References of "Tautz, lutz"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailPerspective: Tyrosine Phosphatases As Novel Targets For Antiplatelet Therapy
Tautz, Lutz; Senis, Yotis; Oury, Cécile ULg et al

in Bioorganic & Medicinal Chemistry (2015), Epub ahead of print

Arterial thrombosis is the primary cause of most cases of myocardial infarction and stroke, the leading causes of death in the developed world. Platelets, highly specialized cells of the circulatory ... [more ▼]

Arterial thrombosis is the primary cause of most cases of myocardial infarction and stroke, the leading causes of death in the developed world. Platelets, highly specialized cells of the circulatory system, are key contributors to thrombotic events. Antiplatelet drugs, which prevent platelets from aggregating, have been very effective in reducing the mortality and morbidity of these conditions. However, approved antiplatelet therapies have adverse side effects, most notably the increased risk of bleeding. Moreover, there remains a considerable incidence of arterial thrombosis in a subset of patients receiving currently available drugs. Thus, there is a pressing medical need for novel antiplatelet agents with a more favorable safety profile and less patient resistance. The discovery of novel antiplatelet targets is the matter of intense ongoing research. Recent findings demonstrate the potential of targeting key signaling molecules, including kinases and phosphatases, to prevent platelet activation and aggregation. Here, we offer perspectives to targeting members of the protein tyrosine phosphatase (PTP) superfamily, a major class of enzymes in signal transduction. We give an overview of previously identified PTPs in platelet signaling, and discuss their potential as antiplatelet drug targets. We also introduce VHR (DUSP3), a PTP that we recently identified as a major player in platelet biology and thrombosis. We review our data on genetic deletion as well as pharmacological inhibition of VHR, providing proof-of-principle for a novel and potentially safer VHR-based antiplatelet therapy. [less ▲]

Detailed reference viewed: 19 (2 ULg)
Full Text
Peer Reviewed
See detailDUSP3 Phosphatase Deficiency or Inhibition Limit Platelet Activation and Arterial Thrombosis
Musumeci, Lucia ULg; Kuijpers, Marijke; Gilio, Karen et al

in Circulation (2015), 131(7), 656-68

Background A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. Better understanding of the molecular mechanisms leading to platelet ... [more ▼]

Background A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. Better understanding of the molecular mechanisms leading to platelet activation is of importance for the development of improved therapies. Recently, protein tyrosine phosphatases (PTPs) have emerged as critical regulators of platelet function. Methods and Results This is the first report implicating the dual-specificity phosphatase 3 (DUSP3) in platelet signaling and thrombosis. This phosphatase is highly expressed in human and mouse platelets. Platelets from DUSP3-deficient mice displayed a selective impairment of aggregation and granule secretion mediated through the collagen receptor glycoprotein VI (GPVI) and the C-type lectin-like receptor 2 (CLEC-2). DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism, compared to wild-type mice, and showed severely impaired thrombus formation upon ferric chloride-induced carotid artery injury. Intriguingly, bleeding times were not altered in DUSP3-deficient mice. At the molecular level, DUSP3 deficiency impaired Syk tyrosine phosphorylation, subsequently reducing phosphorylation of PLCγ2 and calcium fluxes. To investigate DUSP3 function in human platelets, a novel small-molecule inhibitor of DUSP3 was developed. This compound specifically inhibited collagen and CLEC-2-induced human platelet aggregation, thereby phenocopying the effect of DUSP3 deficiency in murine cells. Conclusions DUSP3 plays a selective and essential role in collagen- and CLEC-2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a PTP, implicated in platelet signaling, has been targeted with a small-molecule drug. [less ▲]

Detailed reference viewed: 93 (36 ULg)
Full Text
Peer Reviewed
See detailEvaluating Effects of Tyrosine Phosphatase Inhibitors on T Cell Receptor Signaling
Rahmouni, Souad ULg; Delacroix, Laurence ULg; Liu, Wallace et al

in Phosphatase Modulators, Methods in Molecular Biology (2013)

The importance of tyrosine phosphorylation in normal cell physiology is well established, highlighted by the many human diseases that stem from abnormalities in protein tyrosine kinase (PTK) and protein ... [more ▼]

