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Journal articles on the topic 'Thr protein phosphatases'

Author: Grafiati
Published: 4 June 2021
Last updated: 1 February 2022

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1

Mizunuma, Masataka, Atsushi Kaneko, Shunta Imai, Kazuhiro Furukawa, and Yoshiro Chuman. "Methods for Identification of Substrates/Inhibitors of FCP/SCP Type Protein Ser/Thr Phosphatases." Processes 8, no. 12 (December 4, 2020): 1598. http://dx.doi.org/10.3390/pr8121598.

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Protein phosphorylation is the most widespread type of post-translational modification and is properly controlled by protein kinases and phosphatases. Regarding the phosphorylation of serine (Ser) and threonine (Thr) residues, relatively few protein Ser/Thr phosphatases control the specific dephosphorylation of numerous substrates, in contrast with Ser/Thr kinases. Recently, protein Ser/Thr phosphatases were reported to have rigid substrate recognition and exert various biological functions. Therefore, identification of targeted proteins by individual protein Ser/Thr phosphatases is crucial to clarify their own biological functions. However, to date, information on the development of methods for identification of the substrates of protein Ser/Thr phosphatases remains scarce. In turn, substrate-trapping mutants are powerful tools to search the individual substrates of protein tyrosine (Tyr) phosphatases. This review focuses on the development of novel methods for the identification of Ser/Thr phosphatases, especially small C-terminal domain phosphatase 1 (Scp1), using peptide-displayed phage library with AlF4−/BeF3−, and discusses the identification of putative inhibitors.
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2

Ariño, Joaquín, Antonio Casamayor, and Asier González. "Type 2C Protein Phosphatases in Fungi." Eukaryotic Cell 10, no. 1 (November 12, 2010): 21–33. http://dx.doi.org/10.1128/ec.00249-10.

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ABSTRACT Type 2C Ser/Thr phosphatases are a remarkable class of protein phosphatases, which are conserved in eukaryotes and involved in a large variety of functional processes. Unlike in other Ser/Thr phosphatases, the catalytic polypeptide is not usually associated with regulatory subunits, and functional specificity is achieved by encoding multiple isoforms. For fungi, most information comes from the study of type 2C protein phosphatase (PP2C) enzymes in Saccharomyces cerevisiae , where seven PP2C-encoding genes ( PTC1 to -7 ) with diverse functions can be found. More recently, data on several Candida albicans PP2C proteins became available, suggesting that some of them can be involved in virulence. In this work we review the available literature on fungal PP2Cs and explore sequence databases to provide a comprehensive overview of these enzymes in fungi.
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3

Yoshida, Takuya, Kazuki Yamazaki, Shunta Imai, Akinori Banno, Atsushi Kaneko, Kazuhiro Furukawa, and Yoshiro Chuman. "Identification of a Specific Inhibitor of Human Scp1 Phosphatase Using the Phosphorylation Mimic Phage Display Method." Catalysts 9, no. 10 (October 11, 2019): 842. http://dx.doi.org/10.3390/catal9100842.

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Protein phosphatases are divided into tyrosine (Tyr) phosphatases and serine/threonine (Ser/Thr) phosphatases. While substrate trapping mutants are frequently used to identify substrates of Tyr phosphatases, a rapid and simple method to identify Ser/Thr phosphatase substrates is yet to be developed. The TFIIF-associating component of RNA polymerase II C-terminal domain (CTD) phosphatase/small CTD phosphatase (FCP/SCP) phosphatase family is one of the three types of Ser/Thr protein phosphatases. Defects in these phosphatases are correlated with the occurrence of various diseases such as cancer and neuropathy. Recently, we developed phosphorylation mimic phage display (PMPD) method with AlF4−, a methodology to identify substrates for FCP/SCP type Ser/Thr phosphatase Scp1. Here, we report a PMPD method using BeF3− to identify novel substrate peptides bound to Scp1. After screening peptide phages, we identified peptides that bound to Scp1 in a BeF3−-dependent manner. Synthetic phosphopeptide BeM12-1, the sequence of which was isolated at the highest frequency, directly bound to Scp1. The binding was inhibited by adding BeF3−, indicating that the peptide binds to the active center of catalytic site in Scp1. The phosphorylated BeM12-1 worked as a competitive inhibitor of Scp1. Thus, PMPD method may be applicable for the identification of novel substrates and inhibitors of the FCP/SCP phosphatase family.
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4

Andreeva, Alexandra V., and Mikhail A. Kutuzov. "PPEF/PP7 protein Ser/Thr phosphatases." Cellular and Molecular Life Sciences 66, no. 19 (August 7, 2009): 3103–10. http://dx.doi.org/10.1007/s00018-009-0110-7.

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5

Seok, Seung-Hyeon. "Structural Insights into Protein Regulation by Phosphorylation and Substrate Recognition of Protein Kinases/Phosphatases." Life 11, no. 9 (September 13, 2021): 957. http://dx.doi.org/10.3390/life11090957.

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Protein phosphorylation is one of the most widely observed and important post-translational modification (PTM) processes. Protein phosphorylation is regulated by protein kinases, each of which covalently attaches a phosphate group to an amino acid side chain on a serine (Ser), threonine (Thr), or tyrosine (Tyr) residue of a protein, and by protein phosphatases, each of which, conversely, removes a phosphate group from a phosphoprotein. These reversible enzyme activities provide a regulatory mechanism by activating or deactivating many diverse functions of proteins in various cellular processes. In this review, their structures and substrate recognition are described and summarized, focusing on Ser/Thr protein kinases and protein Ser/Thr phosphatases, and the regulation of protein structures by phosphorylation. The studies reviewed here and the resulting information could contribute to further structural, biochemical, and combined studies on the mechanisms of protein phosphorylation and to drug discovery approaches targeting protein kinases or protein phosphatases.
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6

DESDOUITS, Frédéric, C. Julio SICILIANO, C. Angus NAIRN, Paul GREENGARD, and Jean-Antoine GIRAULT. "Dephosphorylation of Ser-137 in DARPP-32 by protein phosphatases 2A and 2C: different roles in vitro and in striatonigral neurons." Biochemical Journal 330, no. 1 (February 15, 1998): 211–16. http://dx.doi.org/10.1042/bj3300211.

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DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, Mr = 32000) is highly expressed in striatonigral neurons in which its phosphorylation is regulated by several neurotransmitters including dopamine and glutamate. DARPP-32 becomes a potent inhibitor of protein phosphatase 1 when it is phosphorylated on Thr-34 by cAMP- or cGMP-dependent protein kinases. DARPP-32 is also phosphorylated on Ser-137 by protein kinase CK1 (CK1), in vitro and in vivo. This phosphorylation has an important regulatory role since it inhibits the dephosphorylation of Thr-34 by calcineurin in vitro and in striatonigral neurons. Here, we show that DARPP-32 phosphorylated by CK1 is a substrate in vitro for protein phosphatases 2A and 2C, but not protein phosphatase 1 or calcineurin. However, in substantia nigra slices, dephosphorylation of Ser-137 was markedly sensitive to decreased temperature, and not detectably affected by the presence of okadaic acid under conditions in which dephosphorylation of Thr-34 by protein phosphatase 2A was inhibited. These results suggest that, in neurons, phospho-Ser-137-DARPP-32 is dephosphorylated by protein phosphatase 2C, but not 2A. Thus, DARPP-32 appears to be a component of a regulatory cascade of phosphatases in which dephosphorylation of Ser-136 by protein phosphatase 2C facilitates dephosphorylation of Thr-34 by calcineurin, removing the cyclic nucleotide-induced inhibition of protein phosphatase 1.
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7

Kutuzov, Mikhail A., and Alexandra V. Andreeva. "Protein Ser/Thr phosphatases of parasitic protozoa." Molecular and Biochemical Parasitology 161, no. 2 (October 2008): 81–90. http://dx.doi.org/10.1016/j.molbiopara.2008.06.008.

