scholarly journals The Role of Protein Tyrosine Phosphatases in Inflammasome Activation

2020 ◽  
Vol 21 (15) ◽  
pp. 5481
Author(s):  
Marianne R. Spalinger ◽  
Marlene Schwarzfischer ◽  
Michael Scharl
Keyword(s):  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Protein Complexes ◽  
Protein Tyrosine Phosphatases ◽  
Inflammasome Activation ◽  
Tyrosine Phosphatases ◽  
Tyrosine Residues ◽  
Inflammasome Activity ◽  
Activation Status

Inflammasomes are multi-protein complexes that mediate the activation and secretion of the inflammatory cytokines IL-1β and IL-18. More than half a decade ago, it has been shown that the inflammasome adaptor molecule, ASC requires tyrosine phosphorylation to allow effective inflammasome assembly and sustained IL-1β/IL-18 release. This finding provided evidence that the tyrosine phosphorylation status of inflammasome components affects inflammasome assembly and that inflammasomes are subjected to regulation via kinases and phosphatases. In the subsequent years, it was reported that activation of the inflammasome receptor molecule, NLRP3, is modulated via tyrosine phosphorylation as well, and that NLRP3 de-phosphorylation at specific tyrosine residues was required for inflammasome assembly and sustained IL-1β/IL-18 release. These findings demonstrated the importance of tyrosine phosphorylation as a key modulator of inflammasome activity. Following these initial reports, additional work elucidated that the activity of several inflammasome components is dictated via their phosphorylation status. Particularly, the action of specific tyrosine kinases and phosphatases are of critical importance for the regulation of inflammasome assembly and activity. By summarizing the currently available literature on the interaction of tyrosine phosphatases with inflammasome components we here provide an overview how tyrosine phosphatases affect the activation status of inflammasomes.

scholarly journals Activation of Phosphotyrosine-Mediated Signaling Pathways in the Cortex and Spinal Cord of SOD1G93A, a Mouse Model of Familial Amyotrophic Lateral Sclerosis

2018 ◽  
Vol 2018 ◽  
pp. 1-10
Author(s):  
Cinzia Mallozzi ◽  
Alida Spalloni ◽  
Patrizia Longone ◽  
Maria Rosaria Domenici
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Tyrosine Phosphatases ◽  
Direct Stimulation ◽  
Tyrosine Kinase 2 ◽  
Lateral Sclerosis

Degeneration of cortical and spinal motor neurons is the typical feature of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease for which a pathogenetic role for the Cu/Zn superoxide dismutase (SOD1) has been demonstrated. Mice overexpressing a mutated form of the SOD1 gene (SOD1G93A) develop a syndrome that closely resembles the human disease. The SOD1 mutations confer to this enzyme a “gain-of-function,” leading to increased production of reactive oxygen species. Several oxidants induce tyrosine phosphorylation through direct stimulation of kinases and/or phosphatases. In this study, we analyzed the activities of src and fyn tyrosine kinases and of protein tyrosine phosphatases in synaptosomal fractions prepared from the motor cortex and spinal cord of transgenic mice expressing SOD1G93A. We found that (i) protein phosphotyrosine level is increased, (ii) src and fyn activities are upregulated, and (iii) the activity of tyrosine phosphatases, including the striatal-enriched tyrosine phosphatase (STEP), is significantly decreased. Moreover, the NMDA receptor (NMDAR) subunit GluN2B tyrosine phosphorylation was upregulated in SOD1G93A. Tyrosine phosphorylation of GluN2B subunits regulates the NMDAR function and the recruitment of downstream signaling molecules. Indeed, we found that proline-rich tyrosine kinase 2 (Pyk2) and ERK1/2 kinase are upregulated in SOD1G93A mice. These results point out an involvement of tyrosine kinases and phosphatases in the pathogenesis of ALS.

scholarly journals Essence of PTEN: a Broad-Spectrum Therapeutic Target in Cancer

2020 ◽  
Vol 11 (2) ◽  
pp. 9587-9603
Keyword(s):  
Tumor Suppressor ◽  
Tyrosine Kinases ◽  
Cell Cycle Progression ◽  
Protein Tyrosine Phosphatases ◽  
Underlying Mechanism ◽  
Pten Gene ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Tensin Homolog

The levels of protein tyrosine phosphorylation within a cell is regulated by protein tyrosine kinases and protein tyrosine phosphatases. These protein tyrosine phosphatases (PTP) can act both as positive and negative regulators during cell cycle progression and signal transduction. Phosphatase activity is shown by Phosphatase and Tensin homolog (PTEN) protein encoded by PTEN gene localized on human chromosome 10. Earlier findings established the role of PTEN as a tumor suppressor in Cowden’s disease, where PTEN mutations resulted in disease outcomes. Subsequent studies found the role of PTEN mutations in various human cancers, making it one of the vastly studied tumor suppressor genes. The current review has been planned to get a deeper insight into the potential role of PTEN in a variety of physiological processes involved in normal development like cell growth, migration, and differentiation along with the factors, regulation, and underlying mechanism.

scholarly journals Selective Sensing of Tyrosine Phosphorylation in Peptides Using Terbium(III) Complexes

