Protein tyrosine phosphatase <i>Tb</i>PTP1: a molecular switch controlling life cycle differentiation in trypanosomes

Szöőr, Balázs; Wilson, J. A.; McElhinney, Helen; Tabernero, Lydia; Matthews, Keith R.

doi:10.1084/jem20311oia28

Cited by 16 publications

(27 citation statements)

References 13 publications

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“…The structure of TbPTP1 [161] shows a classic PTP fold but lacks the allosteric inhibitor BZ3 binding site. Yet, this inhibitor impairs TbPTP1 activity [159], both in vitro and in the parasite. Thus the mode of binding of this inhibitor remains unknown.…”

Section: Structures Of Protozoan Ptpsmentioning

confidence: 96%

“…LmACR2 from Leishmania major is an intriguing enzyme that shows both arsenate reductase and phosphatase activity in vitro, and displays sequence and structural similarity with Cdc25 which belongs to the rhodanese ⁄ Cdc25 family [158]. Trypanosoma brucei Tyr-specific phosphatase TbPTP1 is a critical switch in regulation of the lifecycle of the parasite [159]. It is also involved in the glycosomal signalling pathway and another STP phosphatase, TbPIP39, was identified as its substrate [160].…”

Section: Structures Of Protozoan Ptpsmentioning

confidence: 99%

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Protein tyrosine phosphatase structure–function relationships in regulation and pathogenesis

et al. 2012

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Protein phosphorylation on tyrosine residues is tightly controlled by protein tyrosine phosphatases (PTPs) at multiple levels: spatio-temporal expression, subcellular localization and post-translational modification. Structural and functional analysis of the PTP domains has provided insight into catalysis and regulatory mechanisms that control the enzymatic activity. Understanding the molecular basis of PTP regulation is of fundamental importance to dissect the pleiotropic effect of these enzymes in both health and disease. Here, we review recent insights into the regulation of receptorlike PTPs by extracellular ligands and into regulation by reversible oxidation that impairs catalysis directly. The physiological roles of PTPs are essential in homeostasis in eukaryotic cells and pertubation of their functional attributes causes different disease states. As an example, we discuss recent findings indicating how inappropriate oxidation of PTPs in cancer cells may contribute to cell transformation. On the other hand, PTPs from many pathogens are key virulence factors and manipulate signalling pathways in the host cells to promote invasion and survival of the microorganisms. This research area has received relatively little attention but has advanced remarkably. We review the structural features of pathogenic PTPs, their similarities and differences with eukaryotic PTPs, and the possible exploitation of this knowledge for therapeutic intervention. Structures of PTPsAnalysis of protein tyrosine phosphatase (PTP) structures is not only important for understanding their function and regulation but also for identifying strategies for pharmacological modulation of PTP activity. Given the progress in establishing PTP deregulation in different pathologies such as cancer, PTPs deserve much attention as candidate drug targets. We focus on Cys-based PTPs [1] and discuss novel insights in PTP structure which may be important for pharmacological modulation, and emphasize novel findings and controversial issues for transmembrane (receptor-like) PTPs (RPTPs).Abbreviations AML, acute myeloid leukaemia; DUSP, dual specificity PTP; FLT3, Fms-like tyrosine kinase 3; FLT3 ⁄ ITD, internal tandem duplication of FLT3; LMWPTP, low molecular weight PTP; PDGF, platelet-defined growth factor; Prx, peroxiredoxin; PTP, protein tyrosine phosphatase; PTPLP, PTP-like phytase; ROS, reactive oxygen species; RPTP, transmembrane PTP; RTK, receptor tyrosine kinase; YopH, Yersinia outer protein H.