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8

IWANICKI, Adam, Anna HERMAN-ANTOSIEWICZ, Marcin PIERECHOD, Simone J. SÉROR, and Michał OBUCHOWSKI. "PrpE, a PPP protein phosphatase from Bacillus subtilis with unusual substrate specificity." Biochemical Journal 366, no. 3 (September 15, 2002): 929–36. http://dx.doi.org/10.1042/bj20011591.

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Bacillus subtilis is a Gram-positive bacterium with a relatively large number of protein phosphatases. Previous studies have shown that some Ser/Thr phosphatases play an important role in the life cycle of this bacterium [Losick and Stragier (1992) Nature (London) 355, 601—604; Yang, Kang, Brody and Price (1996) Genes Dev. 10, 2265—2275]. In this paper, we report the biochemical properties of a putative, previously uncharacterized phosphatase, PrpE, belonging to the PPP family. This enzyme shares homology with other PPP phosphatases as well as with symmetrical diadenosine tetraphosphatases related to ApaH (symmetrical Ap4A hydrolase) from Escherichia coli. A His-tagged recombinant PrpE was purified from E. coli and shown to have Ni2+-dependent and okadaic acid-resistant phosphatase activity against a synthetic phosphorylated peptide and hydrolase activity against diadenosine 5′,5′′′-tetraphosphate. Unexpectedly, PrpE was able to remove phosphate from phosphotyrosine, but not from phosphothreonine or phosphoserine.
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9

Sun, Haipeng, and Yibin Wang. "Novel Ser/Thr Protein Phosphatases in Cell Death Regulation." Physiology 27, no. 1 (February 2012): 43–52. http://dx.doi.org/10.1152/physiol.00034.2011.

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Cell death is regulated by a myriad of intracellular molecular pathways, with many involving protein phosphorylation and dephosphorylation. In this review, we will focus on Ser/Thr phosphatases-mediated regulation in cell apoptosis as well as on their potential roles in cell necrosis. The emerging functional importance of Ser/Thr protein phosphatases in cell death regulation adds new dimension to the signaling mechanisms of cellular function, physiology, and diseases.
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10

Pyo, Jaehyuk, Jaewook Ryu, Wootae Kim, Jae-Sun Choi, Joo-Won Jeong, and Ja-Eun Kim. "The Protein Phosphatase PPM1G Destabilizes HIF-1α Expression." International Journal of Molecular Sciences 19, no. 8 (August 5, 2018): 2297. http://dx.doi.org/10.3390/ijms19082297.

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Hypoxia-inducible factors (HIFs) are key regulators of hypoxic responses, and their stability and transcriptional activity are controlled by several kinases. However, the regulation of HIF by protein phosphatases has not been thoroughly investigated. Here, we found that overexpression of Mg2+/Mn2+-dependent protein phosphatase 1 gamma (PPM1G), one of Ser/Thr protein phosphatases, downregulated protein expression of ectopic HIF-1α under normoxic or acute hypoxic conditions. In addition, the deficiency of PPM1G upregulated protein expression of endogenous HIF-1α under normoxic or acute oxidative stress conditions. PPM1G decreased expression of HIF-1α via the proteasomal pathway. PPM1G-mediated HIF-1α degradation was dependent on prolyl hydroxylase (PHD), but independent of von Hippel-Lindau (VHL). These data suggest that PPM1G is critical for the control of HIF-1α-dependent responses.
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11

Kutuzov, Mikhail A., Olga V. Solov'eva, Alexandra V. Andreeva, and Nelly Bennett. "Protein Ser/Thr phosphatases PPEF interact with calmodulin." Biochemical and Biophysical Research Communications 293, no. 3 (May 2002): 1047–52. http://dx.doi.org/10.1016/s0006-291x(02)00338-8.

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12

BAJPAI, Anil, and Zacharie BRAHMI. "Regulation of natural killer cell-mediated cytotoxicity by serine/threonine phosphatases: identification of a calyculin A-sensitive serine/threonine kinase." Biochemical Journal 320, no. 1 (November 15, 1996): 153–59. http://dx.doi.org/10.1042/bj3200153.

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We have recently reported that Ser/Thr phosphatases play a key role in regulating natural killer (NK) cell lytic activity and that calyculin A and okadaic acid affect this activity differently [Bajpai and Brahmi (1994) J. Biol. Chem. 269, 18864–18869]. Here, we investigate a mechanism that might account for this differential action of calyculin A and okadaic acid on NK cells. Calyculin A specifically inhibited the lytic activity of YT-INDY, an NK-like cell line, and hyperphosphorylated 60 and 78 kDa proteins. The kinetics of appearance of these two proteins was correlated with the loss of lytic activity. In contrast, okadaic acid did not significantly affect either of these activities. The 78 kDa protein is localized in the cytosolic compartment whereas the 60 kDa protein is distributed equally between the membrane and the cytosolic fractions. Both proteins display a kinase activity and are phosphorylated mainly at serine and threonine residues but not at tyrosine residues. The activation of these kinases is specific to calyculin A treatment; it is independent of protein kinase C, protein kinase A, Ca2+, phosphotyrosine phosphatase and protein synthesis de novo. In conclusion, we have demonstrated that calyculin A, but not okadaic acid, hyperphosphorylates two proteins with Ser/Thr kinase activity, thus explaining the differential regulation of NK cells by these two Ser/Thr phosphatase inhibitors.
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13

Ziembik, Magdalena A., Timothy P. Bender, James M. Larner, and David L. Brautigan. "Functions of protein phosphatase-6 in NF-κB signaling and in lymphocytes." Biochemical Society Transactions 45, no. 3 (June 15, 2017): 693–701. http://dx.doi.org/10.1042/bst20160169.

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Protein phosphatase-6 (PP6) is a member of the PPP family of Ser/Thr phosphatases involved in intracellular signaling. PP6 is conserved among all eukaryotes, and genetics in model organisms indicates it has non-redundant functions relative to other PPP phosphatases. PP6 functions in association with conserved SAPS subunits and, in vertebrate species, forms heterotrimers with Ankrd subunits. Multiple studies have demonstrated how PP6 exerts negative control at different steps of nuclear factor kappaB signaling. Expression of PP6 catalytic subunit and the PPP6R1 subunit is especially high in hematopoietic cells and lymphoid tissues. Recent efforts at conditionally knocking out genes for PP6c or PP6R1 (SAPS1) have revealed distinctive effects on development of and signaling in lymphocytes.
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14

Roome, J., T. O'Hare, P. F. Pilch, and D. L. Brautigan. "Protein phosphotyrosine phosphatase purified from the particulate fraction of human placenta dephosphorylates insulin and growth-factor receptors." Biochemical Journal 256, no. 2 (December 1, 1988): 493–500. http://dx.doi.org/10.1042/bj2560493.

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Protein phosphatase activity specific for Tyr(P) (phosphotyrosine) residues (PTP-phosphatase) was found in the cytosol and particulate fractions of human placenta. In the particulate fraction, half of the PTP-phosphatase activity could be extracted with 1% Triton X-100. The PTP-phosphatase remaining in the Triton-insoluble residue was solubilized with 0.6 M-KCl plus 1% CHAPS (3-[(3-cholamidopropyl)-dimethylammonio]propane-1-sulphonate) and was purified 1850-fold by adsorption to DEAE-Sepharose, affinity chromatography on Zn2+-iminodiacetate-agarose, phosphocellulose adsorption, Fractogel filtration and Mono Q chromatography. The cytoskeleton-associated PTP-phosphatase was distinguished from acid, alkaline and other protein Ser(P) (phosphoserine)/Thr(P) (phosphothreonine) phosphatases by its neutral pH optimum, activity in the presence of EDTA, inhibition by Zn2+, vanadate, or molybdate, and low activity with either [Ser(P)]phosphorylase a or p-nitrophenyl phosphate. The PTP-phosphate displayed a Km of 0.15 microM with [Tyr(P)]serum albumin as substrate, 10-100-fold lower than the Km for previously described protein phosphatases. The cytoskeleton-associated PTP-phosphatase catalysed the dephosphorylation of receptors for insulin, insulin-like growth factor-1 and epidermal growth factor labelled by autophosphorylation. The properties of this PTP-phosphatase suggest that it plays a role in the regulation of hormone receptors and cytoskeleton proteins by reversible phosphorylation on tyrosine residues.
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15

Lee, SungRyul, Guillaume Chanoit, Rachel McIntosh, David A. Zvara, and Zhelong Xu. "Molecular mechanism underlying Akt activation in zinc-induced cardioprotection." American Journal of Physiology-Heart and Circulatory Physiology 297, no. 2 (August 2009): H569—H575. http://dx.doi.org/10.1152/ajpheart.00293.2009.

