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Results: 1 to 9 of 9

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Nitrate in the active site of protein tyrosine phosphatase 1B is a putative mimetic of the transition state.
Kenny PW, Newman J, Peat TS
(2014) Acta Crystallogr D Biol Crystallogr 70: 565-71
MeSH Terms: Biocatalysis, Catalytic Domain, Crystallography, X-Ray, Escherichia coli, Humans, Ligands, Models, Molecular, Molecular Mimicry, Nitrates, Promoter Regions, Genetic, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Quantum Theory, Recombinant Proteins, Substrate Specificity
Show Abstract · Added March 20, 2014
The X-ray crystal structure of the complex of protein tyrosine phosphatase 1B with nitrate anion has been determined and modelled quantum-mechanically. Two protomers were present in the structure, one with the mechanistically important WPD loop closed and the other with this loop open. Nitrate was observed bound to each protomer, making close contacts with the S atom of the catalytic cysteine and a tyrosine residue from a crystallographically related protomer.
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16 MeSH Terms
Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice.
Miraldi ER, Sharfi H, Friedline RH, Johnson H, Zhang T, Lau KS, Ko HJ, Curran TG, Haigis KM, Yaffe MB, Bonneau R, Lauffenburger DA, Kahn BB, Kim JK, Neel BG, Saghatelian A, White FM
(2013) Integr Biol (Camb) 5: 940-63
MeSH Terms: Animals, Lipid Metabolism, Liver, Male, Metabolic Syndrome, Mice, Mice, Knockout, Models, Biological, Multivariate Analysis, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Regression Analysis, Tandem Mass Spectrometry
Show Abstract · Added November 15, 2013
Metabolic syndrome describes a set of obesity-related disorders that increase diabetes, cardiovascular, and mortality risk. Studies of liver-specific protein-tyrosine phosphatase 1b (PTP1b) deletion mice (L-PTP1b(-/-)) suggest that hepatic PTP1b inhibition would mitigate metabolic-syndrome through amelioration of hepatic insulin resistance, endoplasmic-reticulum stress, and whole-body lipid metabolism. However, the altered molecular-network states underlying these phenotypes are poorly understood. We used mass spectrometry to quantify protein-phosphotyrosine network changes in L-PTP1b(-/-) mouse livers relative to control mice on normal and high-fat diets. We applied a phosphosite-set-enrichment analysis to identify known and novel pathways exhibiting PTP1b- and diet-dependent phosphotyrosine regulation. Detection of a PTP1b-dependent, but functionally uncharacterized, set of phosphosites on lipid-metabolic proteins motivated global lipidomic analyses that revealed altered polyunsaturated-fatty-acid (PUFA) and triglyceride metabolism in L-PTP1b(-/-) mice. To connect phosphosites and lipid measurements in a unified model, we developed a multivariate-regression framework, which accounts for measurement noise and systematically missing proteomics data. This analysis resulted in quantitative models that predict roles for phosphoproteins involved in oxidation-reduction in altered PUFA and triglyceride metabolism.
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12 MeSH Terms
Tyrosine phosphorylation within the SH3 domain regulates CAS subcellular localization, cell migration, and invasiveness.
