Protein tyrosine phosphatases: dual‐specificity phosphatases in health and disease

Pulido, Rafael; Huijsduijnen, Rob Hooft van

doi:10.1111/j.1742-4658.2008.06250.x

Cited by 89 publications

(70 citation statements)

References 221 publications

(260 reference statements)

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“…With these new discoveries has come an increasing recognition of the importance of protein phosphatases in cellular signaling. Investigation of the interactions, cellular substrates, and modes of action of some of these enzymes has helped us better appreciate their cellular roles and how derailment of their function may contribute to disease (Hendriks et al, 2008;Pulido and Hooft van Huijsduijnen, 2008;Vang et al, 2008;Yi and Lindner, 2008). However, although these advancements have been significant, it is also clear that the rate of elucidation of the cellular function of new protein tyrosine phosphatases has somewhat lagged behind their rate of discovery (Alonso et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Targeting of the Mitochondrial Phosphatase PTPMT1

Doughty-Shenton

Joseph

Zhang

et al. 2010

J Pharmacol Exp Ther

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The dual-specificity protein tyrosine phosphatases (PTPs) play integral roles in the regulation of cell signaling. There is a need for new tools to study these phosphatases, and the identification of inhibitors potentially affords not only new means for their study, but also possible therapeutics for the treatment of diseases caused by their dysregulation. However, the identification of selective inhibitors of the protein phosphatases has proven somewhat difficult. PTP localized to mitochondrion 1 (PTPMT1) is a recently discovered dual-specificity phosphatase that has been implicated in the regulation of insulin secretion. Screening of a commercially available small-molecule library yielded alexidine dihydrochloride, a dibiguanide compound, as an effective and selective inhibitor of PTPMT1 with an in vitro concentration that inhibits response by 50% of 1.08 M. A related dibiguanide analog, chlorhexidine dihydrochloride, also significantly inhibited PTPMT1, albeit with lower potency, while a monobiguanide analog showed very weak inhibition. Treatment of isolated rat pancreatic islets with alexidine dihydrochloride resulted in a dosedependent increase in insulin secretion, whereas treatment of a pancreatic ␤-cell line with the drug affected the phosphorylation of mitochondrial proteins in a manner similar to genetic inhibition of PTPMT1. Furthermore, knockdown of PTPMT1 in rat islets rendered them insensitive to alexidine dihydrochloride treatment, providing evidence for mechanism-based activity of the inhibitor. Taken together, these studies establish alexidine dihydrochloride as an effective inhibitor of PTPMT1, both in vitro and in cells, and support the notion that PTPMT1 could serve as a pharmacological target in the treatment of type II diabetes.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Targeting of the Mitochondrial Phosphatase PTPMT1

Doughty-Shenton

Joseph

Zhang

et al. 2010

J Pharmacol Exp Ther

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“…Dual-specificity protein phosphatases (DSPs) form an evolutionarily conserved subgroup of protein-tyrosine phosphatases (PTPs), originally characterized by their ability to catalyse dephosphorylation of protein phospho-Ser/Thr and phospho-Tyr residues (Camps et al, 2000;Alonso et al, 2004;Pulido and Hooft van Huijsduijnen, 2008). Dusp26 (also referred to as LDP-4, MKP-8 and NEAP) is a recently identified DSP protein and its function remains obscure.…”

Section: Introductionmentioning

confidence: 99%

Protein phosphatase Dusp26 associates with KIF3 motor and promotes N-cadherin-mediated cell–cell adhesion

et al. 2008

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Recent studies have demonstrated essential functions for KIF3, a microtubule-directed protein motor, in subcellular transport of several cancer-related proteins, including the b-catenin-cadherin(s) complex. In this study, we report identification of the protein-phosphatase Dusp26 as a novel regulator of the KIF3 motor. Here we undertake yeast two-hybrid screening and identify Kif3a, a motor subunit of the KIF3 heterotrimeric complex, as a novel Dusp26-binding protein. Co-immunoprecipitation and colocalization experiments revealed that Dusp26 associates not only with Kif3a, but also with Kap3, another subunit of the KIF3 complex. Dephosphorylation experiments in vitro and analysis using mutant forms of Dusp26 in intact cells strongly suggested that Dusp26 is recruited to the KIF3 motor mainly by interaction with Kif3a, and thereby dephosphorylates Kap3. Forced expression of Dusp26, but not its catalytically inactive mutant, promoted distribution of b-catenin/N-cadherin, an established KIF3 cargo, to cell-cell junction sites, resulting in increased cell-cell adhesiveness. We also showed that Dusp26 mRNA expression was downregulated in human glioblastoma samples. These results suggest previously unidentified functions of Dusp26 in intracellular transport and cell-cell adhesion. Downregulation of Dusp26 may contribute to malignant phenotypes of glioma.