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Our previous study demonstrated that zinc prevents cardiac reperfusion injury by targeting the mitochondrial permeability transition pore (mPTP) via Akt and glycogen synthetase kinase 3β (GSK-3β). We aimed to address the mechanism by which zinc activates Akt. Treatment of H9c2 cells with ZnCl2 (10 μM) in the presence of the zinc ionophore pyrithione (4 μM) for 20 min enhanced Akt phosphorylation (Ser473), indicating that zinc can rapidly activate Akt. Zinc did not alter either phosphatase and tensin homolog deleted on chromosome 10 (PTEN) phosphorylation and total PTEN protein levels or PTEN oxidation, implying that PTEN may not play a role in the action of zinc. However, zinc-induced Akt phosphorylation was blocked by both the nonselective receptor tyrosine kinase (RTK) inhibitor genistein and the selective insulin-like growth factor-1 RTK (IGF-1RTK) inhibitor AG1024, indicating that zinc activates Akt via IGF-1RTK. Zinc-induced phosphorylation of protein tyrosine and Ser/Thr was also abolished by AG1024. In addition, zinc markedly enhanced phosphorylation of IGF-1 receptor (IGF-1R), which was again reversed by genistein and AG1024. A confocal imaging study revealed that AG1024 abolished the preventive effect of zinc on oxidant-induced mPTP opening, confirming that IGF-1RTK plays a role in zinc-induced cardioprotection. Furthermore, zinc decreased the activity of protein phosphatase 2A (PP2A), a major protein Ser/Thr phosphatase, implying that protein Ser/Thr phosphatases may also play a role in the action of zinc on Akt activity. Taken together, these findings demonstrate that exogenous zinc activates Akt via IGF-1RTK and prevents the mPTP opening in cardiac cells. Inactivation of Ser/Thr protein phosphatases may also contribute to zinc-induced Akt activation.
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16

Wang, Hong, and David L. Brautigan. "A Novel Transmembrane Ser/Thr Kinase Complexes with Protein Phosphatase-1 and Inhibitor-2." Journal of Biological Chemistry 277, no. 51 (October 21, 2002): 49605–12. http://dx.doi.org/10.1074/jbc.m209335200.

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Protein kinases and protein phosphatases exert coordinated control over many essential cellular processes. Here, we describe the cloning and characterization of a novel human transmembrane protein KPI-2 (Kinase/Phosphatase/Inhibitor-2) that was identified by yeast two-hybrid using protein phosphatase inhibitor-2 (Inh2) as bait. KPI-2 mRNA was predominantly expressed in skeletal muscle. KPI-2 is a 1503-residue protein with two predicted transmembrane helices at the N terminus, a kinase domain, followed by a C-terminal domain. The transmembrane helices were sufficient for targeting proteins to the membrane. KPI-2 kinase domain has about 60% identity with its closest relative, a tyrosine kinase. However, it only exhibited serine/threonine kinase activity in autophosphorylation reactions or with added substrates. KPI-2 kinase domain phosphorylated protein phosphatase-1 (PP1C) at Thr320, which attenuated PP1C activity. KPI-2 C-terminal domain directly associated with PP1C, and this required aVTFmotif. Inh2 associated with KPI-2 C-terminal domain with and without PP1C. Thus, KPI-2 is a kinase with sites to associate with PP1C and Inh2 to form a regulatory complex that is localized to membranes.
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17

Szoor, B., Z. Feher, G. Szabo, P. Gergely, and V. Dombradi. "Detection of Ser/Thr protein phosphatases in Neurospora crassa." Fungal Genetics Reports 41, no. 1 (January 1, 1994): 82–84. http://dx.doi.org/10.4148/1941-4765.1388.

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18

Kutuzov, Mikhail A., and Alexandra V. Andreeva. "Protein Ser/Thr phosphatases with kelch-like repeat domains." Cellular Signalling 14, no. 9 (September 2002): 745–50. http://dx.doi.org/10.1016/s0898-6568(02)00018-9.

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19

Calafí, Carlos, María López-Malo, Marcel Albacar, Antonio Casamayor, and Joaquín Ariño. "The N-Terminal Region of Yeast Protein Phosphatase Ppz1 Is a Determinant for Its Toxicity." International Journal of Molecular Sciences 21, no. 20 (October 19, 2020): 7733. http://dx.doi.org/10.3390/ijms21207733.

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The Ppz enzymes are Ser/Thr protein phosphatases present only in fungi that are characterized by a highly conserved C-terminal catalytic region, related to PP1c phosphatases, and a more divergent N-terminal extension. In Saccharomyces cerevisiae, Ppz phosphatases are encoded by two paralog genes, PPZ1 and PPZ2. Ppz1 is the most toxic protein when overexpressed in budding yeast, halting cell proliferation, and this effect requires its phosphatase activity. We show here that, in spite of their conserved catalytic domain, Ppz2 was not toxic when tested under the same conditions as Ppz1, albeit Ppz2 levels were somewhat lower. Remarkably, a hybrid protein composed of the N-terminal extension of Ppz1 and the catalytic domain of Ppz2 was as toxic as Ppz1, even if its expression level was comparable to that of Ppz2. Similar amounts of yeast PP1c (Glc7) produced an intermediate effect on growth. Mutation of the Ppz1 myristoylable Gly2 to Ala avoided the localization of the phosphatase at the cell periphery but only slightly attenuated its toxicity. Therefore, the N-terminal extension of Ppz1 plays a key role in defining Ppz1 toxicity. This region is predicted to be intrinsically disordered and contains several putative folding-upon-binding regions which are absent in Ppz2 and might be relevant for toxicity.
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20

Lohse, DL, JM Denu, and JE Dixon. "Insights derived from the structures of the Ser/Thr phosphatases calcineurin and protein phosphatase 1." Structure 3, no. 10 (October 1995): 987–90. http://dx.doi.org/10.1016/s0969-2126(01)00234-9.

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21

Brautigan, David L. "Protein Ser/ Thr phosphatases - the ugly ducklings of cell signalling." FEBS Journal 280, no. 2 (May 21, 2012): 324–25. http://dx.doi.org/10.1111/j.1742-4658.2012.08609.x.

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22

Wang, BaiJing, Peng Zhang, and Qun Wei. "Recent progress on the structure of Ser/Thr protein phosphatases." Science in China Series C: Life Sciences 51, no. 6 (May 17, 2008): 487–94. http://dx.doi.org/10.1007/s11427-008-0068-y.

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23

Szalewicz, Agata, Barbara Strzelczyk, Mirosław Sopel, and Aleksandra Kubicz. "The 35 kDa acid metallophosphatase of the frog Rana esculenta liver: studies on its cellular localization and protein phosphatase activity." Acta Biochimica Polonica 50, no. 2 (June 30, 2003): 555–66. http://dx.doi.org/10.18388/abp.2003_3709.