The importance of tyrosine phosphorylation in normal cell physiology is well established, highlighted by the many human diseases that stem from abnormalities in protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) function. Contrary to earlier assumptions, it is now clear that both PTKs and PTPs are highly specific, non-redundant, and tightly regulated enzymes. Hematopoietic cells express particularly high numbers of PTKs and PTPs, and aberrant function of these proteins have been linked to many hematopoietic disorders. While PTK inhibitors are among FDA approved drugs for the treatment of leukemia and other cancers, efforts to develop therapeutics that target specific PTPs are still in its infancy. Here, we describe methods on how to evaluate effects of PTP inhibitors on T cell receptor signaling. Moreover, we provide a comprehensive strategy for compound prioritization, applicable to any drug discovery project involving T cells. We present a testing funnel that starts with relatively high-throughput luciferase reporter assays, followed by immunoblot, calcium flux, flow cytometry, and proliferation assays, continues with cytokine bead arrays, and finishes with specificity assays that involve RNA interference. We provide protocols for experiments in the Jurkat T cell line, but more importantly give detailed instructions, paired with numerous tips, on how to prepare and work with primary human T cells. [less ▲]

Detailed reference viewed: 27 (7 ULg)
Full Text
Peer Reviewed
See detailDynamic interaction between lymphoid tyrosine phosphatase and C-terminal Src kinase controls T cell activation
Tautz, Lutz; Vang, Torkel; Liu, Wallace et al

in FASEB Journal (2012, April), 26

Lymphoid tyrosine phosphatase (LYP) and C-terminal Src kinase (CSK) are negative regulators of signaling mediated through the T cell antigen receptor (TCR) and are thought to act in a cooperative manner ... [more ▼]

Lymphoid tyrosine phosphatase (LYP) and C-terminal Src kinase (CSK) are negative regulators of signaling mediated through the T cell antigen receptor (TCR) and are thought to act in a cooperative manner when forming a complex. Here, we show that dissociation of the LYP/CSK complex is necessary for recruitment of LYP to lipid rafts, where it down-modulates TCR-mediated signaling. Our findings may also explain the reduced TCR signaling associated with a single nucleotide polymorphism, which confers increased risk for autoimmunity and results in the expression of a LYP allele that can no longer bind CSK. Development of a potent and selective chemical probe of LYP allowed us to confirm that the observed down-modulation of TCR-induced signaling was due to the LYP catalytic activity. Our compound also represents a starting point for the development of a LYP-based treatment of autoimmunity. [less ▲]

Detailed reference viewed: 6 (1 ULg)
Full Text
Peer Reviewed
See detailLYP inhibits T-cell activation when dissociated from CSK
Vang; Liu, Wallace H; Delacroix, Laurence ULg et al

in Nature Chemical Biology (2012)

Lymphoid tyrosine phosphatase (LYP) and C-terminal Src kinase (CSK) are negative regulators of signaling mediated through the T-cell antigen receptor (TCR) and are thought to act in a cooperative manner ... [more ▼]

Lymphoid tyrosine phosphatase (LYP) and C-terminal Src kinase (CSK) are negative regulators of signaling mediated through the T-cell antigen receptor (TCR) and are thought to act in a cooperative manner when forming a complex. Here we studied the spatiotemporal dynamics of the LYP–CSK complex in T cells. We demonstrate that dissociation of this complex is necessary for recruitment of LYP to the plasma membrane, where it downmodulates TCR signaling. Development of a potent and selective chemical probe of LYP confirmed that LYP inhibits T-cell activation when removed from CSK. Our findings may explain the reduced TCR-mediated signaling associated with a single-nucleotide polymorphism that confers increased risk for certain autoimmune diseases, including type 1 diabetes and rheumatoid arthritis, and results in expression of a mutant LYP that is unable to bind CSK. Our compound also represents a starting point for the development of a LYP-based treatment of autoimmunity. [less ▲]

Detailed reference viewed: 38 (1 ULg)
Full Text
Peer Reviewed
See detailMultidentate small-molecule inhibitors of vaccinia H1-related (VHR) phosphatase decrease proliferation of cervix cancer cells.
Wu, Shuangding; Vossius, Sofie ULg; Rahmouni, Souad ULg et al

in Journal of Medicinal Chemistry (2009), 52(21), 6716-23

Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. We recently reported that VHR is ... [more ▼]

