scholarly journals Control of Genetically Prescribed Protein Tyrosine Kinase Activities by Environment-Linked Redox Reactions

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Izumi Nakashima ◽  
Yoshiyuki Kawamoto ◽  
Kozue Takeda ◽  
Masashi Kato
Keyword(s):  
Tyrosine Kinases ◽  
Redox Reactions ◽  
Cell Activation ◽  
Tertiary Structure ◽  
Protein Tyrosine Phosphatases ◽  
Covalent Bond ◽  
Membrane Lipid ◽  
Protein Tyrosine ◽  
Signaling Systems ◽  
Catalytic Activities

Recent observations on environment-linked control of genetically prescribed signaling systems for either cell activation or cell death have been reviewed with a focus on the regulation of activities of protein tyrosine kinases (PTKs). The environment-linked redox reactions seem to primarily affect cell surface receptors and cell membrane lipid rafts, and they induce generation of reactive oxygen species (ROS) in cells. ROS thus generated might upregulate the catalytic activities of PTKs through inactivating protein tyrosine phosphatases that dephosphorylate and inactivate autophosphorylated PTKs. Recent evidence has, however, demonstrated that ROS could also directly oxidize SH groups of genetically conserved specific cysteines on PTKs, sometimes producing disulfide-bonded dimers of PTK proteins, either for upregulation or downregulation of their catalytic activities. The basic role of the redox reaction/covalent bond-mediated modification of protein tertiary structure-linked noncovalent bond-oriented signaling systems in living organisms is discussed.

scholarly journals Positive and negative regulation of T-cell activation through kinases and phosphatases

2003 ◽  
Vol 371 (1) ◽  
pp. 15-27 ◽  
Author(s):  
Tomas MUSTELIN ◽  
Kjetil TASKÉN
Keyword(s):  
T Cell ◽  
Tyrosine Phosphorylation ◽  
T Cell Activation ◽  
Tyrosine Kinases ◽  
Cell Activation ◽  
Protein Tyrosine Phosphatases ◽  
Negative Regulation ◽  
Intact Cells ◽  
Protein Tyrosine ◽  
Sequence Of Events

The sequence of events in T-cell antigen receptor (TCR) signalling leading to T-cell activation involves regulation of a number of protein tyrosine kinases (PTKs) and the phosphorylation status of many of their substrates. Proximal signalling pathways involve PTKs of the Src, Syk, Csk and Tec families, adapter proteins and effector enzymes in a highly organized tyrosine-phosphorylation cascade. In intact cells, tyrosine phosphorylation is rapidly reversible and generally of a very low stoichiometry even under induced conditions due to the fact that the enzymes removing phosphate from tyrosine-phosphorylated substrates, the protein tyrosine phosphatases (PTPases), have a capacity that is several orders of magnitude higher than that of the PTKs. It follows that a relatively minor change in the PTK/PTPase balance can have a major impact on net tyrosine phosphorylation and thereby on activation and proliferation of T-cells. This review focuses on the involvement of PTKs and PTPases in positive and negative regulation of T-cell activation, the emerging theme of reciprocal regulation of each type of enzyme by the other, as well as regulation of phosphotyrosine turnover by Ser/Thr phosphorylation and regulation of localization of signal components.

scholarly journals Phosphorylation-Dependent Regulation of T-Cell Activation by PAG/Cbp, a Lipid Raft-Associated Transmembrane Adaptor

2003 ◽  
Vol 23 (6) ◽  
pp. 2017-2028 ◽  
Author(s):  
Dominique Davidson ◽  
Marcin Bakinowski ◽  
Matthew L. Thomas ◽  
Vaclav Horejsi ◽  
André Veillette
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Tyrosine Kinases ◽  
Cell Activation ◽  
Protein Tyrosine Phosphatases ◽  
Dominant Negative ◽  
Negative Regulator ◽  
Cell Fractionation ◽  
Protein Tyrosine