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The cellular localization of the 35 kDa, low molecular mass acid metallophosphatase (LMW AcPase) from the frog (Rana esculenta) liver and its activity towards P-Ser and P-Tyr phosphorylated peptides were studied. This enzyme was localized to the cytoplasm of hepatocytes but did not appear in other cells of liver tissue (endothelium, macrophages, blood cells). This LMW AcPase does not display activity towards (32)P-phosphorylase a under conditions standard for the enzymes of PPP family. Proteins containing P-Ser: rabbit (32)P-phosphorylasea and phosvitin are hydrolysed only at acidic pH and are poor substrates for this enzyme. The frog AcPase is not inhibited by okadaic acid and F(-) ions, the Ser/Thr protein phosphatase inhibitors. Moreover, the frog enzyme does not cross-react with specific antisera directed against N-terminal fragment of human PP2A and C-terminal conserved fragment of the eukaryotic PP2A catalytic subunits. These results exclude LMW AcPase from belonging to Ser/Thr protein phosphatases: PP1c or PP2Ac. In addition to P-Tyr, this enzyme hydrolyses efficiently at acidic pH P-Tyr phosphorylated peptides (hirudin and gastrin fragments). K(m) value for the hirudin fragment (7.55 +/- 1.59 x 10(-6) M) is 2-3 orders of magnitude lower in comparison with other substrates tested. The enzyme is inhibited competitively by typical inhibitors of protein tyrosine phosphatases (PTPases): sodium orthovanadate, molybdate and tungstate. These results may suggest that the LMW AcPase of frog liver can act as PTPase in vivo. A different cellular localization and different response to inhibition by tetrahedral oxyanions (molybdate, vanadate and tungstate) provide further evidence that LMW AcPase of frog liver is distinct from the mammalian tartrate-resistant acid phosphatases.
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24

Claywell, Ja E., and Derek J. Fisher. "CTL0511 from Chlamydia trachomatis Is a Type 2C Protein Phosphatase with Broad Substrate Specificity." Journal of Bacteriology 198, no. 13 (April 25, 2016): 1827–36. http://dx.doi.org/10.1128/jb.00025-16.

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ABSTRACTProtein phosphorylation has become increasingly recognized for its role in regulating bacterial physiology and virulence.Chlamydiaspp. encode two validated Hanks'-type Ser/Thr protein kinases, which typically function with cognate protein phosphatases and appear capable of global protein phosphorylation. Consequently, we sought to identify a Ser/Thr protein phosphatase partner for the chlamydial kinases. CTL0511 fromChlamydia trachomatisL2 434/Bu, which has homologs in all sequencedChlamydiaspp., is a predicted type 2C Ser/Thr protein phosphatase (PP2C). Recombinant maltose-binding protein (MBP)-tagged CTL0511 (rCTL0511) hydrolyzedp-nitrophenyl phosphate (pNPP), a generic phosphatase substrate, in a MnCl2-dependent manner at physiological pH. Assays using phosphopeptide substrates revealed that rCTL0511 can dephosphorylate phosphorylated serine (P-Ser), P-Thr, and P-Tyr residues using either MnCl2or MgCl2, indicating that metal usage can alter substrate preference. Phosphatase activity was unaffected by PP1, PP2A, and PP3 phosphatase inhibitors, while mutation of conserved PP2C residues significantly inhibited activity. Finally, phosphatase activity was detected in elementary body (EB) and reticulate body (RB) lysates, supporting a role for protein dephosphorylation in chlamydial development. These findings support that CTL0511 is a metal-dependent protein phosphatase with broad substrate specificity, substantiating a reversible phosphorylation network inC. trachomatis.IMPORTANCEChlamydiaspp. are obligate intracellular bacterial pathogens responsible for a variety of diseases in humans and economically important animal species. Our work demonstrates thatChlamydiaspp. produce a PP2C capable of dephosphorylating P-Thr, P-Ser, and P-Tyr and thatChlamydia trachomatisEBs and RBs possess phosphatase activity. In conjunction with the chlamydial Hanks'-type kinases Pkn1 and PknD, validation of CTL0511 fulfills the enzymatic requirements for a reversible phosphoprotein network. As protein phosphorylation regulates important cellular processes, including metabolism, differentiation, and virulence, in other bacterial pathogens, these results set the stage for elucidating the role of global protein phosphorylation in chlamydial physiology and virulence.
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Ariño, Joaquín, Diego Velázquez, and Antonio Casamayor. "Ser/Thr protein phosphatases in fungi: structure, regulation and function." Microbial Cell 6, no. 5 (May 6, 2019): 217–56. http://dx.doi.org/10.15698/mic2019.05.677.

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26

Andreeva, Alexandra V., and Mikhail A. Kutuzov. "PPP Family of Protein Ser/Thr Phosphatases: Two Distinct Branches?" Molecular Biology and Evolution 18, no. 3 (March 1, 2001): 448–52. http://dx.doi.org/10.1093/oxfordjournals.molbev.a003823.

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27

Andreeva, Alexandra, David Evans, Chris Hawes, Nelly Bennett, and Mikhail Kutuzov. "PP7, a plant phosphatase representing a novel evolutionary branch of eukaryotic protein Ser/Thr phosphatases." IUBMB Life 44, no. 4 (April 1998): 703–15. http://dx.doi.org/10.1080/15216549800201752.

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28

Csortos, Csilla, Irina Kolosova, and Alexander D. Verin. "Regulation of vascular endothelial cell barrier function and cytoskeleton structure by protein phosphatases of the PPP family." American Journal of Physiology-Lung Cellular and Molecular Physiology 293, no. 4 (October 2007): L843—L854. http://dx.doi.org/10.1152/ajplung.00120.2007.

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Reversible phosphorylation of cytoskeletal and cytoskeleton-associated proteins is a significant element of endothelial barrier function regulation. Therefore, understanding the mechanisms of phosphorylation/dephosphorylation of endothelial cell cytoskeletal proteins is vital to the treatment of severe lung disorders such as high permeability pulmonary edema. In vivo, there is a controlled balance between the activities of protein kinases and phosphatases. Due to various external or internal signals, this balance may be shifted. The actual balances at a given time alter the phosphorylation level of certain proteins with appropriate physiological consequences. The latest information about the structure and regulation of different types of Ser/Thr protein phosphatases participating in the regulation of endothelial cytoskeletal organization and barrier function will be reviewed here.
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Bokník, Peter, Sascha Khorchidi, Geza S. Bodor, Sabine Huke, Jörg Knapp, Bettina Linck, Hartmut Lüss, Frank Ulrich Müller, Wilhelm Schmitz, and Joachim Neumann. "Role of protein phosphatases in regulation of cardiac inotropy and relaxation." American Journal of Physiology-Heart and Circulatory Physiology 280, no. 2 (February 1, 2001): H786—H794. http://dx.doi.org/10.1152/ajpheart.2001.280.2.h786.

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We studied the effects of the protein phosphatase (PP) inhibitor cantharidin (Cant) on time parameters and force of contraction (FOC) in isometrically contracting electrically driven guinea pig papillary muscles. We correlated the mechanical parameters of contractility with phosphorylation of the inhibitory subunit of troponin (TnI-P) and with the site-specific phosphorylation of phospholamban (PLB) at serine-16 (PLB-Ser-16) and threonine-17 (PLB-Thr-17). Cant (after 30 min) started to increase FOC (112 ± 4% of control, n = 10) and TnI-P and PLB-Thr-17 (120 ± 5 and 128 ± 7% of control) without any alteration of relaxation time. Cant (10 μM) started to increase PLB-Ser-16, but the relaxation was shortened at only 100 μM (from 140 ± 9 to 116 ± 12 ms, n = 9). Moreover, 100 μM Cant, 3 min after application, started to increase PLB-Thr-17, TnI-P, and FOC. Cant (100 μM) began to increase PLB-Ser-16 after 20 min. This was accompanied by shortening of relaxation time. Differences in protein kinase activation or different substrate specificities of PP may explain the difference in Cant-induced site-specific phosphorylation of PLB in isometrically contracting papillary muscles. Moreover, PLB-Thr-17 may be important for inotropy, whereas PLB-Ser-16 could be a major determinant of relaxation time.
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30

Zeke, Tamás, Pál Gergely, and Viktor Dombrádi. "The Catalytic Subunits of Ser/Thr Protein Phosphatases from Caenorhabditis elegans." Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 119, no. 2 (February 1998): 317–24. http://dx.doi.org/10.1016/s0305-0491(97)00341-6.

