Protein tyrosine phosphatases (PTPs) are considered to be involved in the etiology of diabetes mellitus, neural diseases such as Alzheimer;s and Parkinson;s disease, regulation of allergy and inflammation, or they are even considered to be responsible for the pathogens; virulence in vivo. Since discovery of first PTP inhibitors such as dephostatin in early 90th years, the research moved on toward search for inhibitors specific for the individual PTP molecules. Currently, dozens of new PTP inhibitors are reported each year, ranging from natural products, natural product analogs, peptides, phosphonates, nonpeptidic inhibitors, mimotopes, metal-containing inhibitors, redox inhibitors, to simply silencing RNAs as widely used inhibitors of PTP expression. Several currently used drugs also show PTP inhibitory activity. Among them are sodium stibogluconate, phenylarsine oxide, alendronate, etidronate, vanadate, gallium nitrate, suramin, or aplidin. However, the market is still waiting for the first clinically approved selective PTP inhibitor. Here in this review are described inhibitors of activity or expression of the particular classical PTPs, with emphasis on specific inhibition of the respective PTP over the others. The inhibitors are not classified according to their chemical composition, but according to their biological activity, which should help to simplify search for inhibitors of particular classical PTPs. Even though PTP inhibitors are difficult to develop, lifting the fog of phosphatase inhibition is of the great market potential and further clinical impact.

• MeSH
• inhibitory enzymů chemie   farmakologie   MeSH
• lidé MeSH
• tyrosinfosfatasy antagonisté a inhibitory   chemie   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• inhibitory enzymů MeSH
• tyrosinfosfatasy MeSH

SIGNIFICANCE: Redox modifications of thiols serve as a molecular code enabling precise and complex regulation of protein tyrosine phosphatases (PTPs) and other proteins. Particular gasotransmitters and even the redox modifications themselves affect each other, of which a typical example is S-nitrosylation-mediated protection against the further oxidation of protein thiols. RECENT ADVANCES: For a long time, PTPs were considered constitutively active housekeeping enzymes. This view has changed substantially over the last two decades, and the PTP family is now recognized as a group of tightly and flexibly regulated fundamental enzymes. In addition to the conventional ways in which they are regulated, including noncovalent interactions, phosphorylation, and oxidation, the evidence that has accumulated during the past two decades suggests that many of these enzymes are also modulated by gasotransmitters, namely by nitric oxide (NO) and hydrogen sulfide (H2S). CRITICAL ISSUES: The specificity and selectivity of the methods used to detect nitrosylation and sulfhydration remains to be corroborated, because several researchers raised the issue of false-positive results, particularly when using the most widespread biotin switch method. Further development of robust and straightforward proteomic methods is needed to further improve our knowledge of the full extent of the gasotransmitters-mediated changes in PTP activity, selectivity, and specificity. FURTHER DIRECTIONS: Results of the hitherto performed studies on gasotransmitter-mediated PTP signaling await translation into clinical medicine and pharmacotherapeutics. In addition to directly affecting the activity of particular PTPs, the use of reversible S-nitrosylation as a protective mechanism against oxidative stress should be of high interest.

• MeSH
• aktivace enzymů MeSH
• lidé MeSH
• reaktivní formy dusíku metabolismus   MeSH
• sulfan metabolismus   MeSH
• tyrosinfosfatasy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• reaktivní formy dusíku MeSH
• sulfan MeSH
• tyrosinfosfatasy MeSH

The antigen-mediated activation of mast cells initiates signaling events leading to their degranulation, to the release of inflammatory mediators, and to the synthesis of cytokines and chemokines. Although rapid and transient microtubule reorganization during activation has been described, the molecular mechanisms that control their rearrangement are largely unknown. Microtubule nucleation is mediated by γ-tubulin complexes. In this study, we report on the regulation of microtubule nucleation in bone marrow-derived mast cells (BMMCs) by Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1; Ptpn6). Reciprocal immunoprecipitation experiments and pull-down assays revealed that SHP-1 is present in complexes containing γ-tubulin complex proteins and protein tyrosine kinase Syk. Microtubule regrowth experiments in cells with deleted SHP-1 showed a stimulation of microtubule nucleation, and phenotypic rescue experiments confirmed that SHP-1 represents a negative regulator of microtubule nucleation in BMMCs. Moreover, the inhibition of the SHP-1 activity by inhibitors TPI-1 and NSC87877 also augmented microtubule nucleation. The regulation was due to changes in γ-tubulin accumulation. Further experiments with antigen-activated cells showed that the deletion of SHP-1 stimulated the generation of microtubule protrusions, the activity of Syk kinase, and degranulation. Our data suggest a novel mechanism for the suppression of microtubule formation in the later stages of mast cell activation.