Janoštiak R, Tolde O, Brůhová Z, Novotný M, Hanks SK, Rösel D, Brábek J
(2011) Mol Biol Cell 22: 4256-67
MeSH Terms: Animals, Cell Adhesion Molecules, Cell Line, Transformed, Cell Line, Tumor, Cell Movement, Cell Transformation, Neoplastic, Crk-Associated Substrate Protein, Focal Adhesion Protein-Tyrosine Kinases, Focal Adhesions, Green Fluorescent Proteins, Humans, Mice, Mutation, Neoplasm Invasiveness, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 12, Signal Transduction, Tyrosine, src Homology Domains
Show Abstract · Added January 20, 2015
Crk-associated substrate (CAS) is a major tyrosine-phosphorylated protein in cells transformed by v-crk and v-src oncogenes and plays an important role in invasiveness of Src-transformed cells. A novel phosphorylation site on CAS, Tyr-12 (Y12) within the ligand-binding hydrophobic pocket of the CAS SH3 domain, was identified and found to be enriched in Src-transformed cells and invasive human carcinoma cells. To study the biological significance of CAS Y12 phosphorylation, phosphomimicking Y12E and nonphosphorylatable Y12F mutants of CAS were studied. The phosphomimicking mutation decreased interaction of the CAS SH3 domain with focal adhesion kinase (FAK) and PTP-PEST and reduced tyrosine phosphorylation of FAK. Live-cell imaging showed that green fluorescent protein-tagged CAS Y12E mutant is, in contrast to wild-type or Y12F CAS, excluded from focal adhesions but retains its localization to podosome-type adhesions. Expression of CAS-Y12F in cas-/- mouse embryonic fibroblasts resulted in hyperphosphorylation of the CAS substrate domain, and this was associated with slower turnover of focal adhesions and decreased cell migration. Moreover, expression of CAS Y12F in Src-transformed cells greatly decreased invasiveness when compared to wild-type CAS expression. These findings reveal an important role of CAS Y12 phosphorylation in the regulation of focal adhesion assembly, cell migration, and invasiveness of Src-transformed cells.
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19 MeSH Terms
Use of human androgen receptor gene analysis to aid the diagnosis of JMML in female noonan syndrome patients.
Lavin VA, Hamid R, Patterson J, Alford C, Ho R, Yang E
(2008) Pediatr Blood Cancer 51: 298-302
MeSH Terms: Female, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Infant, Leukemia, Myelomonocytic, Juvenile, Mutation, Noonan Syndrome, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Receptors, Androgen
Show Abstract · Added March 5, 2014
Noonan syndrome (NS) patients are at increased risk for developing juvenile myelomonocytic leukemia (JMML), an aggressive clonal disorder of aberrant cell proliferation. Many NS patients exhibit spontaneously remitting monocytosis and transient myeloproliferation. The distinction between bone marrow hyperproliferation due to germline mutation and leukemia resulting from clonal transformation can be difficult in NS patients. The GM-CSF hypersensitivity assay, diagnostic of sporadic JMML, can be positive in NS patients at baseline. In this report, we demonstrate the utility of determining the clonal status of the monocyte population by the HUMARA assay in distinguishing JMML and benign myeloproliferation in female NS patients.
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9 MeSH Terms
The homeodomain transcription factors Cdx1 and Cdx2 induce E-cadherin adhesion activity by reducing beta- and p120-catenin tyrosine phosphorylation.
Ezaki T, Guo RJ, Li H, Reynolds AB, Lynch JP
(2007) Am J Physiol Gastrointest Liver Physiol 293: G54-65
MeSH Terms: Animals, CDX2 Transcription Factor, Cadherins, Catenins, Cell Adhesion, Cell Adhesion Molecules, Cell Line, Tumor, Cell Movement, Colonic Neoplasms, Homeodomain Proteins, Humans, Mice, Phosphoproteins, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Protein Tyrosine Phosphatases, Transcription Factors, Transfection, Tyrosine, beta Catenin
Show Abstract · Added March 5, 2014
The homeodomain transcription factors Cdx1 and Cdx2 are regulators of intestine-specific gene expression. They also regulate intestinal cell differentiation and proliferation; however, these effects are poorly understood. Previously, we have shown that expression of Cdx1 or Cdx2 in human Colo 205 cells induces a mature colonocyte morphology characterized by the induction of a polarized, columnar shape with apical microvilli and strong cell-cell adhesion. To elucidate the mechanism underlying this phenomenon, we investigated the adherens junction complex. Cdx1 or Cdx2 expression reduced Colo 205 cell migration and invasion in vitro, suggesting a physiologically significant change in cadherin function. However, Cdx expression did not significantly effect E-cadherin, alpha-, beta-, or gamma-catenin, or p120-catenin protein levels. Additionally, no alteration in their intracellular distribution was observed. Cdx expression did not alter the coprecipitation of beta-catenin with E-cadherin; however, it did reduce p120-catenin-E-cadherin coprecipitation. Tyrosine phosphorylation of beta- and p120-catenin is known to disrupt E-cadherin-mediated cell adhesion and is associated with robust p120-catenin/E-cadherin interactions. We specifically investigated beta- and p120-catenin for tyrosine phosphorylation and found that it was significantly diminished by Cdx1 or Cdx2 expression. We restored beta- and p120-catenin tyrosine phosphorylation in Cdx2-expressing cells by knocking down the expression of protein tyrosine phosphatase 1B and noted a significant decline in cell-cell adhesion. We conclude that Cdx expression in Colo 205 cells induces E-cadherin-dependent cell-cell adhesion by reducing beta- and p120-catenin tyrosine phosphorylation. Ascertaining the mechanism for this novel Cdx effect may improve our understanding of the regulation of cell-cell adhesion in the colonic epithelium.
