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Implementação da análise de acoplamentos estatísticos e sua aplicação à família de proteínas tirosina fosfatases; Implementation of the statistical coupling analysis and its application to the Protein Tyrosine Phosphatases family.

Bleicher, Lucas
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 09/03/2009 PT
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76.07%
A Análise de Acoplamentos Estatísticos é uma técnica computacional capaz de identificar resíduos importantes para a estrutura e função de proteínas em uma família por meio da quantificação de conservação posicional, correlação entre posições e identificação de grupos de resíduos correlacionados entre si. Neste trabalho, a análise de acoplamentos estatísticos foi implementada e aplicada ao estudo das proteínas tirosina fosfatases. Em conjunto com as proteínas tirosina quinases (PTKs), que adicionam um grupo fosforil a um resíduo de tirosina em uma proteína, as proteínas tirosina fosfatases (PTPs), que o removem, são responsáveis por diversos processos de sinalização celular. Elas são um caso de evolução convergente, onde um subgrupo (as proteínas tirosina fosfatases de baixo peso molecular) não apresenta homologia às chamadas PTPs "clássicas", capazes de defosforilar apenas resíduos de tirosina, e às fosfatases de especifidicade dupla, capazes de defosforilar também resíduos de serina e treonina, além de substratos não-protéicos. Em comum, as três subfamílias apresentam apenas o motivo CX5R, característico para todas as PTPs. Através do estudo das três subfamílias utilizando a análise de acoplamentos estatísticos...

Protein tyrosine kinases in Schistosoma mansoni

Bahia,Diana; Andrade,Luiza Freire; Ludolf,Fernanda; Mortara,Renato Arruda; Oliveira,Guilherme
Fonte: Instituto Oswaldo Cruz, Ministério da Saúde Publicador: Instituto Oswaldo Cruz, Ministério da Saúde
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/10/2006 EN
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76.02%
The identification and description of signal transduction molecules and mechanisms are essential to elucidate Schistosoma mansoni host-parasite interactions and parasite biology. This mini review focuses on recent advancements in the study of signalling molecules and transduction mechanisms in S. mansoni, drawing special attention to the recently identified and characterised protein tyrosine kinases of S. mansoni.

Temporal differences in the activation of three classes of non-transmembrane protein tyrosine kinases following B-cell antigen receptor surface engagement.

Saouaf, S J; Mahajan, S; Rowley, R B; Kut, S A; Fargnoli, J; Burkhardt, A L; Tsukada, S; Witte, O N; Bolen, J B
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 27/09/1994 EN
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66.2%
We evaluated in WEHI 231 B cells the time-dependent responses of Lyn, Blk, Btk, Syk, and three members of the Jak family of protein tyrosine kinases following antibody-mediated surface engagement of the B-cell antigen receptor. Our results show that the enzyme activities of Lyn and Blk were stimulated within seconds of antigen receptor engagement and correlated with the initial tyrosine phosphorylation of the Ig alpha and Ig beta subunits of the B-cell antigen receptor. Btk enzyme activity was also transiently stimulated and was maximal at approximately 5 min after B-cell receptor surface binding. Syk activity gradually increased to a maximum at 10-30 min following receptor ligation and was found to parallel the association of Syk with the tyrosine phosphorylated Ig alpha and Ig beta subunits of the receptor. While the specific activities of the Jak1, Jak2, and Tyk2 protein tyrosine kinases were unaltered following B-cell receptor ligation, the abundance of Jak1 and Jak2 were increased 3- to 4-fold within 10 min of receptor engagement. These results demonstrate that multiple families of non-transmembrane protein tyrosine kinases are temporally regulated during the process of B-cell antigen receptor-initiated intracellular signal transduction.

7,12-Dimethylbenz[a]anthracene activates protein-tyrosine kinases Fyn and Lck in the HPB-ALL human T-cell line and increases tyrosine phosphorylation of phospholipase C-gamma 1, formation of inositol 1,4,5-trisphosphate, and mobilization of intracellular calcium.