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“…The latter is shared by the large family of DSPs that dephosphorylate distinct target phosphoproteins both at phosphotyrosine and phosphoserine/phosphothreonine residues. Some DSPs also act on various nonproteinaceous substrates, such as phospholipids or phosphorylated polyglycans (Pulido and Hooft van Huijsduijnen, 2008).…”

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confidence: 99%

The Laforin-Like Dual-Specificity Phosphatase SEX4 from Arabidopsis Hydrolyzes Both C6- and C3-Phosphate Esters Introduced by Starch-Related Dikinases and Thereby Affects Phase Transition of α-Glucans

et al. 2009

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The biochemical function of the Laforin-like dual-specific phosphatase AtSEX4 (EC 3.1.3.48) has been studied. Crystalline maltodextrins representing the A-or the B-type allomorph were prephosphorylated using recombinant glucan, water dikinase (StGWD) or the successive action of both plastidial dikinases (StGWD and AtPWD). AtSEX4 hydrolyzed carbon 6-phosphate esters from both the prephosphorylated A-and B-type allomorphs and the kinetic constants are similar. The phosphatase also acted on prelabeled carbon-3 esters from both crystalline maltodextrins. Similarly, native starch granules prelabeled in either the carbon-6 or carbon-3 position were also dephosphorylated by AtSEX4. The phosphatase did also hydrolyze phosphate esters of both prephosphorylated maltodextrins when the (phospho)glucans had been solubilized by heat treatment. Submillimolar concentrations of nonphosphorylated maltodextrins inhibited AtSEX4 provided they possessed a minimum of length and had been solubilized. As opposed to the soluble phosphomaltodextrins, the AtSEX4-mediated dephosphorylation of the insoluble substrates was incomplete and at least 50% of the phosphate esters were retained in the pelletable (phospho)glucans. The partial dephosphorylation of the insoluble glucans also strongly reduced the release of nonphosphorylated chains into solution. Presumably, this effect reflects fast structural changes that following dephosphorylation occur near the surface of the maltodextrin particles. A model is proposed defining distinct stages within the phosphorylation/ dephosphorylation-dependent transition of a-glucans from the insoluble to the soluble state.The metabolism of starch, the most prominent storage carbohydrate in plants, is assumed to require approximately 30 to 40 distinct (iso)enzymes (Deschamps et al., 2008), but, presumably, the list of the starch-related proteins is not yet complete. Several novel proteins (and protein functions) essential for the normal starch metabolism have recently been identified among which are two a-glucan phosphorylating dikinases. One dikinase (glucan, water dikinase [GWD], EC 2.7.9.4) utilizes ATP as dual phosphate donor and esterifies the C6 position of amylopectin-related glucosyl residues, whereas the other dikinase (phosphoglucan, water dikinase [PWD], EC 2.7.9.5) selectively transfers the b-phosphate group from ATP to the C3 position of glucosyl residues (Ritte et al., 2006).Two other previously unknown starch-related enzymes were designated as SEX4 protein (EC 3

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Protein tyrosine phosphatases: dual‐specificity phosphatases in health and disease

Cited by 89 publications

References 221 publications

Pharmacological Targeting of the Mitochondrial Phosphatase PTPMT1

Pharmacological Targeting of the Mitochondrial Phosphatase PTPMT1

Protein phosphatase Dusp26 associates with KIF3 motor and promotes N-cadherin-mediated cell–cell adhesion

The Laforin-Like Dual-Specificity Phosphatase SEX4 from Arabidopsis Hydrolyzes Both C6- and C3-Phosphate Esters Introduced by Starch-Related Dikinases and Thereby Affects Phase Transition of α-Glucans

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