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20 MeSH Terms
Association of protein tyrosine phosphatase-N1 polymorphisms with coronary calcified plaque in the Diabetes Heart Study.
Burdon KP, Bento JL, Langefeld CD, Campbell JK, Carr JJ, Wagenknecht LM, Herrington DM, Freedman BI, Rich SS, Bowden DW
(2006) Diabetes 55: 651-8
MeSH Terms: Adult, Aged, Aged, 80 and over, Body Mass Index, Calcinosis, Coronary Disease, Diabetes Mellitus, Type 2, Female, Genotype, Haplotypes, Humans, Insulin Resistance, Male, Middle Aged, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Protein Tyrosine Phosphatases
Show Abstract · Added February 15, 2014
Individuals with type 2 diabetes are at increased risk of cardiovascular disease (CVD) mortality and display increased levels of subclinical CVD. Genetic variation in PTPN1, a diabetes susceptibility gene, was investigated for a role in diabetic atherosclerosis. The PTPN1 gene encodes protein tyrosine phosphatase-1B, which is ubiquitously expressed and plays a role in the regulation of several signaling pathways. Subclinical atherosclerosis was assessed in 590 Caucasian participants with type 2 diabetes in the Diabetes Heart Study using B-mode ultrasound measurement of carotid intima-media thickness (IMT) and computed tomography measurement of carotid calcified plaque (CarCP) and coronary calcified plaque (CorCP). Twenty-three single nucleotide polymorphisms (SNPs) in PTPN1 were genotyped and assessed for association with IMT, CarCP, and CorCP. A total of 12 SNPs within a block of linkage disequilibrium encompassing the coding sequence of PTPN1 were significantly associated with CorCP (P values from <0.0001 to 0.043) and 3 SNPs also within the block approached significance (P values from 0.058 to 0.066). In addition, a nine-SNP haplotype (GACTTCAGO) was also associated with increased CorCP under a dominant model (P = 0.01). No association was detected with IMT or CarCP. The associated SNPs and haplotype are the same as those observed to be associated with type 2 diabetes, insulin resistance, and fasting glucose in previous studies. With the inclusion of the most likely haplo-genotype for each individual, the heritability estimate of CorCP increased from 0.53 +/- 0.1 to 0.57 +/- 0.1 (P = 8.1 x 10(-10)), suggesting a modest but detectable effect of this gene on the phenotype of CorCP in type 2 diabetic patients.
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17 MeSH Terms
Resistance to anti-CD45RB-induced tolerance in NOD mice: mechanisms involved.
Moore DJ, Huang X, Lee MK, Lian MM, Chiaccio M, Chen H, Koeberlein B, Zhong R, Markmann JF, Deng S
(2004) Transpl Int 17: 261-9
MeSH Terms: Animals, Antibodies, Diabetes Mellitus, Type 1, Graft Survival, Immune Tolerance, Immunosuppressive Agents, Islets of Langerhans Transplantation, Leukocyte Common Antigens, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred NOD, Models, Animal, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Species Specificity, Time Factors, Transplantation, Homologous
Show Abstract · Added October 24, 2013
While great advances have been made in the success of islet transplantation to cure autoimmune diabetes, this protocol remains limited by our inability to induce donor-specific tolerance within the recipient. The profound resistance of the NOD mouse to tolerance-inducing regimens that are routinely successful in other strains further defines the imposing barriers that must be surmounted. Herein, we have assessed the utility of anti-CD45RB therapy to induce tolerance to allografts in C57BL/6 and NOD-strain mice. We find that, as with other therapies, NOD mice are also resistant to this manipulation, despite robust tolerance induction in the comparison strain. Analysis of cell surface markers revealed a number of changes within the B lymphocyte compartment following contact with antibody and alloantigen in the B6 strain. The absence of reciprocal changes within the NOD lymphocyte compartment suggests that B cells might contribute to the mechanism of action of this therapy and to the resistance to immunological tolerance noted in the NOD strain.
