Allosteric inhibition of protein tyrosine phosphatase 1B

Wiesmann, Christian; Barr, Kenneth J.; Kung, Jenny; Zhu, Jiang; Erlanson, Daniel A.; Wang, Shen; Fahr, Bruce J; Zhong, Min; Taylor, Lisa J.; Randal, Mike; McDowell, Robert S.; Hansen, Steven G.

doi:10.1038/nsmb803

Cited by 483 publications

(659 citation statements)

References 39 publications

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“…Vehicle did not alter cell binding. is a highly specific (Ͼ2 logs) inhibitor of PTP1B (21). PTP1B inhibitor interrupted the adhesion to E-cadherin-Fc of MDCK cells expressing WT ␤-catenin, but it did not affect the adhesion to E-cadherin-Fc of MDCK cells expressing Y489F or Y654F ␤-catenin (Fig.…”

Section: The Effect Of Histamine and Par-2-ap On Adhesion Of L-h1-e-cmentioning

confidence: 99%

Compromised E-cadherin adhesion and epithelial barrier function with activation of G protein-coupled receptors is rescued by Y-to-F mutations in β-catenin

Winter

Shasby²,

Shasby³

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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vation of the type 1 histamine (H1) or the type 2 protease-activated (PAR-2) G protein-coupled receptors interrupts E-cadherin adhesion and decreases the transepithelial resistance (TER) of epithelium. Several reports suggest that cadherin adhesive function depends on the association of cadherin with ␤-catenin and that this association is regulated by phosphorylation of tyrosines in ␤-catenin. We tested the hypothesis that loss of cadherin adhesion and compromise of TER on activation of the H1 or PAR-2 receptor is due to phosphorylation of tyrosines in ␤-catenin. L cells were stably transfected to express E-cadherin (L-E-cad cells) and H1 (L-H1-E-cad cells). L cells and Madin-Darby canine kidney (MDCK) cells constitutively express PAR-2. Stably transfected L-E-cad, L-H1-E-cad, and MDCK cells were also stably transfected with FLAG-tagged wild-type (WT) or mutant ␤-catenin, converting tyrosine 142, 489, or 654 to the nonphosphorylatable mimetic, phenylalanine (WT, Y142F, Y489F, or Y654F). Activation of H1 or PAR-2 interrupted adhesion to an immobilized E-cadherin-Fc fusion protein of L-H1-E-cad, L-E-cad, and MDCK cells expressing WT or Y142F ␤-catenin but did not interrupt adhesion of L-H1-E-cad, L-E-cad, and MDCK cells expressing the Y489F or Y654F mutant ␤-catenins. PAR-2 activation decreased the TER of monolayers of MDCK cells expressing WT or Y142F ␤-catenin 40 -45%. However, PAR-2 activation did not decrease the TER of monolayers of MDCK cells expressing Y489F or Y654F ␤-catenin. The protein tyrosine phosphatase PTP1B binds to the cadherin cytoplasmic domain and dephosphorylates ␤-catenin. Inhibition of PTP1B interrupted adhesion to E-cadherin-Fc of MDCK cells expressing WT ␤-catenin but did not affect the adhesion of MDCK cells expressing Y489F or Y654F ␤-catenin. Similarly, inhibition of PTP1B compromised the TER of MDCK cells expressing WT ␤-catenin but did not affect the TER of MDCK cells expressing Y489F or Y654F ␤-catenin. We conclude that phosphorylation of tyrosines 489 and 654 in ␤-catenin is a necessary step in the process by which G protein-coupled H1 and PAR-2 receptors interrupt Ecadherin adhesion. We also conclude that activation of PAR-2 has no effect on the TER without first interrupting E-cadherin adhesion.AIRWAY EPITHELIA CREATE an important barrier between the tissues of the lung and the environment. This barrier is dependent on molecules that bind the epithelial cells to each other and to molecules of the tight junction that act as resistors to paracellular molecular traffic. E-cadherin mediates calciumdependent homotypic cell-cell adhesion in epithelia. We (24, 27) previously reported that activation of the type 1 histamine (H1) or the type 2 protease-activated receptor (PAR-2) decreased the transepithelial resistance (TER) of airway epithelium by interrupting E-cadherin adhesion. In these reports, activation of the H1 or PAR-2 receptor interrupted E-cadherindependent adhesion of E-cadherin expressing L cells and of primary airway epithelium to immobilized E-cadherin. Activation of H1 or ...

