Version 4.0 of PaxDb: Protein abundance data, integrated across model organisms, tissues, and cell‐lines

Wang, Mingcong; Herrmann, Christina; Simonovic, Milan; Szklarczyk, Damian; Mering, Christian von

doi:10.1002/pmic.201400441

Cited by 527 publications

(578 citation statements)

References 29 publications

(34 reference statements)

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“…This evidence confirms initial studies suggesting that Mkk1 could be a stronger Slt2 activator than Mkk2 (Martin et al 2000). The preeminent role of Mkk1 over Mkk2 cannot be attributed to a higher abundance of Mkk1 because evaluation of the data collected at the PaxDb (Wang et al 2015) indicates that, in most studies, Mkk2 cellular protein levels are found to be similar to or even higher than those of Mkk1. Therefore, alternative possibilities must be considered (i.e., different specific activity or distinct subcellular localization).…”

Section: Discussionsupporting

confidence: 74%

Wide-Ranging Effects of the Yeast Ptc1 Protein Phosphatase Acting Through the MAPK Kinase Mkk1

et al. 2015

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The Saccharomyces cerevisiae type 2C protein phosphatase Ptc1 is required for a wide variety of cellular functions, although only a few cellular targets have been identified. A genetic screen in search of mutations in protein kinase-encoding genes able to suppress multiple phenotypic traits caused by the ptc1 deletion yielded a single gene, MKK1, coding for a MAPK kinase (MAPKK) known to activate the cell-wall integrity (CWI) Slt2 MAPK. In contrast, mutation of the MKK1 paralog, MKK2, had a less significant effect. Deletion of MKK1 abolished the increased phosphorylation of Slt2 induced by the absence of Ptc1 both under basal and CWI pathway stimulatory conditions. We demonstrate that Ptc1 acts at the level of the MAPKKs of the CWI pathway, but only the Mkk1 kinase activity is essential for ptc1 mutants to display high Slt2 activation. We also show that Ptc1 is able to dephosphorylate Mkk1 in vitro. Our results reveal the preeminent role of Mkk1 in signaling through the CWI pathway and strongly suggest that hyperactivation of Slt2 caused by upregulation of Mkk1 is at the basis of most of the phenotypic defects associated with lack of Ptc1 function.KEYWORDS synthetic genetic interactions; cell-wall integrity pathway; protein dephosphorylation; Saccharomyces cerevisiae P ROTEIN kinases play an essential role in nearly every aspect of cell physiology, and the activity of these key players is frequently modulated by phosphorylation. Therefore, protein phosphatases (PPases) are important regulators of protein kinases and cellular homeostasis. Among them, type 2C Ser/Thr PPases constitute an evolutionarily conserved group that, in contrast to other PPase families, are monomeric enzymes apparently lacking regulatory subunits. In the yeast Saccharomyces cerevisiae, seven members (Ptc1-Ptc7) have been identified and at least partially characterized [see Arino et al. (2011) for a review].Ptc1 is the closest homolog of human Wip1, a phosphatase involved in the regulation of stress-induced and DNA damage-induced networks in diverse physiologic and pathologic conditions (Le Guezennec and Bulavin 2010;Zhu and Bulavin 2012) and by far the most widely studied yeast isoform. Both the large number of characteristic phenotypes and the specific changes in the transcriptomic profile (Gonzalez et al. 2006) derived from deletion of the gene suggest that this phosphatase is involved in a large variety of cellular processes not shared by other Ptc family members. Early evidence indicated that Ptc1 was involved in the negative regulation of the high-osmolarity glycerol (HOG) pathway (Maeda et al. 1993;Maeda et al. 1994), and subsequent work demonstrated that Ptc1 could dephosphorylate the Hog1 MAPK in vitro and in vivo (Warmka et al. 2001 interacts with the N-terminal domain of Nbp2, an SH3 domaincontaining protein that serves as an adaptor for the recruitment of Ptc1 to the Pbs2-Hog1 complex, and this interaction is necessary for Ptc1 to participate in the regulation of HOGmediated signaling (Uetz et al. 2000;Ito et al. 2001;Ma...