Archuleta, M M; Schieven, G L; Ledbetter, J A; Deanin, G G; Burchiel, S W
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/07/1993 EN
Relevância na Pesquisa
66.23%
Previous studies have shown that the immunosuppressive and carcinogenic polycyclic aromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA) impairs Ca(2+)-dependent transmembrane signaling in human and murine lymphocytes. The purpose of the present studies was to analyze potential mechanisms of immunosuppression by DMBA and to examine effects on Ca2+ homeostasis and antigen-receptor signaling in human T cells. DMBA produced a rapid and sustained increase in Ca2+ levels in HPB-ALL cells by release of cytoplasmic Ca2+. DMBA also inhibited anti-CD3/CD4 mobilization of Ca2+ in HPB-ALL cells, with half-maximal inhibition occurring at approximately 4 hr. Thus, the kinetics for initial Ca2+ mobilization and inhibition of the anti-CD3/CD4 response differed. The rapid rise in intracellular Ca2+ induced by DMBA alone was accompanied by a rapid but transient increase in inositol 1,4,5-trisphosphate and tyrosine phosphorylation of phospholipase C-gamma 1. The pattern of tyrosine phosphorylation induced by DMBA in HPB-ALL cells was remarkably similar to that induced by anti-CD3/CD4 activation. Thus, DMBA-induced phosphorylation may mimic antigen-receptor activation in T cells, which may lead to alterations in antigen responsiveness. The mechanism of DMBA-induced tyrosine phosphorylation of phospholipase C-gamma 1 may have been due to an increase in protein-tyrosine kinase activity...

CD5 acts as a tyrosine kinase substrate within a receptor complex comprising T-cell receptor zeta chain/CD3 and protein-tyrosine kinases p56lck and p59fyn.

Burgess, K E; Yamamoto, M; Prasad, K V; Rudd, C E
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/10/1992 EN
Relevância na Pesquisa
66.18%
T-cell antigens including CD2, CD4, CD6, CD8, and CD28 serve as coreceptors with the T-cell receptor (TCR)/CD3 complex in control of T-cell growth. The molecular basis by which these antigens fulfill this role has remained a major issue. An initial clue to this question came with our finding that the sensitivity of in vitro kinase labeling (specifically using protein-tyrosine kinase p56lck) allowed detection of a physical association between CD4-p56lck and the TCR/CD3 complexes. Another T-cell antigen, CD5, is structurally related to the macrophage scavenger receptor family and, as such, can directly stimulate and/or potentiate T-cell proliferation. In this study, we reveal that in Brij 96-based cell lysates, anti-CD5 antibodies coprecipitated TCR zeta chain (TCR zeta)/CD3 subunits as well as the protein-tyrosine kinases p56lck and p59fyn. Conversely, anti-CD3 antibody coprecipitated CD5, p56lck, and p59fyn. Indeed, anti-CD5 and anti-CD3 gel patterns were virtually identical, except for a difference in relative intensity of polypeptides. Anti-CD4 coprecipitated p56lck, p32, and CD3/TCR zeta subunits but precipitated less CD5, suggesting the existence of CD4-TCR zeta/CD3 complexes distinct from the CD5-TCR zeta/CD3 complexes. Consistent with the formation of a multimeric CD5-TCR zeta/CD3 complex...

2,3,7,8-Tetrachlorodibenzo-p-dioxin causes increases in expression of c-erb-A and levels of protein-tyrosine kinases in selected tissues of responsive mouse strains.

Bombick, D W; Jankun, J; Tullis, K; Matsumura, F
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1988 EN
Relevância na Pesquisa
66.25%
2,3,7,8,-Tetrachlorodibenzo-p-dioxin (TCDD) administered in vivo causes drastic reduction in the weight of the mouse thymus at low doses (e.g., 30 micrograms/kg single i.p. injection), the reduction becoming statistically significant after 2 days. To understand the cause for such thymic involution TCDD-evoked changes in various biochemical parameters in this tissue were examined. The most noticeable change was observed in the increased activity of specific protein-tyrosine kinases and protein kinase C and an increased level of p21ras-associated binding of [3H]GTP. Since no significant change was observed with cAMP-stimulated protein kinases and cAMP levels, the above changes appear to be a selective effect on these special classes of proteins. As a result of a time sequence study it has become apparent that the rise in protein-tyrosine kinase activities becomes significant within 24 hr, whereas the rise in protein kinase C does not become significant until 48 hr. Among protein-tyrosine kinases, pp60c-src and probably pp561skT were found to be significantly elevated by TCDD treatment. In view of similarities between TCDD and thyroid hormones in causing thymic involution, the levels of c-erb-A expression were assessed in the liver by using avian 32P-labeled v-erb-A probe and RNA transfer blot hybridization technique. The results clearly indicate that TCDD has the property to elevate levels of mRNA bearing homology to v-erb-A. Such changes in c-erb-A expression and protein-tyrosine kinase occurred only in TCDD-susceptible (responsive) strains but not in tolerant (nonresponsive) strains of mice at the dose tested. Based on such observations a hypothesis has been proposed that TCDD owes its potency to its ability to stimulate the expression of one of a family of DNAs bearing homology to v-erb-A and that one of the major consequences of such an action is stimulation of various tyrosine kinases.