• Klíčová slova
• SHP-1 tyrosine phosphatase, bone marrow-derived mast cells, cell activation, microtubule nucleation, γ-tubulin complexes,
• MeSH
• degranulace buněk MeSH
• HEK293 buňky MeSH
• kinasa Syk metabolismus   MeSH
• lidé MeSH
• mastocyty cytologie   metabolismus   MeSH
• MFC-7 buňky MeSH
• mikrotubuly metabolismus   MeSH
• myši MeSH
• tubulin metabolismus   MeSH
• tyrosinfosfatasa nereceptorového typu 6 antagonisté a inhibitory   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kinasa Syk MeSH
• Ptpn6 protein, mouse MeSH Prohlížeč
• Syk protein, mouse MeSH Prohlížeč
• tubulin MeSH
• tyrosinfosfatasa nereceptorového typu 6 MeSH

CD148 is a receptor-like protein-tyrosine phosphatase known to inhibit transduction of mitogenic signals in non-hematopoietic cells. Similarly, in the hematopoietic lineage, CD148 inhibited signal transduction downstream of T cell receptor. However, it also augmented immunoreceptor signaling in B cells and macrophages via dephosphorylating C-terminal tyrosine of Src family kinases (SFK). Accordingly, endogenous CD148 compensated for the loss of the main SFK activator CD45 in murine B cells and macrophages but not in T cells. Hypothetical explanations for the difference between T cells and other leukocyte lineages include the inability of CD148 to dephosphorylate a specific set of SFKs involved in T cell activation or the lack of CD148 expression during critical stages of T cell development. Here we describe striking differences in CD148 expression between human and murine thymocyte subsets, the only unifying feature being the absence of CD148 during the positive selection when the major developmental block occurs under CD45 deficiency. Moreover, we demonstrate that similar to CD45, CD148 has both activating and inhibitory effects on the SFKs involved in TCR signaling. However, in the absence of CD45, activating effects prevail, resulting in functional complementation of CD45 deficiency in human T cell lines. Importantly, this is independent of the tyrosines in the CD148 C-terminal tail, contradicting the recently proposed phosphotyrosine displacement model as a mechanism of SFK activation by CD148. Collectively, our data suggest that differential effects of CD148 in T cells and other leukocyte subsets cannot be explained by the CD148 inability to activate T cell SFKs but rather by its dual inhibitory/activatory function and specific expression pattern.

• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• aktivace enzymů MeSH
• antigeny CD45 nedostatek   MeSH
• fosfolipasa C gama metabolismus   MeSH
• fosforylace MeSH
• hematopoetické kmenové buňky cytologie   enzymologie   metabolismus   MeSH
• Jurkat buňky MeSH
• lidé MeSH
• membránové proteiny metabolismus   MeSH
• myši MeSH
• receptory antigenů T-buněk imunologie   metabolismus   MeSH
• regulace genové exprese enzymů MeSH
• signální transdukce * MeSH
• skupina kinas odvozených od src-genu chemie   metabolismus   MeSH
• T-lymfocyty cytologie   enzymologie   metabolismus   MeSH
• terciární struktura proteinů MeSH
• thymus cytologie   MeSH
• tyrosin metabolismus   MeSH
• tyrosinfosfatasy receptorového typu, třída 3 chemie   genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• antigeny CD45 MeSH
• fosfolipasa C gama MeSH
• LAT protein, human MeSH Prohlížeč
• membránové proteiny MeSH
• PTPRJ protein, human MeSH Prohlížeč
• receptory antigenů T-buněk MeSH
• skupina kinas odvozených od src-genu MeSH
• tyrosin MeSH
• tyrosinfosfatasy receptorového typu, třída 3 MeSH

We identified association of restless legs syndrome (RLS) with PTPRD at 9p23-24 in 2,458 affected individuals and 4,749 controls from Germany, Austria, Czechia and Canada. Two independent SNPs in the 5' UTR of splice variants expressed predominantly in the central nervous system showed highly significant P values (rs4626664, P(nominal/lambda corrected) = 5.91 x 10(-10), odds ratio (OR) = 1.44; rs1975197, P(nominal/lambda corrected) = 5.81 x 10(-9), OR = 1.31). This work identifies PTPRD as the fourth genome-wide significant locus for RLS.