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31

GUO, Yan-Lin, and Stanley J. ROUX. "Partial purification and characterization of a type 1 protein phosphatase in purified nuclei of pea plumules." Biochemical Journal 319, no. 3 (November 1, 1996): 985–91. http://dx.doi.org/10.1042/bj3190985.

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We report the isolation and characterization of a protein Ser/Thr phosphatase from highly purified pea nuclei. In subnuclear fractions, more than 75% of Ser/Thr protein phosphatase activity was associated with the chromatin fraction, whereas the other 25% was in the nuclear membrane/nucleoplasmic fraction when phosphorylase a was used as a substrate. The enzyme was purified approx. 2750-fold to a specific activity of approx. 4000 nmol/min per mg. The molecular mass of the enzyme was 34 kDa as estimated by molecular sieve chromatography, and approx. 40 kDa as estimated by SDS/PAGE. The phosphatase was inhibited by okadaic acid with an IC50 of approx. 15 nM, by rabbit muscle inhibitor 2 with an IC50 of approx. 10 nM, and by microcystin-LR with an IC50 of approx. 0.05 nM. The enzyme did not require Ca2+, Mg2+ or Mn2+ for its activity; instead, these cations showed some inhibitory effects. It was inhibited by NaF or citrate but not by tartrate, molybdate or vanadate under the conditions tested. Its sensitivities towards the various phosphatase inhibitors and its substrate specificity were very similar to those characteristic of the type 1 Ser/Thr protein phosphatases well studied in animal systems. The enzyme was able to selectively dephosphorylate a 92 kDa nuclear protein that had been phosphorylated by one or more endogenous protein kinases.
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32

Swingle, Mark R., and Richard E. Honkanen. "Inhibitors of Serine/Threonine Protein Phosphatases: Biochemical and Structural Studies Provide Insight for Further Development." Current Medicinal Chemistry 26, no. 15 (July 25, 2019): 2634–60. http://dx.doi.org/10.2174/0929867325666180508095242.

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Background:The reversible phosphorylation of proteins regulates many key functions in eukaryotic cells. Phosphorylation is catalyzed by protein kinases, with the majority of phosphorylation occurring on side chains of serine and threonine residues. The phosphomonoesters generated by protein kinases are hydrolyzed by protein phosphatases. In the absence of a phosphatase, the half-time for the hydrolysis of alkyl phosphate dianions at 25º C is over 1 trillion years; knon ~2 x 10-20 sec-1. Therefore, ser/thr phosphatases are critical for processes controlled by reversible phosphorylation.Methods:This review is based on the literature searched in available databases. We compare the catalytic mechanism of PPP-family phosphatases (PPPases) and the interactions of inhibitors that target these enzymes.Results:PPPases are metal-dependent hydrolases that enhance the rate of hydrolysis ([kcat/kM]/knon ) by a factor of ~1021, placing them among the most powerful known catalysts on earth. Biochemical and structural studies indicate that the remarkable catalytic proficiencies of PPPases are achieved by 10 conserved amino acids, DXH(X)~26DXXDR(X)~20- 26NH(X)~50H(X)~25-45R(X)~30-40H. Six act as metal-coordinating residues. Four position and orient the substrate phosphate. Together, two metal ions and the 10 catalytic residues position the phosphoryl group and an activated bridging water/hydroxide nucleophile for an inline attack upon the substrate phosphorous atom. The PPPases are conserved among species, and many structurally diverse natural toxins co-evolved to target these enzymes.Conclusion:Although the catalytic site is conserved, opportunities for the development of selective inhibitors of this important group of metalloenzymes exist.
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33

Klevernic, Iva V., Margaret J. Stafford, Nicholas Morrice, Mark Peggie, Simon Morton, and Philip Cohen. "Characterization of the reversible phosphorylation and activation of ERK8." Biochemical Journal 394, no. 1 (January 27, 2006): 365–73. http://dx.doi.org/10.1042/bj20051288.

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ERK8 (extracellular-signal-regulated protein kinase 8) expressed in Escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the Thr-Glu-Tyr motif. Dephosphorylation of the threonine residue by PP2A (protein serine/threonine phosphatase 2A) decreased ERK8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by PTP1B (protein tyrosine phosphatase 1B) decreased activity by only 15–20%. Wild-type ERK8 expressed in HEK-293 cells was over 100-fold less active than the enzyme expressed in bacteria or insect cells, but activity could be increased by exposure to hydrogen peroxide, by incubation with the protein serine/threonine phosphatase inhibitor okadaic acid, or more weakly by osmotic shock. In unstimulated cells, ERK8 was monophosphorylated at Tyr-177, and exposure to hydrogen peroxide induced the appearance of ERK8 that was dually phosphorylated at both Thr-175 and Tyr-177. IGF-1 (insulin-like growth factor 1), EGF (epidermal growth factor), PMA or anisomycin had little effect on activity. In HEK-293 cells, phosphorylation of the Thr-Glu-Tyr motif of ERK8 was prevented by Ro 318220, a potent inhibitor of ERK8 in vitro. The catalytically inactive mutants ERK8[D154A] and ERK8[K42A] were not phosphorylated in HEK-293 cells or E. coli, whether or not the cells had been incubated with protein phosphatase inhibitors or exposed to hydrogen peroxide. Our results suggest that the activity of ERK8 in transfected HEK-293 cells depends on the relative rates of ERK8 autophosphorylation and dephosphorylation by one or more members of the PPP family of protein serine/threonine phosphatases. The major residue in myelin basic protein phosphorylated by ERK8 (Ser-126) was distinct from that phosphorylated by ERK2 (Thr-97), demonstrating that, although ERK8 is a proline-directed protein kinase, its specificity is distinct from ERK1/ERK2.
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Clotet, Josep, Eloi Garí, Martí Aldea, and Joaquín Ariño. "The Yeast Ser/Thr Phosphatases Sit4 and Ppz1 Play Opposite Roles in Regulation of the Cell Cycle." Molecular and Cellular Biology 19, no. 3 (March 1, 1999): 2408–15. http://dx.doi.org/10.1128/mcb.19.3.2408.

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ABSTRACT Yeast cells overexpressing the Ser/Thr protein phosphatase Ppz1 display a slow-growth phenotype. These cells recover slowly from α-factor or nutrient depletion-induced G1 arrest, showing a considerable delay in bud emergence as well as in the expression of the G1 cyclins Cln2 and Clb5. Therefore, an excess of the Ppz1 phosphatase interferes with the normal transition from G1 to S phase. The growth defect is rescued by overexpression of the HAL3/SIS2 gene, encoding a negative regulator of Ppz1. High-copy-number expression of HAL3/SIS2has been reported to improve cell growth and to increase expression of G1 cyclins in sit4 phosphatase mutants. We show here that the described effects of HAL3/SIS2 onsit4 mutants are fully mediated by the Ppz1 phosphatase. The growth defect caused by overexpression ofPPZ1 is intensified in strains with low G1cyclin levels (such as bck2Δ or cln3Δ mutants), whereas mutation of PPZ1 rescues the synthetic lethal phenotype of sit4 cln3 mutants. These results reveal a role for Ppz1 as a regulatory component of the yeast cell cycle, reinforce the notion that Hal3/Sis2 serves as a negative modulator of the biological functions of Ppz1, and indicate that the Sit4 and Ppz1 Ser/Thr phosphatases play opposite roles in control of the G1/S transition.
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35

Hangan-Steinman, Dolores, Wai-chi Ho, Priti Shenoy, Bosco MC Chan, and Vincent L. Morris. "Differences in phosphatase modulation of α4 β1 and α5 β1 integrin-mediated adhesion and migration of B16F1 cells." Biochemistry and Cell Biology 77, no. 5 (October 1, 1999): 409–20. http://dx.doi.org/10.1139/o99-050.