Mapping of sites on the Src family protein tyrosine kinases p55blk, p59fyn, and p56lyn which interact with the effector molecules phospholipase C-gamma 2, microtubule-associated protein kinase, GTPase-activating protein, and phosphatidylinositol 3-kinase.

Pleiman, C M; Clark, M R; Gauen, L K; Winitz, S; Coggeshall, K M; Johnson, G L; Shaw, A S; Cambier, J C
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1993 EN
Relevância na Pesquisa
66.28%
Engagement of the B-cell antigen receptor complex induces immediate activation of receptor-associated Src family tyrosine kinases including p55blk, p59fyn, p53/56lyn, and perhaps p56lck, and this response is accompanied by tyrosine phosphorylation of distinct cellular substrates. These kinases act directly or indirectly to phosphorylate and/or activate effector proteins including p42 (microtubule-associated protein kinase) (MAPK), phospholipases C-gamma 1 (PLC gamma 1) and C-gamma 2 (PLC gamma 2), phosphatidylinositol 3-kinase (PI 3-K), and p21ras-GTPase-activating protein (GAP). Although coimmunoprecipitation results indicate that the Src family protein tyrosine kinases interact physically with some of these effector molecules, the molecular basis of this interaction has not been established. Here, we show that three distinct sites mediate the interaction of these kinases with effectors. The amino-terminal 27 residues of the unique domain of p56lyn mediate association with PLC gamma 2, MAPK, and GAP. Binding to PI 3-K is mediated through the Src homology 3 (SH3) domains of the Src family kinases. Relatively small proportions of cellular PI 3-K, PLC gamma 2, MAPK, and GAP, presumably those which are tyrosine phosphorylated, bind to the SH2 domains of these kinases. Comparative analysis of binding activities of Blk...

Differential modulation of plasminogen activator gene expression by oncogene-encoded protein tyrosine kinases.

Bell, S M; Connolly, D C; Maihle, N J; Degen, J L
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /09/1993 EN
Relevância na Pesquisa
66.22%
Urokinase-type plasminogen activator (uPA) gene transcription is increased > or = 50-fold in chicken embryo fibroblasts (CEF) following transformation by the protein tyrosine kinase pp60v-src. Protein phosphorylation appears to play a critical role in uPA gene expression in these cells; protein kinase C-activating phorbol esters cooperate with pp60v-src to synergistically increase uPA mRNA, whereas cyclic AMP (cAMP)-dependent protein kinase-activating agents (e.g., 8-bromo cAMP) repress uPA mRNA levels. To explore the relationship between transforming oncogenes and uPA gene expression, uPA mRNA levels were measured in CEF infected with selected avian retroviruses. We report that v-ras and the transforming protein tyrosine kinases v-src, v-yes, and v-ros all increase cellular uPA mRNAs. However, transformation with the protein tyrosine kinase encoded by v-erbB, or the nuclear proteins encoded by v-jun, v-ski, or v-myc, did not increase uPA mRNA detectably. Ras and all of the protein tyrosine kinases analyzed, including the v-erbB product, but none of the nuclear oncoproteins sensitized cells to phorbol ester induction of uPA gene expression. Thus, increased uPA gene expression is not simply a secondary consequence of cell transformation but...

Association between B-lymphocyte membrane immunoglobulin and multiple members of the Src family of protein tyrosine kinases.