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Section: Discussionsupporting

confidence: 74%

Wide-Ranging Effects of the Yeast Ptc1 Protein Phosphatase Acting Through the MAPK Kinase Mkk1

et al. 2015

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“…of protein) in the liver (PaxDb version 4.0) to reduce bias towards abundant proteins (Wang et al, 2015). The phospholipase 2 protein (PLA2G4D) came to the fore.…”

Section: Tap-tagged Dengue Virus and Host-virus Interactionsmentioning

confidence: 99%

Development of viable TAP-tagged dengue virus for investigation of host–virus interactions in viral replication

Poyomtip

Hodge

Matangkasombut

et al. 2016

Journal of General Virology

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Dengue virus (DENV) is a mosquito-borne flavivirus responsible for life-threatening dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). The viral replication machinery containing the core non-structural protein 5 (NS5) is implicated in severe dengue symptoms but molecular details remain obscure. To date, studies seeking to catalogue and characterize interaction networks between viral NS5 and host proteins have been limited to the yeast twohybrid system, computational prediction and co-immunoprecipitation (IP) of ectopically expressed NS5. However, these traditional approaches do not reproduce a natural course of infection in which a number of DENV NS proteins colocalize and tightly associate during the replication process. Here, we demonstrate the development of a recombinant DENV that harbours a TAP tag in NS5 to study host-virus interactions in vivo. We show that our engineered DENV was infective in several human cell lines and that the tags were stable over multiple viral passages, suggesting negligible structural and functional disturbance of NS5. We further provide proof-of-concept for the use of rationally tagged virus by revealing a high confidence NS5 interaction network in human hepatic cells. Our analysis uncovered previously unrecognized hnRNP complexes and several low-abundance fatty acid metabolism genes, which have been implicated in the viral life cycle. This study sets a new standard for investigation of host-flavivirus interactions.

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“…Its best-studied signaling effects are mediated by the oxidation of thiolates in transcription factors [2], kinases [3,4] and phosphatases [5][6][7][8]. However, whereas the redox active thiolates in these targets react with H 2 O 2 with rate constants in the range of 9−164 M −1 s −1 [5,6,9,1], the cell cytoplasm contains very abundant peroxiredoxins I and II (PrxI, PrxII) [10,11], which react with H 2 O 2 with rate constants in the range of 10 7 -10 8 M −1 s −1 [12,13].…”

Section: Introductionmentioning

confidence: 99%

Localized redox relays as a privileged mode of cytoplasmic hydrogen peroxide signaling

Travasso

Aidos

Abranches

et al. 2017

Free Radical Biology and Medicine

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A B S T R A C THydrogen peroxide (H 2 O 2 ) is a key signaling agent. Its best characterized signaling actions in mammalian cells involve the early oxidation of thiols in cytoplasmic phosphatases, kinases and transcription factors. However, these redox targets are orders of magnitude less H 2 O 2 -reactive and abundant than cytoplasmic peroxiredoxins. How can they be oxidized in a signaling time frame? Here we investigate this question using computational reaction-diffusion models of H 2 O 2 signaling. The results show that at H 2 O 2 supply rates commensurate with mitogenic signaling a H 2 O 2 concentration gradient with a length scale of a few tenths of μm is established. Even near the supply sites H 2 O 2 concentrations are far too low to oxidize typical targets in an early mitogenic signaling time frame. Furthermore, any inhibition of the peroxiredoxin or increase in H 2 O 2 supply able to drastically increase the local H 2 O 2 concentration would collapse the concentration gradient and/or cause an extensive oxidation of the peroxiredoxins I and II, inconsistent with experimental observations. In turn, the local concentrations of peroxiredoxin sulfenate and disulfide forms exceed those of H 2 O 2 by several orders of magnitude. Redox targets reacting with these forms at rate constants much lower than that for, say, thioredoxin could be oxidized within seconds. Moreover, the spatial distribution of the concentrations of these peroxiredoxin forms allows them to reach targets within 1 μm from the H 2 O 2 sites while maintaining signaling localized. The recruitment of peroxiredoxins to specific sites such as caveolae can dramatically increase the local concentrations of the sulfenic and disulfide forms, thus further helping these species to outcompete H 2 O 2 for the oxidation of redox targets. Altogether, these results suggest that H 2 O 2 signaling is mediated by localized redox relays whereby peroxiredoxins are oxidized to sulfenate and disulfide forms at H 2 O 2 supply sites and these forms in turn oxidize the redox targets near these sites.

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Version 4.0 of PaxDb: Protein abundance data, integrated across model organisms, tissues, and cell‐lines

Cited by 527 publications

References 29 publications

Wide-Ranging Effects of the Yeast Ptc1 Protein Phosphatase Acting Through the MAPK Kinase Mkk1

Wide-Ranging Effects of the Yeast Ptc1 Protein Phosphatase Acting Through the MAPK Kinase Mkk1

Development of viable TAP-tagged dengue virus for investigation of host–virus interactions in viral replication

Localized redox relays as a privileged mode of cytoplasmic hydrogen peroxide signaling

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