK2, have intracellular counterparts, one has to exclude that an ecto-localization originates from intracellular counterparts after cell damage. Protein kinase CK2 is involved in cellular key processes such as cell cycle progression, inhibition of apoptosis, DNA damage repair, differentiation and many other processes. CK2 is composed of two catalytic CK2α or CK2α' subunits and two non-catalytic CK2β subunits. Progress in the ecto-kinase and in particular ecto-CK2 studies was made with the use of transfected tagged CK2 subunits, which allowed to follow their individual transport and localization on the cell surface after transfection. Furthermore, immunofluorescence studies with antibodies against CK2 subunits as well as affinity chromatography with a binding partner of CK2 subunits have improved ecto-kinase research. The use of new and more specific inhibitors as well as of substrates, which do not cross the plasma membrane, have further improved the specificity for ecto-CK2. From the various substrates of ecto-CK2, it can be concluded that ecto-CK2 plays a role in Alzheimer disease, cell adhesion, platelet aggregation, immune response and cellular signalling. New tools and techniques, to study ecto-CK2 activity, are required to identify new substrates and thereby new functional implications for ecto-CK2.

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“…Due to this, there has been increasing interest in investigating kinases on a global scale. Kinase based investigations generally focus on one of two major categories; (1) the phosphoproteome[ 1 – 4 ], the set of kinase targets and, (2) the kinome[ 5 – 9 ], the set of cellular kinases. Kinome analysis can focus on either quantification of kinase abundance or activity.…”

Section: Introductionmentioning

confidence: 99%

Kinomics toolbox—A web platform for analysis and viewing of kinomic peptide array data

et al. 2018

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Kinomics is an emerging field of science that involves the study of global kinase activity. As kinases are essential players in virtually all cellular activities, kinomic testing can directly examine protein function, distinguishing kinomics from more remote, upstream components of the central dogma, such as genomics and transcriptomics. While there exist several different approaches for kinomic research, peptide microarrays are the most widely used and involve kinase activity assessment through measurement of phosphorylation of peptide substrates on the array. Unfortunately, bioinformatic tools for analyzing kinomic data are quite limited necessitating the development of accessible open access software in order to facilitate standardization and dissemination of kinomic data for scientific use. Here, we examine and present tools for data analysis for the popular PamChip® (PamGene International) kinomic peptide microarray. As a result, we propose (1) a procedural optimization of kinetic curve data capture, (2) new methods for background normalization, (3) guidelines for the detection of outliers during parameterization, and (4) a standardized data model to store array data at various analytical points. In order to utilize the new data model, we developed a series of tools to implement the new methods and to visualize the various data models. In the interest of accessibility, we developed this new toolbox as a series of JavaScript procedures that can be utilized as either server side resources (easily packaged as web services) or as client side scripts (web applications running in the browser). The aggregation of these tools within a Kinomics Toolbox provides an extensible web based analytic platform that researchers can engage directly and web programmers can extend. As a proof of concept, we developed three analytical tools, a technical reproducibility visualizer, an ANOVA based detector of differentially phosphorylated peptides, and a heatmap display with hierarchical clustering.

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From phosphoproteins to phosphoproteomes: a historical account

Cited by 32 publications

References 90 publications

Comparative and integrative metabolomics reveal that S-nitrosation inhibits physiologically relevant metabolic enzymes

Comparative and integrative metabolomics reveal that S-nitrosation inhibits physiologically relevant metabolic enzymes

Ecto‑protein kinase CK2, the neglected form of CK2 (Review)

Kinomics toolbox—A web platform for analysis and viewing of kinomic peptide array data

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