Campbell, M A; Sefton, B M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/1992 EN
Relevância na Pesquisa
66.22%
Treatment of B lymphocytes with antibodies to membrane immunoglobulin (Ig) stimulates protein tyrosine phosphorylation. We have examined the phosphorylation in vitro of proteins associated with membrane Ig. The Src family protein tyrosine kinases p53/56lyn, p59fyn, and p56lck are associated with membrane Ig in spleen B cells and B-cell lines and undergo phosphorylation in vitro. The pattern of expression of Src family protein tyrosine kinases in B cells varied. Our studies suggest that multiple kinases can potentially interact with membrane Ig and that within any one B-cell type, all of the Src family kinases expressed can be found in association with membrane Ig. We also observed that the Ig-associated Ig alpha protein, multiple forms of Ig beta, and proteins of 100 and 25 kDa were tyrosine phosphorylated in vitro. The 100- and 25-kDa proteins remain unidentified.

A noncatalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus P130gag-fps.

Sadowski, I; Stone, J C; Pawson, T
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1986 EN
Relevância na Pesquisa
66.22%
Proteins encoded by oncogenes such as v-fps/fes, v-src, v-yes, v-abl, and v-fgr are cytoplasmic protein tyrosine kinases which, unlike transmembrane receptors, are localized to the inside of the cell. These proteins possess two contiguous regions of sequence identity: a C-terminal catalytic domain of 260 residues with homology to other tyrosine-specific and serine-threonine-specific protein kinases, and a unique domain of approximately 100 residues which is located N terminal to the kinase region and is absent from kinases that span the plasma membrane. In-frame linker insertion mutations in Fujinami avian sarcoma virus which introduced dipeptide insertions into the most stringently conserved segment of this N-terminal domain in P130gag-fps impaired the ability of Fujinami avian sarcoma virus to transform rat-2 cells. The P130gag-fps proteins encoded by these transformation-defective mutants were deficient in protein-tyrosine kinase activity in rat cells. However v-fps polypeptides derived from the mutant Fujinami avian sarcoma virus genomes and expressed in Escherichia coli as trpE-v-fps fusion proteins displayed essentially wild-type enzymatic activity, even though they contained the mutated sites. Deletion of the N-terminal domain from wild-type and mutant v-fps bacterial proteins had little effect on autophosphorylating activity. The conserved N-terminal domain of P130gag-fps is therefore not required for catalytic activity...

Haemophilus ducreyi LspA Proteins Are Tyrosine Phosphorylated by Macrophage-Encoded Protein Tyrosine Kinases▿

Deng, Kaiping; Mock, Jason R.; Greenberg, Steven; van Oers, Nicolai S. C.; Hansen, Eric J.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
66.18%
The LspA proteins (LspA1 and LspA2) of Haemophilus ducreyi are necessary for this pathogen to inhibit the phagocytic activity of macrophage cell lines, an event that can be correlated with a reduction in the level of active Src family protein tyrosine kinases (PTKs) in these eukaryotic cells. During studies investigating this inhibitory mechanism, it was discovered that the LspA proteins themselves were tyrosine phosphorylated after wild-type H. ducreyi cells were incubated with macrophages. LspA proteins in cell-free concentrated H. ducreyi culture supernatant fluid could also be tyrosine phosphorylated by macrophages. This ability to tyrosine phosphorylate the LspA proteins was not limited to immune cell lineages but could be accomplished by both HeLa and COS-7 cells. Kinase inhibitor studies with macrophages demonstrated that the Src family PTKs were required for this tyrosine phosphorylation activity. In silico methods and site-directed mutagenesis were used to identify EPIYG and EPVYA motifs in LspA1 that contained tyrosines that were targets for phosphorylation. A total of four tyrosines could be phosphorylated in LspA1, with LspA2 containing eight predicted tyrosine phosphorylation motifs. Purified LspA1 fusion proteins containing either the EPIYG or EPVYA motifs were shown to be phosphorylated by purified Src PTK in vitro. Macrophage lysates could also tyrosine phosphorylate the LspA proteins and an LspA1 fusion protein via a mechanism that was dependent on the presence of both divalent cations and ATP. Several motifs known to interact with or otherwise affect eukaryotic kinases were identified in the LspA proteins.