ABSTRACT PAG/Cbp (hereafter named PAG) is a transmembrane adaptor molecule found in lipid rafts. In resting human T cells, PAG is tyrosine phosphorylated and associated with Csk, an inhibitor of Src-related protein tyrosine kinases. These modifications are rapidly lost in response to T-cell receptor (TCR) stimulation. Overexpression of PAG was reported to inhibit TCR-mediated responses in Jurkat T cells. Herein, we have examined the physiological relevance and the mechanism of PAG-mediated inhibition in T cells. Our studies showed that PAG tyrosine phosphorylation and association with Csk are suppressed in response to activation of normal mouse T cells. By expressing wild-type and phosphorylation-defective (dominant-negative) PAG polypeptides in these cells, we found that the inhibitory effect of PAG is dependent on its capacity to be tyrosine phosphorylated and to associate with Csk. PAG-mediated inhibition was accompanied by a repression of proximal TCR signaling and was rescued by expression of a constitutively activated Src-related kinase, implying that it is due to an inactivation of Src kinases by PAG-associated Csk. We also attempted to identify the protein tyrosine phosphatases (PTPs) responsible for dephosphorylating PAG in T cells. Through cell fractionation studies and analyses of genetically modified mice, we established that PTPs such as PEP and SHP-1 are unlikely to be involved in the dephosphorylation of PAG in T cells. However, the transmembrane PTP CD45 seems to play an important role in this process. Taken together, these data provide firm evidence that PAG is a bona fide negative regulator of T-cell activation as a result of its capacity to recruit Csk. They also suggest that the inhibitory function of PAG in T cells is suppressed by CD45. Lastly, they support the idea that dephosphorylation of proteins on tyrosine residues is critical for the initiation of T-cell activation.

scholarly journals Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP)

2021 ◽  
Vol 22 (9) ◽  
pp. 4417
Author(s):  
Lester J Lambert ◽  
Stefan Grotegut ◽  
Maria Celeridad ◽  
Palak Gosalia ◽  
Laurent JS De Backer ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
Tyrosine Kinases ◽  
High Throughput Screening ◽  
Kinase Inhibitors ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Synaptic Function ◽  
Label Free ◽  
Protein Tyrosine

Many human diseases are the result of abnormal expression or activation of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Not surprisingly, more than 30 tyrosine kinase inhibitors (TKIs) are currently in clinical use and provide unique treatment options for many patients. PTPs on the other hand have long been regarded as “undruggable” and only recently have gained increased attention in drug discovery. Striatal-enriched tyrosine phosphatase (STEP) is a neuron-specific PTP that is overactive in Alzheimer’s disease (AD) and other neurodegenerative and neuropsychiatric disorders, including Parkinson’s disease, schizophrenia, and fragile X syndrome. An emergent model suggests that the increase in STEP activity interferes with synaptic function and contributes to the characteristic cognitive and behavioral deficits present in these diseases. Prior efforts to generate STEP inhibitors with properties that warrant clinical development have largely failed. To identify novel STEP inhibitor scaffolds, we developed a biophysical, label-free high-throughput screening (HTS) platform based on the protein thermal shift (PTS) technology. In contrast to conventional HTS using STEP enzymatic assays, we found the PTS platform highly robust and capable of identifying true hits with confirmed STEP inhibitory activity and selectivity. This new platform promises to greatly advance STEP drug discovery and should be applicable to other PTP targets.

The phosphatase domains of LAR, CD45, and PTP1B: structural correlations with peptide-based inhibitors1

2000 ◽  
Vol 78 (1) ◽  
pp. 39-50 ◽  
Author(s):  
Nicholas R Glover ◽  
Alan S Tracey
Keyword(s):  
Insulin Receptor ◽  
Charge Distribution ◽  
T Cell Activation ◽  
Active Site ◽  
Cell Activation ◽  
Cell Function ◽  
Protein Tyrosine Phosphatases ◽  
Surface Topology ◽  
X Ray ◽  
Protein Tyrosine

PTP1B is a cytosolic protein tyrosine phosphatase that is a regulator of the kinase activity of the insulin receptor; the two protein tyrosine phosphatases LAR and CD45 are receptor type phosphatases crucially important to cell function. LAR also is involved in regulation of the insulin receptor while CD45 is critical for T-cell activation. Although LAR and CD45 are both transmembrane phosphatases, these enzymes manifest their phosphatase activity through a catalytic cytosolic domain. We have utilized X-ray coordinates of related phosphatases (RPTPalpha and RPTPµ) and comparative protein modeling to obtain molecular models of the D1 catalytic domains of CD45 and LAR. The models were tested using established protocols and found to be comparable to low resolution X-ray structures. The structure obtained for LAR was compared with the recently reported X-ray structure. Both the CD45-D1 and LAR-D1 structures were then compared to and contrasted with PTP1B. The active site of pockets of the three enzymes were found to be very uniform in structure and charge distribution. Also, the gross surface topology around the active site was found to be somewhat similar for the 3 phosphatases. However, there were significant differences in surface topology, and, more importantly, large changes in surface charge distribution. The differences between the surface features of these enzymes provide an explanation for the selectivity of inhibition by a number of peptides.