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Section: Structures Of Protozoan Ptpsmentioning

confidence: 96%

Section: Structures Of Protozoan Ptpsmentioning

confidence: 99%

Protein tyrosine phosphatase structure–function relationships in regulation and pathogenesis

et al. 2012

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“…When TbPTP1 activity is inhibited by RNAi or biochemically inhibited with the specific inhibitor BZ3, the process of differentiating into procyclic forms occurs spontaneously in the absence of any exogenous trigger. Thus, the form shows all of the markers from the procyclic stage, such as EP and GPEET procyclins and the stage-specific cytoskeletal antigen CAP5.5 [76]. The stumpy cells were uniformly arrested in G1/G0 and initiated differentiation synchronously and efficiently [77].…”

Section: Trypanosoma Bruceimentioning

confidence: 99%

“…The stumpy cells were uniformly arrested in G1/G0 and initiated differentiation synchronously and efficiently [77]. The enzyme TbPTP2 seems not to contribute to the observed differentiation phenotype because RNAi against this enzyme did not elicit differentiation of the bloodstream forms [76], which suggests that TbPTP1 normally inhibits this differentiation step [76,78]. Although only a small proportion of cultured monomorphic bloodstream forms were differentiated, uniformly arrested stumpy forms differentiated with an efficiency of nearly 100% when exposed to the inhibitor.…”

Section: Trypanosoma Bruceimentioning

confidence: 99%

“…The trypanosomatid kinome has an abundance of STE and CMGC family protein kinases, which include the members of the canonical MAP kinase cascade (MAPKs, MAPKKs and MAPKKKs) involved in environmentally regulated cell cycle control, differentiation and the cellular response to various stress signals [18]. These two families alone make up more than 40% of the conserved trypanosomatid kinome [76]. Various members of the MAPK family and MAPK-like kinases were found in T. brucei.…”

Section: Trypanosoma Bruceimentioning

confidence: 99%

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Intracellular Signaling Pathways Involved in Cell Differentiation in Trypanosomatids

Lopes

Gomes²,

Dutra³

et al. 2010

TOPARAJ

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Knowledge of cell signaling pathways in trypanosomatids is crucial for the future design of new drugs to treat diseases caused by these parasites. The publication of the complete genome sequences of three pathogenic trypanosomatids, Trypanosoma brucei, T. cruzi and Leishmania major, revealed numerous protein members of signaling pathways that modulate important processes, such as cell differentiation. Even so, little is known about the role that these proteins play in the physiology of trypanosomatids. This review aims to stimulate discussion on this subject to encourage further studies of the signaling pathways involved in the cell differentiation of trypanosomatids.

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Biochemical characterization of a protein tyrosine phosphatase from Trypanosoma cruzi involved in metacyclogenesis and cell invasion

Gallo

Ramos

Tavares

et al. 2011

Biochemical and Biophysical Research Communications

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Protein tyrosine phosphatases (PTPs) form a large family of enzymes involved in the regulation of numerous cellular functions in eukaryotes. Several protein tyrosine phosphatases have been recently identified in trypanosomatides. Here we report the purification and biochemical characterization of TcPTP1, a protein tyrosine phosphatase from Trypanosoma cruzi, the causing agent of Chagas' disease. The enzyme was cloned and expressed recombinantly in Escherichia coli and purified by Ni-affinity chromatography. Biochemical characterization of recombinant TcPTP1 with the PTP pseudo-substrate pNPP allowed the estimation of a Michaelis-Menten constant K(m) of 4.5mM and a k(cat) of 2.8s(-1). We were able to demonstrate inhibition of the enzyme by the PTP1b inhibitor BZ3, which on its turn was able to accelerate the differentiation of epimastigotes into metacyclic forms of T. cruzi induced by nutritional stress. Additionally, this compound was able to inhibit by 50% the infectivity of T. cruzi trypomastigotes in a separate cellular assay. In conclusion our results indicate that TcPTP1 is of importance for cellular differentiation and invasivity of this parasite and thus is a valid target for the rational drug design of potential antibiotics directed against T. cruzi.

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Protein tyrosine phosphatase TbPTP1: a molecular switch controlling life cycle differentiation in trypanosomes

Cited by 16 publications

References 13 publications

Protein tyrosine phosphatase structure–function relationships in regulation and pathogenesis

Protein tyrosine phosphatase structure–function relationships in regulation and pathogenesis

Intracellular Signaling Pathways Involved in Cell Differentiation in Trypanosomatids

Biochemical characterization of a protein tyrosine phosphatase from Trypanosoma cruzi involved in metacyclogenesis and cell invasion

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