Heme Controls the Regulation of Protein Tyrosine Kinases Jak2 and Src

Yao, Xiao; Balamurugan, Parimaladevi; Arvey, Aaron; Leslie, Christina; Zhang, Li
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
66.23%
Protein tyrosine kinases play key roles in many molecular and cellular processes in diverse living organisms. Their proper functioning is crucial for the normal growth, development, and health in humans, whereas their dysfunction can cause serious diseases, including various cancers. As such, intense studies have been performed to understand the molecular mechanisms by which the activities of protein tyrosine kinases are regulated in mammalian cells. Particularly, small molecules that can modulate the activity of tyrosine kinases are of great importance for discovering therapeutic drug candidates for numerous diseases. Notably, heme can not only serve as a prosthetic group for hemoglobins and enzymes, but it also is a small signaling molecule that can control the activity of diverse signaling and regulatory proteins. Using a computational search, we found that a group of non-membrane spanning tyrosine kinases contains one or more CP motifs that can potentially bind to heme and mediate heme regulation. We then used experimental approaches to determine whether heme can affect the activity of any of these tyrosine kinases. We found that heme indeed affects the phosphorylation of key tyrosine residues in Jak2 and Src, and is therefore able to modulate Jak2 and Src activity. Further experiments showed that Jak2 and Src indeed bind to heme and that the presence of heme alters the sensitivity of Jak2 and Src to trypsin digestion. These results suggest that heme actively interacts with Jak2 and Src and alters their conformation.

Microbial Protein-tyrosine Kinases*

Chao, Joseph D.; Wong, Dennis; Av-Gay, Yossef
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
66.35%
Microbial ester kinases identified in the past 3 decades came as a surprise, as protein phosphorylation on Ser, Thr, and Tyr amino acids was thought to be unique to eukaryotes. Current analysis of available microbial genomes reveals that “eukaryote-like” protein kinases are prevalent in prokaryotes and can converge in the same signaling pathway with the classical microbial “two-component” systems. Most microbial tyrosine kinases lack the “eukaryotic” Hanks domain signature and are designated tyrosine kinases based upon their biochemical activity. These include the tyrosine kinases termed bacterial tyrosine kinases (BY-kinases), which are responsible for the majority of known bacterial tyrosine phosphorylation events. Although termed generally as bacterial tyrosine kinases, BY-kinases can be considered as one family belonging to the superfamily of prokaryotic protein-tyrosine kinases in bacteria. Other members of this superfamily include atypical “odd” tyrosine kinases with diverse mechanisms of protein phosphorylation and the “eukaryote-like” Hanks-type tyrosine kinases. Here, we discuss the distribution, phylogeny, and function of the various prokaryotic protein-tyrosine kinases, focusing on the recently discovered Mycobacterium tuberculosis PtkA and its relationship with other members of this diverse family of proteins.

Clinical Targeting of Mutated and Wild-Type Protein Tyrosine Kinases in Cancer

Drake, Justin M.; Lee, John K.; Witte, Owen N.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /05/2014 EN
Relevância na Pesquisa
66.3%
Clinical therapies for cancer have evolved from toxic, nontargeted agents to manageable, highly targeted therapies. Protein tyrosine kinases are a family of signaling molecules implicated in nearly every cancer type and are the foundation for the development of modern targeted agents. Recent genomic analyses have identified activating mutations, translocations, and amplifications of tyrosine kinases. Selective targeting of these genetically altered tyrosine kinases has resulted in significant clinical advances, including increased patient survival. This indicates that altered protein tyrosine kinases are the main drivers of many different cancers. However, lost during analyses of genetic lesions are the contributions of activated, wild-type kinases on tumor-dependent pathways. New approaches in phosphoproteomic technologies have identified several wild-type tyrosine kinase activation states, suggesting that non-genetically altered kinases can be essential “nodes” for signal transduction. Here, we summarize the evidence supporting the common mechanisms of protein tyrosine kinase activation in cancer and provide a personal perspective on the kinases BCR-ABL and BTK, as well as nonmutated kinase targets in prostate cancer, through our work. We outline the mechanisms of tyrosine kinase activation in the absence of direct mutation and discuss whether non-genetically altered tyrosine kinases or their associated downstream signaling pathways can be effectively targeted.

Protein Tyrosine Phosphatase Pez : its role in the regulation of cell-cell adhesions.