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Jun Sumaoka ◽  
Hiroki Akiba ◽  
Makoto Komiyama
Keyword(s):  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
High Selectivity ◽  
Protein Tyrosine Phosphatases ◽  
Protein Tyrosine Kinases ◽  
Selective Detection ◽  
Protein Tyrosine ◽  
Tyrosine Residues ◽  
Recent Developments ◽  
Efficient Screening

Phosphorylation of tyrosine residues in proteins, as well as their dephosphorylation, is closely related to various diseases. However, this phosphorylation is usually accompanied by more abundant phosphorylation of serine and threonine residues in the proteins and covers only 0.05% of the total phosphorylation. Accordingly, highly selective detection of phosphorylated tyrosine in proteins is an urgent subject. In this review, recent developments in this field are described. Monomeric and binuclearTbIIIcomplexes, which emit notable luminescence only in the presence of phosphotyrosine (pTyr), have been developed. There, the benzene ring of pTyr functions as an antenna and transfers its photoexcitation energy to theTbIIIion as the emission center. Even in the coexistence of phosphoserine (pSer) and phosphothreonine (pThr), pTyr can be efficintly detected with high selectivity. Simply by adding theseTbIIIcomplexes to the solutions, phosphorylation of tyrosine in peptides by protein tyrosine kinases and dephosphorylation by protein tyrosine phosphatases can be successfully visualized in a real-time fashion. Furthermore, the activities of various inhibitors on these enzymes are quantitatively evaluated, indicating a strong potential of the method for efficient screening of eminent inhibitors from a number of candidates.

scholarly journals Inflammasomes inMycobacterium tuberculosis-Driven Immunity

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Sebastian Wawrocki ◽  
Magdalena Druszczynska
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Inflammatory Response ◽  
Immune Responses ◽  
Proinflammatory Cytokines ◽  
Immune Cells ◽  
Protein Complexes ◽  
Inflammasome Activation ◽  
Host Immune Responses ◽  
Multimeric Protein

The development of effective innate and subsequent adaptive host immune responses is highly dependent on the production of proinflammatory cytokines that increase the activity of immune cells. The key role in this process is played by inflammasomes, multimeric protein complexes serving as a platform for caspase-1, an enzyme responsible for proteolytic cleavage of IL-1βand IL-18 precursors. Inflammasome activation, which triggers the multifaceted activity of these two proinflammatory cytokines, is a prerequisite for developing an efficient inflammatory response against pathogenicMycobacterium tuberculosis(M.tb). This review focuses on the role of NLRP3 and AIM2 inflammasomes inM.tb-driven immunity.

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 Na+/H+ exchange activity during phagocytosis in human neutrophils: role of Fcgamma receptors and tyrosine kinases.

1996 ◽  
Vol 132 (6) ◽  
pp. 1037-1052 ◽  
Author(s):  
T Fukushima ◽  
T K Waddell ◽  
S Grinstein ◽  
G G Goss ◽  
J Orlowski ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Plasma Membranes ◽  
Kinase Inhibitors ◽  
Human Neutrophils ◽  
Cross Linking ◽  
Fcgamma Receptors ◽  
Beta2 Integrins ◽  
Cytosolic Acidification

In neutrophils, binding and phagocytosis facilitate subsequent intracellular killing of microorganisms. Activity of Na+/H+ exchangers (NHEs) participates in these events, especially in regulation of intracellular pH (pHi) by compensating for the H+ load generated by the respiratory burst. Despite the importance of these functions, comparatively little is known regarding the nature and regulation of NHE(s) in neutrophils. The purpose of this study was to identify which NHE(s) are expressed in neutrophils and to elucidate the mechanisms regulating their activity during phagocytosis. Exposure of cells to the phagocytic stimulus opsonized zymosan (OpZ) induced a transient cytosolic acidification followed by a prolonged alkalinization. The latter was inhibited in Na+-free medium and by amiloride analogues and therefore was due to activation of Na+/H+ exchange. Reverse transcriptase PCR and cDNA sequencing demonstrated that mRNA for the NHE-1 but not for NHE-2, 3, or 4 isoforms of the exchanger was expressed. Immunoblotting of purified plasma membranes with isoform-specific antibodies confirmed the presence of NHE-1 protein in neutrophils. Since phagocytosis involves Fcgamma (FcgammaR) and complement receptors such as CR3 (a beta2 integrin) which are linked to pathways involving alterations in intracellular [Ca2+]i and tyrosine phosphorylation, we studied these pathways in relation to activation of NHE-1. Cross-linking of surface bound antibodies (mAb) directed against FcgammaRs (FcgammaRII > FcgammaRIII) but not beta2 integrins induced an amiloride-sensitive cytosolic alkalinization. However, anti-beta2 integrin mAb diminished OpZ-induced alkalinization suggesting that NHE-1 activation involved cooperation between integrins and FcgammaRs. The tyrosine kinase inhibitors genistein and herbimycin blocked cytosolic alkalinization after OpZ or FcgammaR cross-linking suggesting that tyrosine phosphorylation was involved in NHE-I activation. An increase in [Ca2+]i was not required for NHE-1 activation because neither removal of extracellular Ca2+ nor buffering of changes in [Ca2+]i inhibited alkalinization after OpZ or Fc-gammaR cross-linking. In summary, Fc-gammaRs and beta2 integrins cooperate in activation of NHE-1 in neutrophils during phagocytosis by a signaling pathway involving tyrosine phosphorylation.

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