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Section: The Effect Of Histamine and Par-2-ap On Adhesion Of L-h1-e-cmentioning

confidence: 99%

Compromised E-cadherin adhesion and epithelial barrier function with activation of G protein-coupled receptors is rescued by Y-to-F mutations in β-catenin

Winter

Shasby²,

Shasby³

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…As expected, dysidine exhibited potent inhibitory activity against PTP1B (Table S1 and Figure 6A), with an IC 50 of 1.5 µmol/L. To assay the selectivity of dysidine over other PTPs, a panel of PTPs was investigated, including PTP1B, TC-PTP, and CD45 [35] , and compound-2 [36] was used as a positive control. Table S1 shows the preference by dysidine for inhibition of PTP1B compared with other PTPs.…”

Section: Resultsmentioning

confidence: 99%

A sesquiterpene quinone, dysidine, from the sponge Dysidea villosa, activates the insulin pathway through inhibition of PTPases

Zhang

Guo

et al. 2009

Acta Pharmacol Sin

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Aim:The sesquiterpene hydroquinones/quinones belong to one class of marine sponge metabolites, and they have received considerable attention due to their varied biological activities, including anti-tumor, anti-HIV, and anti-inflammatory action. In order to probe the potential anti-diabetic effect of the sesquiterpene hydroquinones/quinones, the effect of dysidine on the insulin pathway was studied. Methods: The promotion of glucose uptake by dysidine was studied in differentiated 3T3-L1 cells. The increase in membrane-located GLUT4 by dysidine was studied in CHO-K1/GLUT4 and 3T3-L1 cells by immuno-staining. The activation of the insulin signaling pathway by dysidine was probed by Western blotting. The inhibition of PTPases by dysidine was detected in vitro. Results: Dysidine, found in the Hainan sponge Dysidea villosa in the Chinese South Sea, effectively activated the insulin signaling pathway, greatly promoted glucose uptake in 3T3-L1 cells, and showed strong insulin-sensitizing activities. The potential targets of action for dysidine were probed, and the results indicated that dysidine exhibited its cellular effects through activation of the insulin pathway, possibly through the inhibition of protein tyrosine phosphatases, with more specific inhibition against protein tyrosine phosphatase 1B (PTP1B). Conclusion: Our findings are expected to expand understanding of the biological activities of sesquiterpene hydroquinones/quinones, and they show that dysidine could be a potential lead compound in the development of an alternative adjuvant in insulin therapy.

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“…The current understanding of the structure and function of PTP-1B is derived from a number of different sources and tech-niques, including a wealth of crystal structures of the catalytic domain, protein-protein interaction data, post-translational modifications, biochemical methods, and computer-aided predictions (30,31,(63)(64)(65). The composite information from the abundant crystal structures defines the catalytic core of the enzyme (1-298) and the interaction of various substrates and inhibitors.…”

Section: Discussionmentioning

confidence: 99%

The Role of the C-terminal Domain of Protein Tyrosine Phosphatase-1B in Phosphatase Activity and Substrate Binding

Picha

Patel

Mandiyan

et al. 2007

Journal of Biological Chemistry

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Protein tyrosine phosphatase 1B (PTP-1B) has been implicated in the regulation of the insulin receptor. Dephosphorylation of the insulin receptor results in decreased insulin signaling and thus decreased glucose uptake. PTP-1B ؊/؊ mice have increased insulin sensitivity and are resistant to weight gain when fed a high fat diet, validating PTP-1B as a potential target for the treatment of type 2 diabetes. Many groups throughout the world have been searching for selective inhibitors for PTP-1B, and most of them target inhibitors to PTP-1B-(1-298), the N-terminal catalytic domain of the enzyme. However, the C-terminal domain is quite large and could influence the activity of the enzyme. Using two constructs of PTP-1B and a phosphopeptide as substrate, steady state assays showed that the presence of the C-terminal domain decreased both the K m and the k cat 2-fold. Pre-steady state kinetic experiments showed that the presence of the C-terminal domain improved the affinity of the enzyme for a phosphopeptide 2-fold, primarily because the offrate was slower. This suggests that the C-terminal domain of PTP-1B may contact the phosphopeptide in some manner, allowing it to remain at the active site longer. This could be useful when screening libraries of compounds for inhibitors of PTP-1B. A compound that is able to make contacts with the C-terminal domain of PTP-1B would not only have a modest improvement in affinity but may also provide for specificity over other phosphatases.

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Allosteric inhibition of protein tyrosine phosphatase 1B

Cited by 483 publications

References 39 publications

Compromised E-cadherin adhesion and epithelial barrier function with activation of G protein-coupled receptors is rescued by Y-to-F mutations in β-catenin

Compromised E-cadherin adhesion and epithelial barrier function with activation of G protein-coupled receptors is rescued by Y-to-F mutations in β-catenin

A sesquiterpene quinone, dysidine, from the sponge Dysidea villosa, activates the insulin pathway through inhibition of PTPases

The Role of the C-terminal Domain of Protein Tyrosine Phosphatase-1B in Phosphatase Activity and Substrate Binding

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