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It is well established that a biphasic relationship exists between the adhesive strength of β1 integrins and their ability to mediate cell movement. Thus, cell movement increases progressively with adhesive strength, but beyond a certain point of optimal interaction, cell movement is reduced with further increases in adhesive function. The interplay between the various kinase and phosphatase activities provides the balance in β1 integrin-mediated cell adhesion and migration. In the present study, the significance of protein tyrosine phosphatases (PTP) and ser/thr protein phosphatases (PP) in α4β1 and α5β1 integrin-mediated mouse melanoma B16F1 cell anchorage and migration on fibronectin was characterized using phosphatase inhibitors. At low fibronectin concentration, α5β1 functioned as the predominant receptor for cell movement; a role for α4β1 in B16F1 cell migration increased progressively with fibronectin concentration. Treatment of B16F1 cells with PTP inhibitors, sodium orthovanadate (Na3VO4) and phenylarsine oxide (PAO), or PP-1/2A inhibitor, okadaic acid (OA), abolished cell movement. Inhibition of cell movement by PAO and OA was associated by a reduction in the adhesive strength of α4β1 and α5β1. In contrast, treatment of B16F1 cells with Na3VO4 resulted in selective stimulation of the adhesive function of α5β1, but not α4β1. Therefore, our results demonstrate that (i) both PTP and PP-1/2A have roles in cell movement, (ii) modulation of cell movement by PTP and PP-1/2A may involve either a stimulation or reduction of β1 integrin adhesive strength, and (iii) distinct phosphatase-mediated signaling pathways for differential regulation of the various β1 integrins exist. Key words: phosphatases, integrins, cell movement, cell adhesion.
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36

Hadler, Kieran S., Thomas Huber, A. Ian Cassady, Jane Weber, Jodie Robinson, Allan Burrows, Gregory Kelly, et al. "Identification of a non-purple tartrate-resistant acid phosphatase: an evolutionary link to Ser/Thr protein phosphatases?" BMC Research Notes 1, no. 1 (2008): 78. http://dx.doi.org/10.1186/1756-0500-1-78.

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37

Huxtable, Adrianne G., Timothy J. Peterson, Jonathan N. Ouellette, Jyoti J. Watters, and Gordon S. Mitchell. "Spinal protein phosphatase 1 constrains respiratory plasticity after sustained hypoxia." Journal of Applied Physiology 125, no. 5 (November 1, 2018): 1440–46. http://dx.doi.org/10.1152/japplphysiol.00641.2018.

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Plasticity is an important aspect of the neural control of breathing. One well-studied form of respiratory plasticity is phrenic long-term facilitation (pLTF) induced by acute intermittent but not sustained hypoxia. Okadaic acid-sensitive protein phosphatases (PPs) differentially regulate phrenic nerve activity with intermittent vs. sustained hypoxia, at least partially accounting for pLTF pattern sensitivity. However, okadaic acid inhibits multiple serine/threonine phosphatases, and the relevant phosphatase (PP1, PP2A, PP5) for pLTF pattern sensitivity has not been identified. Here, we demonstrate that sustained hypoxia (25 min, 9–10.5% O2) elicits phrenic motor facilitation in rats pretreated with bilateral intrapleural injections of small interfering RNAs (siRNAs; Accell-modified to preferentially transfect neurons, 3.33 μM, 3 days) targeting PP1 mRNA (48 ± 14% change from baseline, n = 6) but not PP2A (14 ± 9% baseline, n = 6) or nontargeting siRNAs (4 ± 10% baseline, n = 7). In time control rats (no hypoxia) treated with siRNAs ( n = 6), no facilitation was evident (−9 ± 9% baseline). siRNAs had no effect on the hypoxic phrenic response. Immunohistochemistry revealed PP1 and PP2A protein in identified phrenic motoneurons. Although PP1 and PP2A siRNAs significantly decreased PP1 and PP2A mRNA in PC12 cell cultures, we were not able to verify “knockdown” in vivo after siRNA treatment. On the other hand, PP1 and PP2A siRNAs significantly decreased PP1 and PP2A mRNA in PC12 cell cultures, verifying the intended siRNA effects. In conclusion, PP1 (not PP2A) is the relevant okadaic acid-sensitive phosphatase constraining phrenic motor facilitation after sustained hypoxia and likely contributing to pLTF pattern sensitivity. NEW & NOTEWORTHY This study demonstrates that the relevant okadaic acid-sensitive Ser/Thr protein phosphatase (PP) constraining facilitation after sustained hypoxia is PP1 and not PP2A. It suggests that PP1 may be critical in the pattern sensitivity of hypoxia-induced phrenic motor plasticity.
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38

WERA, Stefaan, Mathieu BOLLEN, Luc MOENS, and Willy STALMANS. "Time-dependent pseudo-activation of hepatic glycogen synthase b by glucose 6-phosphate without involvement of protein phosphatases." Biochemical Journal 315, no. 1 (April 1, 1996): 91–96. http://dx.doi.org/10.1042/bj3150091.

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During a 30 min incubation at 25 °C in the presence of 5–10 mM glucose 6-phosphate, pure glycogen-bound glycogen synthase b from dog liver was progressively converted into a form that was fully catalytically active in the presence of 10 mM Na2SO4 plus 0.5 mM glucose 6-phosphate. The latter enzyme was unlike synthase a (which does not require glucose 6-phosphate for activity), and unlike synthase b (which is strongly inhibited by sulphate). The conversion was insensitive to various inhibitors of Ser/Thr-protein phosphatases and alkaline phosphatases, and was therefore termed ‘pseudo-activation’. Kinetically, pseudo-activation increased the Vmax 4-fold without affecting the Km for the substrate UDP-glucose. Pseudo-activation appeared to be an irreversible process, but several lines of evidence argue against a limited proteolysis. Pseudo-activation of glycogen synthase occurred also readily in a rat liver cytosol, but it was not observed with purified synthase from skeletal muscle. These observations have important implications for the assay of liver glycogen-synthase phosphatase; the possible physiological implications remain to be explored.
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39

Wehenkel, Annemarie, Marco Bellinzoni, Martin Graña, Rosario Duran, Andrea Villarino, Pablo Fernandez, Gwénaëlle Andre-Leroux, et al. "Mycobacterial Ser/Thr protein kinases and phosphatases: Physiological roles and therapeutic potential." Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1784, no. 1 (January 2008): 193–202. http://dx.doi.org/10.1016/j.bbapap.2007.08.006.

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40

Pradhan, Subhashree, Tanvir Khatlani, Satya P. Kunapuli, and K. Vinod Vijayan. "Gβ1 a Component Of The Heterotrimeric G Protein Is a New Protein Phosphatase 1c Interacting Protein That Regulates Platelet Activation." Blood 122, no. 21 (November 15, 2013): 3508. http://dx.doi.org/10.1182/blood.v122.21.3508.3508.