Copyright 2004 Springer-Verlag
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17 MeSH Terms
Discovery and structure-activity relationship of oxalylarylaminobenzoic acids as inhibitors of protein tyrosine phosphatase 1B.
Liu G, Szczepankiewicz BG, Pei Z, Janowick DA, Xin Z, Hajduk PJ, Abad-Zapatero C, Liang H, Hutchins CW, Fesik SW, Ballaron SJ, Stashko MA, Lubben T, Mika AK, Zinker BA, Trevillyan JM, Jirousek MR
(2003) J Med Chem 46: 2093-103
MeSH Terms: 4-Aminobenzoic Acid, Administration, Oral, Amino Acid Sequence, Aminobenzoates, Animals, Biological Availability, Blood Glucose, Caco-2 Cells, Catalytic Domain, Crystallography, X-Ray, Enzyme Inhibitors, Humans, Hypoglycemic Agents, Magnetic Resonance Spectroscopy, Male, Mice, Models, Molecular, Molecular Sequence Data, Permeability, Phenylalanine, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Protein Tyrosine Phosphatases, Rats, Stereoisomerism, Structure-Activity Relationship, para-Aminobenzoates
Show Abstract · Added March 5, 2014
Protein Tyrosine phosphatase 1B (PTP1B) has been implicated as a key negative regulator of both insulin and leptin signaling pathways. Using an NMR-based screening approach with 15N- and 13C-labeled PTP1B, we have identified 2,3-dimethylphenyloxalylaminobenzoic acid (1) as a general, reversible, and competitive PTPase inhibitor. Structure-based approach guided by X-ray crystallography facilitated the development of 1 into a novel series of potent and selective PTP1B inhibitors occupying both the catalytic site and a portion of the noncatalytic, second phosphotyrosine binding site. Interestingly, oral biovailability has been observed in rats for some compounds. Furthermore, we demonstrated in vivo plasma glucose lowering effects with compound 12d in ob/ob mice.
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26 MeSH Terms
Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy.
Szczepankiewicz BG, Liu G, Hajduk PJ, Abad-Zapatero C, Pei Z, Xin Z, Lubben TH, Trevillyan JM, Stashko MA, Ballaron SJ, Liang H, Huang F, Hutchins CW, Fesik SW, Jirousek MR
(2003) J Am Chem Soc 125: 4087-96
MeSH Terms: Amino Acid Sequence, Binding Sites, Binding, Competitive, Catalysis, Drug Design, Enzyme Inhibitors, Kinetics, Ligands, Models, Molecular, Molecular Sequence Data, Nuclear Magnetic Resonance, Biomolecular, Oxamic Acid, Protein Conformation, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Protein Tyrosine Phosphatases, Structure-Activity Relationship
Show Abstract · Added March 5, 2014
Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that downregulates the insulin receptor. Inhibition of PTP1B is expected to improve insulin action, and the design of small molecule PTP1B inhibitors to treat type II diabetes has received considerable attention. In this work, NMR-based screening identified a nonselective competitive inhibitor of PTP1B. A second site ligand was also identified by NMR-based screening and then linked to the catalytic site ligand by rational design. X-ray data confirmed that the inhibitor bound with the catalytic site in the native, "open" conformation. The final compound displayed excellent potency and good selectivity over many other phosphatases. The modular approach to drug design described in this work should be applicable for the design of potent and selective inhibitors of other therapeutically relevant protein tyrosine phosphatases.
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16 MeSH Terms