• MeSH
• 5' nepřekládaná oblast genetika   MeSH
• genetická predispozice k nemoci * MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• studie případů a kontrol MeSH
• syndrom neklidných nohou genetika   MeSH
• tyrosinfosfatasy receptorového typu, třída 2 genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Kanada MeSH
• Německo MeSH
• Rakousko MeSH
• Názvy látek
• 5' nepřekládaná oblast MeSH
• PTPRD protein, human MeSH Prohlížeč
• tyrosinfosfatasy receptorového typu, třída 2 MeSH

Protein tyrosine and lipid phosphorylations are early and critical events in type 1 Fc(epsilon) receptor (Fc(epsilon)RI)-mediated activation of mast cells and basophils. Tyrosine phosphorylation of Fc(epsilon)RI subunits as well as other signal transduction molecules reflects the balance between the action of protein tyrosine kinases and phosphatases. Similarly, the phosphate content of inositol phospholipids, involved in the recruitment of signalling molecules to the plasma membrane and the generation of secondary messengers, is the net result of the opposing effects of phosphoinositide kinases and lipid phosphatases. This review summarizes the current understanding of the structural and functional aspects of nonreceptor protein tyrosine phosphatases (SHP-1, SHP-2, HePTP, PTP20, PRL1, PRL2, PTP-MEG1 and PTP-MEG2) and lipid phosphatases (SHIP and SHIP2) in the activation of mast cells and basophils after Fc(epsilon)RI aggregation. New approaches towards a deeper understanding of the role of phosphatases in mast cell physiology are also discussed.

• MeSH
• bazofily enzymologie   imunologie   MeSH
• fosfatasy chemie   fyziologie   MeSH
• fosfatidylinositol-3,4,5-trisfosfát-5-fosfatasy MeSH
• lidé MeSH
• mastocyty enzymologie   imunologie   MeSH
• modely imunologické MeSH
• receptory IgE imunologie   MeSH
• signální transdukce MeSH
• terciární struktura proteinů MeSH
• tyrosinfosfatasa nereceptorového typu 1 MeSH
• tyrosinfosfatasy chemie   fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• fosfatasy MeSH
• fosfatidylinositol-3,4,5-trisfosfát-5-fosfatasy MeSH
• INPPL1 protein, human MeSH Prohlížeč
• receptory IgE MeSH
• tyrosinfosfatasa nereceptorového typu 1 MeSH
• tyrosinfosfatasy MeSH

Protein tyrosine phosphatases (PTPs) are increasingly recognized as important effectors of host-pathogen interactions. Since Guan and Dixon reported in 1990 that phosphatase YopH serves as an essential virulence determinant of Yersinia, the field shifted significantly forward, and dozens of PTPs were identified in various microorganisms and even in viruses. The discovery of extensive tyrosine signaling networks in non-metazoan organisms refuted the moth-eaten paradigm claiming that these organisms rely exclusively on phosphoserine/phosphothreonine signaling. Similarly to humans, phosphotyrosine signaling is thought to comprise a small fraction of total protein phosphorylation, but plays a disproportionately important role in cell-cycle control, differentiation, and invasiveness. Here we summarize the state-of-art knowledge on PTPs of important non-metazoan pathogens (Listeria monocytogenes, Staphylococcus aureus, Porphyromonas gingivalis, Caulobacter crescentus, Yersinia, Synechocystis, Leishmania, Plasmodium falciparum, Entamoeba histolytica, etc.), and focus also at the microbial proteins affecting directly or indirectly the PTPs of the host (Mycobacterium tuberculosis MTSA-10, Bacillus anthracis anthrax toxin, streptococcal β protein, Helicobacter pylori CagA and VacA, Leishmania GP63 and EF-1α, Plasmodium hemozoin, etc.). This is the first review summarizing the knowledge on biological activity and pharmacological inhibition of non-metazoan PTPs, with the emphasis of those important in host-pathogen interactions. Targeting of numerous non-metazoan PTPs is simplified by the fact that they act either as ectophosphatases or are secreted outside of the pathogen. Interfering with tyrosine phosphorylation represents a powerful pharmacologic approach, and even though the PTP inhibitors are difficult to develop, lifting the fog of phosphatase inhibition is of the great market potential and further clinical impact.