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Abstract Platelet activation at the site of injury is tied to signal transduction events that are mediated by protein kinases and phosphatases. Reversible tyrosine, serine/threonine (Ser/Thr) phosphorylation-dependent assembly and/or disassembly of effector (cytoskeletal, signaling and adaptor) protein complexes propagate signaling downstream of G protein coupled receptors (GPCRs). Compared to kinases, the contribution of Ser/Thr phosphatases and its effectors in GPCR signaling studies is not well explored. Our previous studies had revealed that the catalytic subunit of protein phosphatase 1γ (PP1cγ) support GPCR signaling and thrombus formation. Since cell signaling networks are dependent on protein-protein interactions, we sought to identify the potential effectors of PP1cγ. We employed yeast two-hybrid interaction studies with the full length PP1cγ fused to GAL4 activating domain as bait and screened human bone marrow library. A novel interaction of PP1cγ with a protein called Gβ1 (GNB1) was identified. Gβ1 is a component of the heterotrimeric G proteins like the Gα and couple to GPCR. However, unlike Gα subunits, Gβ1 is unexplored in platelets. Co-immunoprecipitation (co-IP) studies validated PP1cγ-Gβ1 interaction in 293 cells expressing PP1cγ-HA and Gβ1-FLAG. Importantly, Gβ1 interacted with all the PP1c isoforms, suggesting that Gβ1 could target all PP1c isoforms to the GPCR complex. Purified PP1c bound to recombinant Gβ1-GST protein but not to GST protein, indicating that the in vitro interaction of PP1c with Gβ1 was direct and independent of Gα and Gγ subunits. A small molecule inhibitor of G protein βγ, gallein decreased thrombin-induced human platelet aggregation and adhesion to immobilized fibrinogen. There is a paucity of Gβ1-/- platelets because Gβ1-/- mice die within 2 days of birth due to microencephaly. siRNA mediated depletion of Gβ1 in murine megakaryocytes reduced PAR4-activating peptide induced soluble fibrinogen binding to αIIbβ3. These studies suggest a functional role for Gβ1 in GPCR signaling. PP1c co-immunoprecipitated with Gβ1 in resting platelets and agonist (thrombin and ADP) treatment under non-stirring conditions induced dissociation of PP1c from Gβ1. These studies indicate that Gβ1-PP1c complex in platelets is responsive to agonist. Furthermore, PP1c and Gβ1 associated with P2Y12 receptor in resting but not agonist activated platelets in a co-IP assay, suggesting a role for this complex in G protein signaling. Finally, agonist induced dissociation of PP1c from Gβ1 correlated with the association of PP1c with the downstream GPCR effector phospholipase C β3 (PLCβ3) with a concomitant dephosphorylation of PLCβ3 at Ser1105. Since previous studies have revealed that PLCβ3 activity is inhibited by Ser1105 phosphorylation, our observation suggest that agonist-induced association of PP1c with PLCβ3 facilitates dephosphorylation and activation of PLCβ3. These studies highlight a coupling of GPCR signaling with the phosphatase driven signal transduction during platelet activation. Disclosures: No relevant conflicts of interest to declare.
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Guerra, Barbara, and Olaf-Georg Issinger. "Natural Compounds and Derivatives as Ser/Thr Protein Kinase Modulators and Inhibitors." Pharmaceuticals 12, no. 1 (January 1, 2019): 4. http://dx.doi.org/10.3390/ph12010004.

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The need for new drugs is compelling, irrespective of the disease. Focusing on medical problems in the Western countries, heart disease and cancer are at the moment predominant illnesses. Owing to the fact that ~90% of all 21,000 cellular proteins in humans are regulated by phosphorylation/dephosphorylation it is not surprising that the enzymes catalysing these reactions (i.e., protein kinases and phosphatases, respectively) have attracted considerable attention in the recent past. Protein kinases are major team players in cell signalling. In tumours, these enzymes are found to be mutated disturbing the proper function of signalling pathways and leading to uncontrolled cellular growth and sustained malignant behaviour. Hence, the search for small-molecule inhibitors targeting the altered protein kinase molecules in tumour cells has become a major research focus in the academia and pharmaceutical companies.
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42

Luong, H., K. D. Winestock, and D. S. Finbloom. "Inhibitors of serine/threonine phosphatases enhance phosphorylation of the interferon-gamma receptor while selectively attenuating interferon-gamma-induced gene expression in human peripheral-blood monocytes." Biochemical Journal 299, no. 3 (May 1, 1994): 799–803. http://dx.doi.org/10.1042/bj2990799.

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Since many events following ligand-induced receptor clustering are controlled by serine and threonine (Ser/Thr) phosphorylation, we initiated an investigation into the role of Ser/Thr phosphatases in both phosphorylation of the interferon-gamma (IFN-gamma) receptor and IFN gamma-induced gene expression in human peripheral-blood monocytes. Whereas IFN gamma alone did not enhance phosphorylation of the IFN gamma receptor, treatment of monocytes with the Ser/Thr phosphatase inhibitors, okadaic acid and calyculin A, resulted in increased phosphorylation of the IFN gamma receptor. However, when these cells were analysed for IFN gamma-induced IP-10 gene expression, there was profound inhibition. Using three IFN gamma-induced early-response genes, IP-10, the Fc gamma receptor type I (Fc gamma RI) and ISG-54, we found selective sensitivity to pretreatment with okadaic acid and calyculin A. Whereas IFN gamma induction of IP-10 was blocked by both inhibitors, only calyculin A prevented Fc gamma RI-gene expression. Neither inhibitor prevented ISG-54 induction by IFN gamma. IFN-gamma-activated formation of the DNA-binding-protein complex FcRF gamma (which binds to the promoter of the Fc gamma RI gene) remained unaffected by okadaic acid or calyculin A. Therefore these data suggest that Ser/Thr phosphatases have no major part in IFN gamma-initiated signal transduction across the membrane, but selectively control the ultimate transcription of a set of early-response genes.
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43

van WILLIGEN, Gijsbert, Ingeborg HERS, Gertie GORTER, and Jan-Willem N. AKKERMAN. "Exposure of ligand-binding sites on platelet integrin αIIB/β3 by phosphorylation of the β3 subunit." Biochemical Journal 314, no. 3 (March 15, 1996): 769–79. http://dx.doi.org/10.1042/bj3140769.

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The exposure of ligand-binding sites for adhesive proteins on platelet integrin αIIB/β3 (glycoprotein IIB/IIIA) by platelet-activating factor (PAF) is transient, whereas sites exposed by α-thrombin remain accessible. The same difference is seen in the phosphorylation of the β3 subunit. Inhibition of protein kinases (1 μM staurosporine) and protein kinase C (10 μM bisindolylmaleimide) closes binding sites exposed by both agonists and induces dephosphorylation of β3. Inhibition of Tyr-kinases (20 μM Herbimycin A) has only a slight effect. Inhibition of Ser/Thr-phosphatases (1 μM okadaic acid, 30 s preincubation) changes the transient exposure and β3 phosphorylation by PAF into the ‘permanent’ patterns induced by α-thrombin. Inhibition of Tyr-phosphatases (100 μM vanadate) has little effect. Preincubation with okadaic acid makes exposed binding sites and phosphorylated β3 insensitive to staurosporine, resulting in exposed αIIB/β3 independent of concurrent phosphorylation/dephosphorylation. The stoichiometry of β3 phosphorylation by α-thrombin is 0.80±0.10. Thus, one of the mechanisms that regulates exposure and closure of ligand-binding sites on the αIIB/β3 is phosphorylation/dephosphorylation of a Ser/Thr-residue in the β3 subunit.
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44

Andreeva, Alexandra V., and Mikhail A. Kutuzov. "Physcomitrella patens Gene/cDNA Fragments Related to Genes Encoding Protein Ser/Thr Phosphatases." Journal of Plant Physiology 155, no. 2 (August 1999): 153–58. http://dx.doi.org/10.1016/s0176-1617(99)80001-7.

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45

Yamamoto, M., Y. Suzuki, H. Kihira, H. Miwa, K. Kita, M. Nagao, S. Tamura, H. Shiku, and M. Nishikawa. "Expressions of four major protein Ser/Thr phosphatases in human primary leukemic cells." Leukemia 13, no. 4 (April 1999): 595–600. http://dx.doi.org/10.1038/sj.leu.2401372.

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46

Ishida, Atsuhiko, Kumiko Tsumura, Megu Oue, Yasuhiro Takenaka, Yasushi Shigeri, Naoki Goshima, Yasuhiro Ishihara, et al. "An Active C-Terminally Truncated Form of Ca2+/Calmodulin-Dependent Protein Kinase Phosphatase-N (CaMKP-N/PPM1E)." BioMed Research International 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/134813.

