A novel protein phosphatase 2A (PP2A) is involved in the transformation of human protozoan parasite Trypanosoma cruzi

González, Jorge; Cornejo, Alberto; Santos, Marcia Rodrigues dos; Cordero, Esteban; Gutiérrez, Bessy; Porcile, Patricio; Mortara, Renato Arruda; Sagua, H; Silveira, José Franco da; Araya, Jorge E.

doi:10.1042/bj20030215

Cited by 39 publications

(35 citation statements)

References 53 publications

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“…To determine whether the inhibitory effect of palmitate on AMPK phosphorylation was due to the activation of PP2A, we applied a cell-permeable inhibitor of PP2A, OA, which inhibits PP2A at a very low concentration (2 nM) (28). As depicted in Fig.…”

Section: Effects Of Palmitate On Phosphorylation Of Ampk and Its Downmentioning

confidence: 99%

Activation of Protein Phosphatase 2A by Palmitate Inhibits AMP-activated Protein Kinase

Song

et al. 2007

Journal of Biological Chemistry

248

220

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Evidence accumulated over the past several years indicates that the AMP-activated protein kinase (AMPK) 2 may be a therapeutic target for treating insulin resistance and type 2 diabetes (1). AMPK is a heterotrimeric protein formed by an ␣ subunit, which contains the catalytic activity, and by the ␤ and ␥ regulatory subunits important in maintaining stability of the heterotrimer complex (2). AMPK belongs to a family of energy-sensing enzymes functioning as a "fuel gauge" that monitors changes in the energy status of a cell (3, 4). When activated, AMPK shuts down anabolic pathways and promotes catabolism in response to an elevated AMP/ATP ratio by down-regulating the activity of several key enzymes of intermediary metabolism (4). Two primary acute consequences of AMPK activation are 1) an increase in glucose uptake by induction of glucose 4 transporter microvesicle cytoplasm to membrane translocation and fusion and 2) an increase in fatty acid oxidation by phosphorylation and inactivation of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in fatty acid synthesis (5). Therefore, the AMPK signal pathways are thought to play a central role in the regulation of cellular glucose and lipid homeostasis. The control of AMPK activity is complex, and the classic view is that AMPK is activated allosterically by an increase in the intracellular AMP/ATP ratios and/or by the phosphorylation of threonine 172 within the ␣ subunit. Several protein kinases responsible for this phosphorylation have been identified. They include Peutz-Jeghers syndrome kinase LKB1 (LKB1) (6), and the Ca 2ϩ /calmodulin-dependent protein kinase kinase (7). Protein phosphorylation signal transduction systems are balanced and regulated delicately by both phosphatase and kinase. Since AMPK is activated by (a) protein kinase(s) at the threonine 172 residue, one can easily assume that AMPK can be regulated negatively by (a) serine/threonine phosphatase(s). To date, a wide range of physiological stressors, pharmacological agents, and hormones associated with increase in the intracellular AMP/ATP ratios have been demonstrated to activate AMPK (8). AMPK is also thought to be regulated by glycogen (9), which is the major cellular storage form of carbohydrates and thus, an additional indicator of cellular energy status. Lipids are the other major energy source for cellular metabolism. Recent studies (10, 11) in heart and liver have revealed that AMPK may be sensitive to the "lipid status" of a cell, and activation may be influenced by intracellular fatty BSA, bovine serum albumin; eNOS, endothelial nitric-oxide synthase; LKB1, Peutz-Jeghers syndrome kinase LKB1; OA, okadaic acid; ONOO Ϫ , peroxynitrite; VSMC, vascular smooth muscle cell; siRNA, short interference RNA; FFA, free fatty acid; EBM, endothelial basal medium; 2-BrP, 2-bromopalmitate; HFD, high fat diet; PP2C, protein phosphatase 2C.

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Section: Effects Of Palmitate On Phosphorylation Of Ampk and Its Downmentioning

confidence: 99%

Activation of Protein Phosphatase 2A by Palmitate Inhibits AMP-activated Protein Kinase

Song

et al. 2007

Journal of Biological Chemistry

248

220

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“…Grellier and collaborators have shown that tissue-culturederived trypomastigotes that are exposed to phosphatase inhibitors, such as calyculin A, start to differentiate into rounded, extracellular amastigote-like cells even at a physiological pH (26). Furthermore, okadaic acid, another phosphatase inhibitor, represses axenic acidic-pH-induced amastigogenesis, strengthening the hypothesis that phosphorylation/dephosphorylation events are implicated in T. cruzi amastigogenesis (27).…”

mentioning

confidence: 65%

Quantitative Proteomic and Phosphoproteomic Analysis of Trypanosoma cruzi Amastigogenesis