Wadham, Carol
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2003
Relevância na Pesquisa
76.05%
The balance of tyrosine phosphorylation in the cell is maintained by the opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Investigation into tyrosine phosphorylation was initially focused on the action of PTKs. However, research over the past decade has revealed that PTPs also play a key role in signal transduction. The multi-protein complexes that constitute the cell-cell adhesions in endothelial and epithelial tissues are dynamically restructured in response to extracellular and intracellular signalling. Tyrosine phosphorylation is involved in the regulation of both adherens junctions and tight junctions. Inhibitors of PTPs have been shown to disrupt cell-cell adhesions indicating that PTPs are important in maintaining adhesion integrity. The maintenance of a selectively permeable barrier is an essential function of endothelial cells, which are the cells that line the lumen of blood vessels. Therefore, it is important to understand the normal functioning of the proteins in the cell-cell adhesion complexes. The aims of this research were to ascertain which members of the PTP family are expressed in human umbilical vein endothelial cells (HUVEC) and to characterise a PTP that may potentially be involved in the regulation of cell-cell adhesions. A homology screen identified a cytosolic phosphatase...

The role of bacterial protein tyrosine phosphatases in the regulation of the biosynthesis of secreted polysaccharides

Standish, A.; Morona, R.
Fonte: Mary Ann Liebert Publicador: Mary Ann Liebert
Tipo: Artigo de Revista Científica
Publicado em //2014 EN
Relevância na Pesquisa
66.18%
SIGNIFICANCE: Tyrosine phosphorylation and associated protein tyrosine phosphatases are gaining prominence as critical mechanisms in the regulation of fundamental processes in a wide variety of bacteria. In particular, these phosphatases have been associated with the control of the biosynthesis of capsular polysaccharides and extracellular polysaccharides, critically important virulence factors for bacteria.RECENT ADVANCES: Deletion and over-expression of the phosphatases result in altered polysaccharide biosynthesis in a range of bacteria. The recent structures of associated auto-phosphorylating tyrosine kinases has suggested that the phosphatases may be critical for the cycling of the kinases between monomers and higher order oligomers. CRITICAL ISSUES: Additional substrates of the phosphatases apart from cognate kinases are currently being identified. These are likely to be critical to our understanding of the mechanism by which polysaccharide biosynthesis is regulated. FUTURE DIRECTIONS: Ultimately, these protein tyrosine phosphatases are an attractive target for the development of novel anti-microbials. This is particularly the case for the polymerase and histidinol phosphatase family, which are predominantly found in bacteria. Furthermore...

Structural and functional studies of bacterial protein tyrosine kinases

Lee, Daniel Cho-En
Fonte: Quens University Publicador: Quens University
Tipo: Tese de Doutorado Formato: 21191105 bytes; application/pdf
EN; EN
Relevância na Pesquisa
76.29%
While protein tyrosine kinases (PTKs) have been extensively characterized in eukaryotes, far less is known about their emerging counterparts in prokaryotes. Studies of close to 20 homologs of bacterial protein tyrosine (BY) kinases have inaugurated a blooming new field of research, all since just the end of the last decade. These kinases are key regulators in the polymerization and exportation of the virulence-determining polysaccharides which shield the bacterial from the non-specific defenses of the host. This research is aimed at furthering our understanding of the BY kinases through the use of X-ray crystallography and various in vitro and in vivo experiments. We reported the first crystal structure of a bacterial PTK, the C-terminal kinase domain of E. coli tyrosine kinase (Etk) at 2.5Å resolution. The fold of the Etk kinase domain differs markedly from that of eukaryotic PTKs. Based on the observed structure and supporting evidences, we proposed a unique activation mechanism for BY kinases in Gram-negative bacteria. The phosphorylation of tyrosine residue Y574 at the active site and the specific interaction of P-Y574 with a previously unidentified key arginine residue, R614, unblock the Etk active site and activate the kinase. Both in vitro kinase activity and in vivo antibiotics resistance studies utilizing structure-guided mutants further support the novel activation mechanism. In addition...

Src family protein tyrosine kinases induce autoactivation of Bruton's tyrosine kinase.

