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Ismail Suliman Elgenaidi, James Paul Spiers
BACKGROUND AND PURPOSE: Although protein phosphatases regulate several aspects of cellular function, their expression pattern and modulation under hypoxia remains poorly understood. We investigated the expression of key components of the protein phosphatase system in human cardiovascular cells under normoxic/hypoxic conditions and the mechanism by which hypoxia alters PP2A activity. EXPERIMENTAL APPROACH: Cardiovascular cell lines were cultured in cell type specific media under normoxic or hypoxic conditions (1% O2 )...
March 1, 2019: British Journal of Pharmacology
Shen Tang, Cailing Lu, Laiming Mo, Xinhang Wang, Ziwei Liang, Fu Qin, Yinpin Liu, Yuyang Liu, Haiyan Huang, Yue Huang, Haiqing Cai, Deqiang Xiao, Songchao Guo, Yiqiang Ouyang, Bin Sun, Xiyi Li
AIMS: Protein phosphatase methylesterase-1 (PME-1) is a serine hydrolase that catalyzes protein phosphatase 2A (PP2A) demethylation and negatively regulates its activity. PME-1 is compartmentalized within cells to precisely control the demethylation of PP2A. This study investigated the localization of PME-1 in human fibroblast cells (HDF) under oxidative stress. MAIN METHODS: Alkaline demethylation and peptide competition assays were applied to detect the methylation sensitivity of anti-PP2Ac...
October 16, 2018: Life Sciences
Ryotaro Yabe, Shunya Tsuji, Satoru Mochida, Tsuyoshi Ikehara, Tatsuya Usui, Takashi Ohama, Koichi Sato
Reversible methyl-esterification (methylation) of Leu309 in the protein phosphatase 2A catalytic subunit (PP2Ac) is essential for proper biogenesis of the PP2A holoenzyme. Accumulating evidence links PP2Ac methylation to diseases, including cancer and neurodegenerative disorders. Protein phosphatase methyl-esterase (PME-1) specifically catalyzes PP2Ac demethylation. We demonstrate that PP2Ac is demethylated in cell extracts even at 0 °C unless prevented by a PME-1 methyl-esterase inhibitor. This promotes dissociation of PP2A heterotrimers with B55 or PR72 subunits, but not those with B56 subunits...
September 2018: FEBS Open Bio
Chul-Hyun Cho, Yong-Ho Lee, Kwang-Soon Song, Kyung-Jae Lee, Si-Wook Lee, Sung-Moon Lee
Background: The aim of this study was to assess the consistency between preoperative ultrasonographic and intraoperative measurements of the ulnar nerve in patients with cubital tunnel syndrome. Methods: Twenty-six cases who underwent anterior transposition of the ulnar nerve for cubital tunnel syndrome were enrolled prospectively. On preoperative ultrasonography, largest cross-sectional diameters of the ulnar nerve were measured at the level of medial epicondyle (ME) and 3 cm proximal (PME) and distal (DME) to the ME on the transverse scan by a single experienced radiologist...
September 2018: Clinics in Orthopedic Surgery
Sergio A Acuna, Tyler R Chesney, Sonali T Amarasekera, Nancy N Baxter
INTRODUCTION: Quality of surgical resection metrics (QSRMs) have been used as surrogates for long-term oncologic outcomes in non-inferiority randomized clinical trials (RCTs) comparing laparoscopic and open surgery for rectal cancer. However, non-inferiority margins (ΔNI ) for QSRMs have not been previously defined. METHODS: A two-round, web-based Delphi was used to define ΔNI for four QSRMs: positive circumferential resection margin (CRM), incomplete plane of mesorectal excision (PME), positive distal resection margin (DRM), and a composite of these outcomes...
October 2018: Annals of Surgical Oncology
Cuicui Yang, Xuelian Li, Wenbin Gao, Qi Wang, Li Zhang, Yali Li, Lin Li, Lan Zhang
Neurofibrillary pathology contributes to neuronal dysfunction and correlates with the clinical progression of Alzheimer's disease (AD). Tau phosphorylation is mainly regulated by a balance of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) activities. Cornel iridoid glycoside (CIG) is a main component extracted from Cornus officinalis . The purpose of this study was to investigate the effects of CIG on GSK-3β and PP2A, thus to explore the mechanisms of CIG to inhibit tau hyperphosphorylation...