• MeSH
• Bacteria účinky léků   enzymologie   MeSH
• bakteriální proteiny antagonisté a inhibitory   metabolismus   MeSH
• inhibitory enzymů chemie   farmakologie   MeSH
• interakce hostitele a patogenu MeSH
• Leishmania účinky léků   enzymologie   MeSH
• lidé MeSH
• protozoální proteiny antagonisté a inhibitory   metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• tyrosinfosfatasy antagonisté a inhibitory   metabolismus   MeSH
• virové proteiny antagonisté a inhibitory   metabolismus   MeSH
• viry účinky léků   enzymologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• bakteriální proteiny MeSH
• inhibitory enzymů MeSH
• protozoální proteiny MeSH
• reaktivní formy kyslíku MeSH
• tyrosinfosfatasy MeSH
• virové proteiny MeSH

Activation of mast cells and basophils is accompanied by the production of reactive oxygen and nitrogen species that regulate diverse signaling pathways leading to the release of inflammatory mediators and production of a variety of cytokines. Although the functional pathways of reactive oxygen and nitrogen species in vivo are not completely understood, some novel metabolic pathways can be envisioned based on recent findings that protein tyrosine phosphatases can be regulated by reversible oxidation. In this review, we describe major sources and targets of reactive oxide and nitrogen species in mast cells and basophils. Direct and indirect regulations of class I and II Cys-based protein tyrosine phosphatases (LMW-PTP, PTEN, PTP-PEST, SHP-2, PTP1B, PTPalpha, PTPepsilon, DEP-1, TC45, SHP-1, HePTP and LAR) are discussed. The combined data highlight the role of redox-regulated protein tyrosine phosphatases as targets in the development of new ways of therapeutic intervention in allergies and inflammatory diseases.

• MeSH
• bazofily enzymologie   metabolismus   MeSH
• cystein metabolismus   MeSH
• lidé MeSH
• mastocyty enzymologie   metabolismus   MeSH
• reaktivní formy dusíku metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• tyrosinfosfatasy klasifikace   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• cystein MeSH
• reaktivní formy dusíku MeSH
• reaktivní formy kyslíku MeSH
• tyrosinfosfatasy MeSH

OBJECTIVE: To investigate the role of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in the pathogenesis of rheumatoid arthritis (RA). METHODS: Synovial tissue samples from patients with RA and patients with osteoarthritis (OA) were stained for PTPN2. Synovial fibroblasts were stimulated with tumor necrosis factor (TNF) and interleukin-1β (IL-1β), lipopolysaccharide (LPS), TRAIL, or thapsigargin. The expression of PTPN2 in synovial fibroblasts and peripheral blood mononuclear cells (PBMCs) was analyzed by real-time polymerase chain reaction and Western blotting. Cell death, the release of IL-6 and IL-8, and the induction of autophagy were analyzed after PTPN2 silencing. Methylated DNA immunoprecipitation analysis was used to evaluate DNA methylation-regulated gene expression of PTPN2. RESULTS: PTPN2 was significantly overexpressed in synovial tissue samples from RA patients compared to OA patients. Patients receiving anti-TNF therapy showed significantly reduced staining for PTPN2 compared with patients treated with nonbiologic agents. PTPN2 expression was higher in RA synovial fibroblasts (RASFs) than in OASFs. This differential expression was not regulated by DNA methylation. PTPN2 was further up-regulated after stimulation with TNF, TNF combined with IL-1β, or LPS. There was no significant difference in basal PTPN2 expression in PBMCs from patients with RA, ankylosing spondylitis, or systemic lupus erythematosus or healthy controls. Most interestingly, PTPN2 silencing in RASFs significantly increased the production of the inflammatory cytokine IL-6 but did not affect levels of IL-8. Moreover, functional analysis showed that high PTPN2 levels contributed to the increased apoptosis resistance of RASFs and increased autophagy. CONCLUSION: This is the first study of PTPN2 in RASFs showing that PTPN2 regulates IL-6 production, cell death, and autophagy. Our findings indicate that PTPN2 is linked to the pathogenesis of RA via synovial fibroblasts.