Loss of VHR phosphatase causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells. We recently reported that VHR is upregulated in several cervix cancer cell lines as well as in carcinomas of the uterine cervix. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and exhibit antiproliferative effects on cervix cancer cells. Chemical library screening was used to identify hit compounds, which were further prioritized in profiling and kinetic experiments. SAR analysis was applied in the search for analogs with improved potency and selectivity, resulting in the discovery of novel inhibitors that are able to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR’s active site. This multidentate binding mode was confirmed by X-ray crystallography. The inhibitors decreased the proliferation of cervix cancer cells, while growth of primary normal keratinocytes was not affected. These compounds may be a starting point to develop drugs for the treatment of cervical cancer. [less ▲]

Detailed reference viewed: 70 (23 ULg)
Full Text
See detailSmall-Molecule Inhibitors of Vaccinia-H1-Related Phosphatase VHR.
Tautz, lutz; Mustelin, Tomas; Wu, Shuangding et al

Report (2009)

Vaccinia H1-related (VHR) protein tyrosine phosphatase dephosphorylates and thereby inactivates extracellular signal-regulated kinases Erk1/2 and c-Jun N-terminal kinases Jnk1/2. These mitogen-activated ... [more ▼]

Vaccinia H1-related (VHR) protein tyrosine phosphatase dephosphorylates and thereby inactivates extracellular signal-regulated kinases Erk1/2 and c-Jun N-terminal kinases Jnk1/2. These mitogen-activated protein (MAP) kinases mediate major signaling pathways triggered by extracellular growth factor, stress, or cytokines and regulate cellular processes such as differentiation, proliferation and apoptosis. Unlike many MAP kinase phosphatases (MKPs), VHR expression is not induced in response to activation of MAP kinases, but is instead regulated during cell cycle progression. The loss of VHR causes cell cycle arrest in HeLa carcinoma cells, suggesting that VHR inhibition may be a useful approach to halt the growth of cancer cells without detrimental effects on normal cells. Here we report the development of multidentate small-molecule inhibitors of VHR that inhibit its enzymatic activity at nanomolar concentrations and are selective for VHR over HePTP and MKP-1. This novel small molecular probe, ML113 (CID-6161281) appears to interact with both the phosphate-binding pocket and several distinct hydrophobic regions within VHR's active site. As a result, it will serve as a useful tool in probing these interactions and elucidating the molecular mechanism underlying the selectivity against this phosphatase, in addition to providing greater understanding of the functional consequences for cancer biology. [less ▲]

Detailed reference viewed: 52 (4 ULg)
Full Text
Peer Reviewed
See detailCervix carcinoma is associated with an up-regulation and nuclear localization of the dual-specificity protein phosphatase VHR.
Henkens, Rachel ULg; Delvenne, Philippe ULg; Arafa, Mohammad et al

in BMC Cancer (2008), 8

BACKGROUND: The 21-kDa Vaccinia virus VH1-related (VHR) dual-specific protein phosphatase (encoded by the DUSP3 gene) plays a critical role in cell cycle progression and is itself regulated during the ... [more ▼]

BACKGROUND: The 21-kDa Vaccinia virus VH1-related (VHR) dual-specific protein phosphatase (encoded by the DUSP3 gene) plays a critical role in cell cycle progression and is itself regulated during the cell cycle. We have previously demonstrated using RNA interference that cells lacking VHR arrest in the G1 and G2 phases of the cell cycle and show signs of beginning of cell senescence. METHODS: In this report, we evaluated successfully the expression levels of VHR protein in 62 hysterectomy or conization specimens showing the various (pre) neoplastic cervical epithelial lesions and 35 additional cases of hysterectomy performed for non-cervical pathologies, from patients under 50 years of age. We used a tissue microarray and IHC technique to evaluate the expression of the VHR phosphatase. Immunofluorescence staining under confocal microscopy, Western blotting and RT-PCR methods were used to investigate the localization and expression levels of VHR. RESULTS: We report that VHR is upregulated in (pre) neoplastic lesions (squamous intraepithelial lesions; SILs) of the uterine cervix mainly in high grade SIL (H-SIL) compared to normal exocervix. In the invasive cancer, VHR is also highly expressed with nuclear localization in the majority of cells compared to normal tissue where VHR is always in the cytoplasm. We also report that this phosphatase is highly expressed in several cervix cancer cell lines such as HeLa, SiHa, CaSki, C33 and HT3 compared to primary keratinocytes. The immunofluorescence technique under confocal microscopy shows that VHR has a cytoplasmic localization in primary keratinocytes, while it localizes in both cytoplasm and nucleus of the cancer cell lines investigated. We report that the up-regulation of this phosphatase is mainly due to its post-translational stabilization in the cancer cell lines compared to primary keratinocytes rather than increases in the transcription of DUSP3 locus. CONCLUSION: These results together suggest that VHR can be considered as a new marker for cancer progression in cervix carcinoma and potential new target for anticancer therapy. [less ▲]