Queiroz

Charneau

Mandacaru

et al. 2014

Molecular & Cellular Proteomics

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Chagas disease is a tropical neglected disease endemic in Latin America caused by the protozoan Trypanosoma cruzi. The parasite has four major life stages: epimastigote, metacyclic trypomastigote, bloodstream trypomastigote, and amastigote. The differentiation from infective trypomastigotes into replicative amastigotes, called amastigogenesis, takes place in vivo inside mammalian host cells after a period of incubation in an acidic phagolysosome. This differentiation process can be mimicked in vitro by incubating tissue-culture-derived trypomastigotes in acidic DMEM. Here we used this well-established differentiation protocol to perform a comprehensive quantitative proteomic and phosphoproteomic analysis of T. cruzi amastigogenesis. Samples from fully differentiated forms and two biologically relevant intermediate time points were Lys-C/trypsin digested, iTRAQ-labeled, and multiplexed. Subsequently, phosphopeptides were enriched using a TiO 2 matrix. Non-phosphorylated peptides were fractionated via hydrophilic interaction liquid chromatography prior to LC-MS/MS analysis. LC-MS/MS and bioinformatics procedures were used for protein and phosphopeptide quantitation, identification, and phosphorylation site assignment. We were able to identify regulated proteins and pathways involved in coordinating amastigogenesis. We also observed that a significant proportion of the regulated proteins were membrane proteins. Modulated phosphorylation events coordinated by protein kinases and phosphatases that are part of the signaling cascade induced by incubation in acidic medium were also evinced. To our knowledge, this work is the most comprehensive quantitative proteomics study of T. cruzi amastigogenesis, and these data will serve as a trustworthy basis for future studies, and possibly for new potential drug targets. Molecular & Cellular Proteomics 13:

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“…PP2A localizes to and regulates microtubule dynamics in a variety of cell types and its localization changes upon various stimuli [14][15][16][17][18]. Moreover, PP2A is involved in differentiation of Trypanosoma cruzi and Plasmodium falciparum [19][20][21]. Therefore, we asked whether PP2A-C might localize to unique elements of the giardial cytoskeleton and be an important mediator of its differentiation.…”

Section: Introductionmentioning

confidence: 99%

Protein phosphatase 2A plays a crucial role in Giardia lamblia differentiation

Lauwaet

Davids

Torres-Escobar

et al. 2007

Molecular and Biochemical Parasitology

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The ability of Giardia lamblia to undergo two distinct differentiations in response to physiologic stimuli is central to its pathogenesis. The giardial cytoskeleton changes drastically during encystation and excystation. However, the signal transduction pathways mediating these transformations are poorly understood. We tested the hypothesis that PP2A, a highly conserved serine/threonine protein phosphatase, might be important in giardial differentiation. We found that in vegetatively growing trophozoites, gPP2A-C protein localizes to basal bodies/centrosomes, and to cytoskeletal structures unique to Giardia: the ventral disk, and the dense rods of the anterior, posterior-lateral, and caudal flagella. During encystation, gPP2A-C protein disappears from only the anterior flagellar dense rods. During excystation, gPP2A-C localizes to the cyst wall in excysting cysts but is not found in the wall of cysts with emerging excyzoites. Transcriptome and immunoblot analyses indicated that gPP2A-C mRNA and protein are upregulated in mature cysts and during the early stage of excystation that models passage through the host stomach. Stable expression of gPP2A-C antisense RNA did not affect vegetative growth, but strongly inhibited the formation of encystation secretory vesicles (ESV) and water-resistant cysts. Moreover, the few cysts that formed were highly defective in excystation.Thus, gPP2A-C localizes to universal cytoskeletal structures and to structures unique to Giardia. It is also important for encystation and excystation, crucial giardial transformations that entail entry into and exit from dormancy.

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A novel protein phosphatase 2A (PP2A) is involved in the transformation of human protozoan parasite Trypanosoma cruzi

Cited by 39 publications

References 53 publications

Activation of Protein Phosphatase 2A by Palmitate Inhibits AMP-activated Protein Kinase

Activation of Protein Phosphatase 2A by Palmitate Inhibits AMP-activated Protein Kinase

Quantitative Proteomic and Phosphoproteomic Analysis of Trypanosoma cruzi Amastigogenesis

Protein phosphatase 2A plays a crucial role in Giardia lamblia differentiation

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