• MeSH
• apoptóza účinky léků   MeSH
• autofagie účinky léků   MeSH
• biologické přípravky farmakologie   MeSH
• fibroblasty účinky léků   metabolismus   patologie   MeSH
• interleukin-1beta farmakologie   MeSH
• interleukin-6 metabolismus   MeSH
• kultivované buňky MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipopolysacharidy farmakologie   MeSH
• osteoartróza metabolismus   patologie   MeSH
• protein TRAIL farmakologie   MeSH
• revmatoidní artritida metabolismus   patologie   MeSH
• senioři MeSH
• synoviální membrána účinky léků   metabolismus   patologie   MeSH
• thapsigargin farmakologie   MeSH
• TNF-alfa antagonisté a inhibitory   farmakologie   MeSH
• tyrosinfosfatasa nereceptorového typu 2 metabolismus   MeSH
• upregulace účinky léků   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické přípravky MeSH
• interleukin-1beta MeSH
• interleukin-6 MeSH
• lipopolysacharidy MeSH
• protein TRAIL MeSH
• PTPN2 protein, human MeSH Prohlížeč
• thapsigargin MeSH
• TNF-alfa MeSH
• tyrosinfosfatasa nereceptorového typu 2 MeSH

The earliest known biochemical step that occurs after ligand binding to the multichain immune recognition receptor is tyrosine phosphorylation of the receptor subunits. In mast cells and basophils activated by multivalent antigen-IgE complexes, this step is mediated by Src family kinase Lyn, which phosphorylates the high affinity IgE receptor (Fc epsilonRI). However, the exact molecular mechanism of this phosphorylation step is incompletely understood. In this study, we tested the hypothesis that changes in activity and/or topography of protein-tyrosine phosphatases (PTPs) could play a major role in the Fc epsilonRI triggering. We found that exposure of rat basophilic leukemia cells or mouse bone marrow-derived mast cells to PTP inhibitors, H(2)O(2) or pervanadate, induced phosphorylation of the Fc epsilonRI subunits, similarly as Fc epsilonRI triggering. Interestingly, and in sharp contrast to antigen-induced activation, neither H(2)O(2) nor pervanadate induced any changes in the association of Fc epsilonRI with detergent-resistant membranes and in the topography of Fc epsilonRI detectable by electron microscopy on isolated plasma membrane sheets. In cells stimulated with pervanadate, H(2)O(2) or antigen, enhanced oxidation of active site cysteine of several PTPs was detected. Unexpectedly, most of oxidized phosphatases bound to the plasma membrane were associated with the actin cytoskeleton. Several PTPs (SHP-1, SHP-2, hematopoietic PTP, and PTP-MEG2) showed changes in their enzymatic activity and/or oxidation state during activation. Based on these and other data, we propose that down-regulation of enzymatic activity of PTPs and/or changes in their accessibility to the substrates play a key role in initial tyrosine phosphorylation of the Fc epsilonRI and other multichain immune receptors.

• MeSH
• aktivace enzymů účinky léků   genetika   imunologie   MeSH
• antigeny imunologie   metabolismus   farmakologie   MeSH
• fosforylace účinky léků   genetika   imunologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• krysa rodu Rattus MeSH
• mastocyty imunologie   metabolismus   MeSH
• membránové mikrodomény genetika   imunologie   metabolismus   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• oxidace-redukce účinky léků   MeSH
• oxidancia farmakologie   MeSH
• peroxid vodíku farmakologie   MeSH
• receptory IgE genetika   imunologie   metabolismus   MeSH
• skupina kinas odvozených od src-genu genetika   imunologie   metabolismus   MeSH
• transport proteinů účinky léků   genetika   imunologie   MeSH
• tyrosinfosfatasy antagonisté a inhibitory   genetika   imunologie   metabolismus   MeSH
• vanadáty farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny MeSH
• inhibitory enzymů MeSH
• lyn protein-tyrosine kinase MeSH Prohlížeč
• oxidancia MeSH
• peroxid vodíku MeSH
• pervanadate MeSH Prohlížeč
• receptory IgE MeSH
• skupina kinas odvozených od src-genu MeSH
• tyrosinfosfatasy MeSH
• vanadáty MeSH