Detailed reference viewed: 85 (16 ULg)
Full Text
Peer Reviewed
See detailLipid raft targeting of hematopoietic protein tyrosine phosphatase by protein kinase C theta-mediated phosphorylation.
Nika, Konstantina; Charvet, Celine; Williams, Scott et al

in Molecular & Cellular Biology (2006), 26(5), 1806-16

Protein kinase C theta (PKC theta) is unique among PKC isozymes in its translocation to the center of the immune synapse in T cells and its unique downstream signaling. Here we show that the hematopoietic ... [more ▼]

Protein kinase C theta (PKC theta) is unique among PKC isozymes in its translocation to the center of the immune synapse in T cells and its unique downstream signaling. Here we show that the hematopoietic protein tyrosine phosphatase (HePTP) also accumulates in the immune synapse in a PKC theta-dependent manner upon antigen recognition by T cells and is phosphorylated by PKC theta at Ser-225, which is required for lipid raft translocation. Immune synapse translocation was completely absent in antigen-specific T cells from PKC theta-/- mice. In intact T cells, HePTP-S225A enhanced T-cell receptor (TCR)-induced NFAT/AP-1 transactivation, while the acidic substitution mutant was as efficient as wild-type HePTP. We conclude that HePTP is phosphorylated in the immune synapse by PKC theta and thereby targeted to lipid rafts to temper TCR signaling. This represents a novel mechanism for the active immune synapse recruitment and activation of a phosphatase in TCR signaling. [less ▲]

Detailed reference viewed: 36 (6 ULg)
Full Text
Peer Reviewed
See detailLow-Molecular-Weight Protein Tyrosine Phosphatases of Bacillus subtilis
Musumeci, Lucia ULg; Bongiorni, Cristina; Tautz, Lutz et al

in Journal of Bacteriology (2005), 187(14), 4945-4956

In gram-negative organisms, enzymes belonging to the low-molecular-weight protein tyrosine phosphatase (LMPTP) family are involved in the regulation of important physiological functions, including stress ... [more ▼]

In gram-negative organisms, enzymes belonging to the low-molecular-weight protein tyrosine phosphatase (LMPTP) family are involved in the regulation of important physiological functions, including stress resistance and synthesis of the polysaccharide capsule. LMPTPs have been identified also in gram-positive bacteria, but their functions in these organisms are presently unknown. We cloned two putative LMPTPs from Bacillus subtilis, YfkJ and YwlE, which are highly similar to each other in primary structure as well as to LMPTPs from gram-negative bacteria. When purified from overexpressing Escherichia coli strains, both enzymes were able to dephosphorylate p-nitrophenyl-phosphate and phosphotyrosine-containing substrates in vitro but showed significant differences in kinetic parameters and sensitivity to inhibitors. Transcriptional analyses showed that yfkJ was transcribed at a low level throughout the growth cycle and underwent a σB-dependent transcriptional upregulation in response to ethanol stress. The transcription of ywlE was growth dependent but stress insensitive. Genomic deletion of each phosphatase-encoding gene led to a phenotype of reduced bacterial resistance to ethanol stress, which was more marked in the ywlE deletion strain. Our study suggests that YfkJ and YwlE play roles in B. subtilis stress resistance. [less ▲]

Detailed reference viewed: 36 (0 ULg)
Full Text
Peer Reviewed
See detailIn vitro characterization of the Bacillus subtilis protein tyrosine phosphatase YwqE
Mijakovic, Ivan; Musumeci, Lucia ULg; Tautz, Lutz et al

in Journal of Bacteriology (2005), 187(10), 3384-90

Both gram-negative and gram-positive bacteria possess protein tyrosine phosphatases (PTPs) with a catalytic Cys residue. In addition, many gram-positive bacteria have acquired a new family of PTPs, whose ... [more ▼]