scholarly journals Protein tyrosine phosphatases and signalling

2005 ◽  
Vol 185 (1) ◽  
pp. 19-33 ◽  
Author(s):  
Andrew W Stoker
Keyword(s):  
Tyrosine Kinases ◽  
Current Knowledge ◽  
Insulin Signalling ◽  
Cell Signalling ◽  
Protein Tyrosine Phosphatases ◽  
Protein Tyrosine Kinases ◽  
Tyrosine Phosphatases ◽  
Large Protein ◽  
Protein Tyrosine ◽  
Wide Range

A cornerstone of many cell-signalling events rests on reversible phosphorylation of tyrosine residues on proteins. The reversibility relies on the coordinated actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs), both of which exist as large protein families. This review focuses on the rapidly evolving field of the PTPs. We now know that rather than simply scavenging phosphotyrosine, the PTPs specifically regulate a wide range of signalling pathways. To illustrate this and to highlight current areas of agreement and contention in the field, this review will present our understanding of PTP action in selected areas and will present current knowledge surrounding the regulatory mechanisms that control PTP enzymes themselves. It will be seen that PTPs control diverse processes such as focal adhesion dynamics, cell–cell adhesion and insulin signalling, and their own actions are in turn regulated by dimerisation, phosphorylation and reversible oxidation.

scholarly journals Noncatalytic Inhibition of Cyclic Nucleotide–gated Channels by Tyrosine Kinase Induced by Genistein

1999 ◽  
Vol 113 (1) ◽  
pp. 45-56 ◽  
Author(s):  
Elena Molokanova ◽  
Alexei Savchenko ◽  
Richard H. Kramer
Keyword(s):  
Tyrosine Phosphorylation ◽  
Cyclic Nucleotide ◽  
Tyrosine Kinases ◽  
Time Course ◽  
Protein Tyrosine Phosphatases ◽  
Competitive Inhibitor ◽  
Rod Photoreceptor ◽  
Protein Tyrosine ◽  
Atp Binding Site ◽  
Cng Channel

Rod photoreceptor cyclic nucleotide–gated (CNG) channels are modulated by tyrosine phosphorylation. Rod CNG channels expressed in Xenopus oocytes are associated with constitutively active protein tyrosine kinases (PTKs) and protein tyrosine phosphatases that decrease and increase, respectively, the apparent affinity of the channels for cGMP. Here, we examine the effects of genistein, a competitive inhibitor of the ATP binding site, on PTKs. Like other PTK inhibitors (lavendustin A and erbstatin), cytoplasmic application of genistein prevents changes in the cGMP sensitivity that are attributable to tyrosine phosphorylation of the CNG channels. However, unlike these other inhibitors, genistein also slows the activation kinetics and reduces the maximal current through CNG channels at saturating cGMP. These effects occur in the absence of ATP, indicating that they do not involve inhibition of a phosphorylation event, but rather involve an allosteric effect of genistein on CNG channel gating. This could result from direct binding of genistein to the channel; however, the time course of inhibition is surprisingly slow (>30 s), raising the possibility that genistein exerts its effects indirectly. In support of this hypothesis, we find that ligands that selectively bind to PTKs without directly binding to the CNG channel can nonetheless decrease the effect of genistein. Thus, ATP and a nonhydrolyzable ATP derivative competitively inhibit the effect of genistein on the channel. Moreover, erbstatin, an inhibitor of PTKs, can noncompetitively inhibit the effect of genistein. Taken together, these results suggest that in addition to inhibiting tyrosine phosphorylation of the rod CNG channel catalyzed by PTKs, genistein triggers a noncatalytic interaction between the PTK and the channel that allosterically inhibits gating.

scholarly journals PAH- and PCB-induced Alterations of Protein Tyrosine Kinase and Cytokine Gene Transcription in Harbor Seal (Phoca Vitulina) PBMC

2005 ◽  
Vol 12 (2) ◽  
pp. 91-97 ◽  
Author(s):  
Jennifer C. C. Neale ◽  
Thomas P. Kenny ◽  
Ronald S. Tjeerdema ◽  
M. Eric Gershwin
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Tyrosine Kinases ◽  
Cell Activation ◽  
Critical Role ◽  
Harbor Seal ◽  
Lymphocyte Function ◽  
Altered Expression ◽  
Protein Tyrosine