Mahajan, S; Fargnoli, J; Burkhardt, A L; Kut, S A; Saouaf, S J; Bolen, J B
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1995 EN
Relevância na Pesquisa
66.3%
Bruton's tyrosine kinase (Btk) is tyrosine phosphorylated and enzymatically activated following ligation of the B-cell antigen receptor. These events are temporally regulated, and Btk activation follows that of various members of the Src family of protein tyrosine kinases, thus raising the possibility that Src kinases participate in the Btk activation process. We have evaluated the mechanism underlying Btk enzyme activation and have explored the potential regulatory relationship between Btk and Src protein kinases. We demonstrate in COS transient-expression assays that Btk can be activated through intramolecular autophosphorylation at tyrosine 551 and that Btk autophosphorylation is required for Btk catalytic functions. Coexpression of Btk with members of the Src family of protein tyrosine kinases, but not Syk, led to Btk tyrosine phosphorylation and activation. Using a series of point mutations in Blk (a representative Src protein kinase) and Btk, we show that Src kinases activate Btk through an indirect mechanism that requires membrane association of the Src enzymes as well as functional Btk SH3 and SH2 domains. Our results are compatible with the idea that Src protein tyrosine kinases contribute to Btk activation by indirectly stimulating Btk intramolecular autophosphorylation.

Protein Tyrosine Phosphatase Receptor Type S (PTPRS) Regulates Hematopoietic Stem Cell Self-Renewal

Quarmyne, Mamle
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2015
Relevância na Pesquisa
76.02%

Hematopoietic stem cell (HSC) self-renewal, proliferation and differentiation are regulated by signaling through protein tyrosine kinases (PTK) such as c-kit, Flt-3 and Tie2. PTKs work in concert with receptor protein tyrosine phosphatases (PTPs) to maintain cellular equilibrium. The functions of PTPs in counterbalancing PTK signaling in HSCs however remain incompletely understood. Our laboratory has demonstrated that a heparin binding growth factor, Pleiotrophin (PTN), promotes the expansion of murine long-term (LT)-HSCs via binding to a PTP, protein tyrosine phosphatase receptor type Z (PTPRZ). The addition of PTN to murine PTPRZ-/- c-Kit+Sca-1+Lineage- (KSL) cells caused no expansion of HSCs in culture, suggesting that PTPRZ mediates PTN effects on HSC growth. We subsequently screened for the expression of other receptor PTPs in murine HSCs. Among 21 different receptor PTPs, we found that protein tyrosine phosphatase receptor type S (PTPRS) was significantly overexpressed in mouse and human HSCs compared to more mature hematopoietic cells. Ptprs-/- mice displayed no difference in mature blood counts or phenotypic HSC frequency compared to Ptprs+/+ mice. However, competitive transplantation of bone marrow (BM) cells from Ptprs-/- mice resulted in more than 8-fold increased multilineage hematopoietic repopulation in primary and secondary recipient mice compared to mice transplanted with BM cells from Ptprs+/+ mice. While Ptprs-/- mice displayed no differences in cell cycle status...

Protein Tyrosine Kinases: Challenges in the Development of Drugs Aimed at Cancer Therapy; Proteínas Tirosinas Quinases: Desafios do Desenvolvimento de Fármacos para a Terapia do Câncer

Carolina M. Avila; Universidade Federal do Rio de Janeiro; Nelilma C. Romeiro; Universidade Federal do Rio de Janeiro
Fonte: Revista Virtual de Química Publicador: Revista Virtual de Química
Tipo: ; Formato: binary/octet-stream
Publicado em 07/09/2010 PT
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96.11%
This paper describes recent information on protein tyrosine kinases and their importance as molecular targets in cancer therapy, as well as the challenges involved in selective binding of drugs while overcoming resistance. Special attention is given to X-ray diffraction studies of enzyme-inhibitor co-crystals, which have demonstrated new binding modes of the second generation of anticancer drugs, tyrosine kinase inhibitors. DOI: 10.5935/1984-6835.20100007; Este trabalho descreve informações recentes sobre as proteínas tirosinas quinases e sua importância como alvos moleculares na terapia do câncer. Atenção especial é dada aos estudos de difração de raios-X de complexos inibidores-enzimas que elucidaram novos modos de ligação da segunda geração de fármacos anticâncer, inibidores de tirosinas quinases. DOI: 10.5935/1984-6835.20100007