Both gram-negative and gram-positive bacteria possess protein tyrosine phosphatases (PTPs) with a catalytic Cys residue. In addition, many gram-positive bacteria have acquired a new family of PTPs, whose first characterized member was CpsB from Streptococcus pneumoniae. Bacillus subtilis contains one such CpsB-like PTP, YwqE, in addition to two class II Cys-based PTPs, YwlE and YfkJ. The substrates for both YwlE and YfkJ are presently unknown, while YwqE was shown to dephosphorylate two phosphotyrosine-containing proteins implicated in UDP-glucuronate biosynthesis, YwqD and YwqF. In this study, we characterize YwqE, compare the activities of the three B. subtilis PTPs (YwqE, YwlE, and YfkJ), and demonstrate that the two B. subtilis class II PTPs do not dephosphorylate the physiological substrates of YwqE. [less ▲]

Detailed reference viewed: 15 (0 ULg)
Full Text
Peer Reviewed
See detailAutoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant.
Vang, Torkel; Congia, Mauro; Macis, Maria Doloretta et al

in Nature genetics (2005), 37(12), 1317-9

A SNP in the gene PTPN22 is associated with type 1 diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease and other autoimmune disorders. T cells from carriers of the predisposing ... [more ▼]

A SNP in the gene PTPN22 is associated with type 1 diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease and other autoimmune disorders. T cells from carriers of the predisposing allele produce less interleukin-2 upon TCR stimulation, and the encoded phosphatase has higher catalytic activity and is a more potent negative regulator of T lymphocyte activation. We conclude that the autoimmune-predisposing allele is a gain-of-function mutant. [less ▲]

Detailed reference viewed: 21 (2 ULg)
Full Text
Peer Reviewed
See detailYersinia phosphatase induces mitochondrially dependent apoptosis of T cells.
Bruckner, Shane; Rahmouni, Souad ULg; Tautz, Lutz et al

in Journal of Biological Chemistry (2005), 280(11), 10388-94

To evade the immune system, the etiologic agent of plague, Yersinia pestis, injects an exceptionally active tyrosine phosphatase called YopH into host cells using a type III secretion system. We recently ... [more ▼]

To evade the immune system, the etiologic agent of plague, Yersinia pestis, injects an exceptionally active tyrosine phosphatase called YopH into host cells using a type III secretion system. We recently reported that YopH acutely inhibits T cell antigen receptor signaling by dephosphorylating the Lck tyrosine kinase. Here, we show that prolonged presence of YopH in primary T cells or Jurkat T leukemia cells causes apoptosis, detected by annexin V binding, mitochondrial breakdown, caspase activation, and internucleosomal fragmentation. YopH also causes cell death when expressed in HeLa cells, and this cell death was inhibited by YopH-specific small molecule inhibitors. Cell death induced by YopH was also prevented by caspase inhibition or co-expression of Bcl-xL. We conclude that YopH not only paralyzes T cells acutely, but also ensures that the cells will not recover to induce a protective immune response but instead undergo mitochondrially regulated programmed cell death. [less ▲]

Detailed reference viewed: 26 (4 ULg)
Full Text
Peer Reviewed
See detailProtein tyrosine phosphatases in T cell physiology.
Mustelin, Tomas; Alonso, Andres; Bottini, Nunzio et al

in Molecular Immunology (2004), 41(6-7), 687-700

The molecular mechanisms of signal transduction have been the focus of intense research during the last decade. In T cells, much of the work has centered on protein tyrosine kinase-mediated signaling from ... [more ▼]

The molecular mechanisms of signal transduction have been the focus of intense research during the last decade. In T cells, much of the work has centered on protein tyrosine kinase-mediated signaling from the TCR and cytokine receptors, while the study of protein tyrosine phosphatases has lagged behind. Nevertheless, it has now become clear that many protein tyrosine phosphatases play equally important roles in T cell physiology and that no kinase-regulated system would work without the counterbalancing participation of phosphatases. In fact, we have learned that many processes are regulated primarily on the phosphatase side. This minireview summarizes the current state-of-the art in our understanding of the regulation and biology of protein tyrosine phosphatases in T lymphocyte physiology. [less ▲]

Detailed reference viewed: 23 (3 ULg)