Mechanisms underlyingin vitroimmunomodulatory effects of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) were investigated in harbor seal peripheral leukocytes, via real-time PCR. We examined the relative genetic expression of the protein tyrosine kinases (PTKs)FynandItk, which play a critical role in T cell activation, and IL-2, a cytokine of central importance in initiating adaptive immune responses. IL-1, the macrophage-derived pro-inflammatory cytokine of innate immunity, was also included as a measure of macrophage function. Harbor seal PBMC were exposed to the prototypic immunotoxic PAH benzo[a]pyrene (BaP), 3,3',4,4',5,5'-hexachlorobiphenyl (CB-169), a model immunotoxic PCB, or DMSO (vehicle control). Exposure of Con A-stimulated harbor seal PBMC to both BaP and CB-169 produced significantly altered expression in all four targets relative to vehicle controls. The PTKsFynandItkwere both up-regulated following exposure to BaP and CB-169. In contrast, transcripts for IL-2 and IL-1 were decreased relative to controls by both treatments. Our findings are consistent with those of previous researchers working with human and rodent systems and support a hypothesis of contaminant-altered lymphocyte function mediated (at least in part) by disruption of T cell receptor (TCR) signaling and cytokine production.

scholarly journals RPTPμ tyrosine phosphatase promotes adipogenic differentiation via modulation of p120 catenin phosphorylation

2011 ◽  
Vol 22 (24) ◽  
pp. 4883-4891 ◽  
Author(s):  
Won Kon Kim ◽  
Hyeyun Jung ◽  
Eun Young Kim ◽  
Do Hyung Kim ◽  
Yee Sook Cho ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Adipocyte Differentiation ◽  
Adipogenic Differentiation ◽  
Tyrosine Phosphatase ◽  
Ectopic Expression ◽  
Protein Tyrosine Phosphatases ◽  
P120 Catenin ◽  
Protein Tyrosine ◽  
Functional Roles ◽  
Novel Target

Adipocyte differentiation can be regulated by the combined activity of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). In particular, PTPs act as key regulators in differentiation-associated signaling pathways. We recently found that receptor-type PTPμ (RPTPμ) expression is markedly increased during the adipogenic differentiation of 3T3-L1 preadipocytes and mesenchymal stem cells. Here, we investigate the functional roles of RPTPμ and the mechanism of its involvement in the regulation of signal transduction during adipogenesis of 3T3-L1 cells. Depletion of endogenous RPTPμ by RNA interference significantly inhibited adipogenic differentiation, whereas RPTPμ overexpression led to an increase in adipogenic differentiation. Ectopic expression of p120 catenin suppressed adipocyte differentiation, and the decrease in adipogenesis by p120 catenin was recovered by introducing RPTPμ. Moreover, RPTPμ induced a decrease in the cytoplasmic p120 catenin expression by reducing its tyrosine phosphorylation level, consequently leading to enhanced translocation of Glut-4 to the plasma membrane. On the basis of these results, we propose that RPTPμ acts as a positive regulator of adipogenesis by modulating the cytoplasmic p120 catenin level. Our data conclusively demonstrate that differentiation into adipocytes is controlled by RPTPμ, supporting the utility of RPTPμ and p120 catenin as novel target proteins for the treatment of obesity.

Roles of protein tyrosine phosphatases in cell migration and adhesion

1999 ◽  
Vol 77 (6) ◽  
pp. 493-505 ◽  
Author(s):  
Alexandre Angers-Loustau ◽  
Jean-François Côté ◽  
Michel L Tremblay
Keyword(s):  
Tyrosine Kinases ◽  
Protein Tyrosine Phosphatases ◽  
Cellular Migration ◽  
Tyrosine Phosphatases ◽  
Integrin Receptors ◽  
Protein Tyrosine ◽  
Kinase C ◽  
Cell Adhesion And Migration ◽  
And Migration ◽  
The Individual

Signal transduction pathways are often seen as cascades of kinases, whereas phosphatases are relinquished to the housekeeping function of resetting the individual elements to a resting state. However, critical biological processes such as cellular migration require a coordinated and constant remodeling of the actin cytoskeleton as well as a rapid turnover of the cell-substratum linkages that necessitate the concomitant action of antagonistic enzymes. Tyrosine phosphorylation was long known to be involved in adhesion and de-adhesion mediated via the integrin receptors. As the roles of tyrosine kinases such as focal adhesion kinase, c-Src, and Csk in this pathway are being extensively studied, increasing evidence is emerging about the importance of protein tyrosine phosphatases (PTP). In this review we discuss examples of PTPs that were recently shown to play a role in cell adhesion and migration and their mechanism of action.Key words: protein tyrosine phosphatases (PTP), migration, adhesion, FAK, p130Cas, Src.

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