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Ca2+/calmodulin-dependent protein kinase phosphatase (CaMKP/PPM1F) and its nuclear homolog CaMKP-N (PPM1E) are Ser/Thr protein phosphatases that belong to the PPM family. CaMKP-N is expressed in the brain and undergoes proteolytic processing to yield a C-terminally truncated form. The physiological significance of this processing, however, is not fully understood. Using a wheat-embryo cell-free protein expression system, we prepared human CaMKP-N (hCaMKP-N(WT)) and the truncated form, hCaMKP-N(1–559), to compare their enzymatic properties using a phosphopeptide substrate. The hCaMKP-N(1–559) exhibited a much higherVmaxvalue than the hCaMKP-N(WT) did, suggesting that the processing may be a regulatory mechanism to generate a more active species. The active form, hCaMKP-N(1–559), showed Mn2+or Mg2+-dependent phosphatase activity with a strong preference for phospho-Thr residues and was severely inhibited by NaF, but not by okadaic acid, calyculin A, or 1-amino-8-naphthol-2,4-disulfonic acid, a specific inhibitor of CaMKP. It could bind to postsynaptic density and dephosphorylate the autophosphorylated Ca2+/calmodulin-dependent protein kinase II. Furthermore, it was inactivated by H2O2treatment, and the inactivation was completely reversed by treatment with DTT, implying that this process is reversibly regulated by oxidation/reduction. The truncated CaMKP-N may play an important physiological role in neuronal cells.
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47

Grzechnik, Agnieszka T., and Alexandra C. Newton. "PHLPPing through history: a decade in the life of PHLPP phosphatases." Biochemical Society Transactions 44, no. 6 (December 2, 2016): 1675–82. http://dx.doi.org/10.1042/bst20160170.

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In the decade since their discovery, the PH domain leucine-rich repeat protein phosphatases (PHLPP) have emerged as critical regulators of cellular homeostasis, and their dysregulation is associated with various pathophysiologies, ranging from cancer to degenerative diseases, such as diabetes and heart disease. The two PHLPP isozymes, PHLPP1 and PHLPP2, were identified in a search for phosphatases that dephosphorylate Akt, and thus suppress growth factor signaling. However, given that there are over 200 000 phosphorylated residues in a single cell, and fewer than 50 Ser/Thr protein phosphatases, it is not surprising that PHLPP has many other cellular functions yet to be discovered, including a recently identified role in regulating the epigenome. Both PHLPP1 and PHLPP2 are commonly deleted in human cancers, supporting a tumor suppressive role. Conversely, the levels of one isozyme, PHLPP1, are elevated in diabetes. Thus, mechanisms to correctly control PHLPP activity in cells are critical for normal cellular homeostasis. This review summarizes the known functions of PHLPP and its role in disease.
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48

Gushiken, Francisca C., Nawaf Alrehani, Subhashree Pradhan, Lavanya Kailasam, Rolando Rumbaut, and K. Vinod Vijayan. "Suppression of Murine Platelet Activation by the β Isoform of the Catalytic Subunit of Protein Phosphatase 2B." Blood 118, no. 21 (November 18, 2011): 190. http://dx.doi.org/10.1182/blood.v118.21.190.190.

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Abstract Abstract 190 Signal transduction mediated by the kinases and phosphatases are critical for platelet activation at the site of vascular injury. Compared to the kinases, a role for phosphatases in platelet activation is less understood. Our previous studies have focused on the roles of serine/threonine protein phosphatase 1 (PP1) and 2A (PP2A) in regulating integrin αIIbβ3functions. However, platelets also express protein phosphatase 2B (PP2B) and its role in platelet function is unexplored. PP2B-Aα and PP2B-Aβ constitute two ubiquitous isoforms of the PP2B catalytic subunit. Due to the general concerns regarding the specificity of the PP2B inhibitors, we have utilized mice deficient in the β isoform of the catalytic subunit of PP2B (PP2B-Aβ) to explore the role of PP2B in platelet functions. Mice lacking PP2B-Aα are short lived and are not considered in this study. Loss of PP2B-Aβ did not cause any compensatory increase in the PP2B-Aα levels in platelets. Compared to the wild type (WT) platelets, PP2B-Aβ−/− platelets displayed increased aggregation in response to low doses of protease-activated receptor 4-activating peptide (PAR4-AP), ADP, collagen and collagen related peptide (CRP). Enhanced α granule secretion in response to the low doses of PAR4-AP and CRP was noticed in PP2B-Aβ−/− platelets, relative to the WT platelets. Functions regulated by the outside-in αIIbβ3 integrin signaling like adhesion to immobilized fibrinogen and fibrin clot retraction were enhanced in the PP2B-Aβ−/− platelets. These studies indicate that PP2B-Aβ negatively regulate platelet functions in vitro. Consistent with these observations, PP2B-Aβ−/− mice exhibited a shorter tail bleeding time compared to the WT mice. In a FeCl3 induced endothelial denudation injury model, PP2B-Aβ−/− mice showed decreased time to occlusion in the carotid artery, and reduced number of emboli compared to the WT mice. These studies indicate that PP2B-Aβ suppress multiple murine platelet functions that contribute to an occlusive thrombi. Unlike a positive thrombus promoting role for the PP1cγ that was noticed in our previous study, PP2B-Aβ suppressed murine platelet activation, suggesting that different subtypes of Ser/Thr phosphatases have distinct roles in murine platelet activation. Disclosures: No relevant conflicts of interest to declare.
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49

Zhang, Chunyi, Antonio de la Torre, José Pérez-Martín, and Joaquín Ariño. "Protein Phosphatase Ppz1 Is Not Regulated by a Hal3-Like Protein in Plant Pathogen Ustilago maydis." International Journal of Molecular Sciences 20, no. 15 (August 5, 2019): 3817. http://dx.doi.org/10.3390/ijms20153817.

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Abstract:
Ppz enzymes are type-1 related Ser/Thr protein phosphatases that are restricted to fungi. In S. cerevisiae and other fungi, Ppz1 is involved in cation homeostasis and is regulated by two structurally-related inhibitory subunits, Hal3 and Vhs3, with Hal3 being the most physiologically relevant. Remarkably, Hal3 and Vhs3 have moonlighting properties, as they participate in an atypical heterotrimeric phosphopantothenoyl cysteine decarboxylase (PPCDC), a key enzyme for Coenzyme A biosynthesis. Here we identify and functionally characterize Ppz1 phosphatase (UmPpz1) and its presumed regulatory subunit (UmHal3) in the plant pathogen fungus Ustilago maydis. UmPpz1 is not an essential protein in U. maydis and, although possibly related to the cell wall integrity pathway, is not involved in monovalent cation homeostasis. The expression of UmPpz1 in S. cerevisiae Ppz1-deficient cells partially mimics the functions of the endogenous enzyme. In contrast to what was found in C. albicans and A. fumigatus, UmPpz1 is not a virulence determinant. UmHal3, an unusually large protein, is the only functional PPCDC in U. maydis and, therefore, an essential protein. However, when overexpressed in U. maydis or S. cerevisiae, UmHal3 does not reproduce Ppz1-inhibitory phenotypes. Indeed, UmHal3 does not inhibit UmPpz1 in vitro (although ScHal3 does). Therefore, UmHal3 might not be a moonlighting protein.
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50

Mao, Xinguo, Yuying Li, Shoaib Ur Rehman, Lili Miao, Yanfei Zhang, Xin Chen, Chunmei Yu, Jingyi Wang, Chaonan Li, and Ruilian Jing. "The Sucrose Non-Fermenting 1-Related Protein Kinase 2 (SnRK2) Genes Are Multifaceted Players in Plant Growth, Development and Response to Environmental Stimuli." Plant and Cell Physiology 61, no. 2 (December 13, 2019): 225–42. http://dx.doi.org/10.1093/pcp/pcz230.

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Abstract Reversible protein phosphorylation orchestrated by protein kinases and phosphatases is a major regulatory event in plants and animals. The SnRK2 subfamily consists of plant-specific protein kinases in the Ser/Thr protein kinase superfamily. Early observations indicated that SnRK2s are mainly involved in response to abiotic stress. Recent evidence shows that SnRK2s are multifarious players in a variety of biological processes. Here, we summarize the considerable knowledge of SnRK2s, including evolution, classification, biological functions and regulatory mechanisms at the epigenetic, post-transcriptional and post-translation levels.
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