2018: Frontiers in Pharmacology
Hao Tian, Yongquan Lu, Jia Liu, Weijin Liu, Lingling Lu, Chunli Duan, Ge Gao, Hui Yang
The pathology of Parkinson's disease (PD) is characterized by intracellular neurofibrillary tangles of phosphorylated α-synuclein (α-syn). Protein phosphatase 2A (PP2A) is responsible for α-syn dephosphorylation. Previous work has demonstrated that α-syn can regulate PP2A activity. However, the mechanisms underlying α-syn regulation of PP2A activity are not well understood. In this study, we found that α-syn overexpression induced increased α-syn phosphorylation at serine 129 (Ser129), and PP2A inhibition, in vitro and in vivo ...
2018: Frontiers in Aging Neuroscience
Shen Tang, Fu Qin, Xinhang Wang, Ziwei Liang, Haiqing Cai, Laiming Mo, Yue Huang, Boyin Liang, Xuejing Wei, Qingqing Ao, Yilu Xu, Yuyang Liu, Deqiang Xiao, Songchao Guo, Cailing Lu, Xiyi Li
Mammalian target of rapamycin (mTOR) is a Ser/Thr protein kinase that functions as an ATP and amino acid sensor to govern cell growth and proliferation by mediating mitogen- and nutrient-dependent signal transduction. Protein phosphatase 2A (PP2A), a ubiquitously expressed serine/threonine phosphatase, negatively regulates mTOR signaling. Methylation of PP2A is catalyzed by leucine carboxyl methyltransferase-1 (LCMT1) and reversed by protein phosphatase methylesterase 1 (PME-1), which regulates PP2A activity and substrate specificity...
May 12, 2018: Cell Biology International
Hye-Jin Park, Kang-Woo Lee, Stephanie Oh, Run Yan, Jie Zhang, Thomas G Beach, Charles H Adler, Michael Voronkov, Steven P Braithwaite, Jeffry B Stock, M Maral Mouradian
Hyperphosphorylated tau aggregates are characteristic of tauopathies including progressive supranuclear palsy (PSP) and Alzheimer disease (AD), but factors contributing to pathologic tau phosphorylation are not well understood. Here, we studied the regulation of the major tau phosphatase, the heterotrimeric AB55αC protein phosphatase 2 A (PP2A), in PSP and AD. The assembly and activity of this PP2A isoform are regulated by reversible carboxyl methylation of its catalytic C subunit, while the B subunit confers substrate specificity...
February 1, 2018: Journal of Neuropathology and Experimental Neurology
Amanpreet Kaur, Jukka Westermarck
Protein phosphatase 2A (PP2A) plays a major role in maintaining cellular signaling homeostasis by dephosphorylation of a variety of signaling proteins and acts as a tumor suppressor. Protein phosphatase methylesterase-1 (PME-1) negatively regulates PP2A activity by highly complex mechanisms that are reviewed here. Importantly, recent studies have shown that PME-1 promotes oncogenic MAPK/ERK and AKT pathway activities in various cancer types. In human glioma, high PME-1 expression correlates with tumor progression and kinase inhibitor resistance...
December 15, 2016: Biochemical Society Transactions
Hye-Jin Park, Kang-Woo Lee, Eun S Park, Stephanie Oh, Run Yan, Jie Zhang, Thomas G Beach, Charles H Adler, Michael Voronkov, Steven P Braithwaite, Jeffry B Stock, M Maral Mouradian
OBJECTIVE: Protein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme composed of a catalytic C subunit, a structural A subunit, and one of several regulatory B subunits that confer substrate specificity. The assembly and activity of PP2A are regulated by reversible methylation of the C subunit. α -Synuclein, which aggregates in Parkinson disease (PD) and dementia with Lewy bodies (DLB), is phosphorylated at Ser129 , and PP2A containing a B55 α subunit is a major phospho-Ser129 phosphatase...
October 2016: Annals of Clinical and Translational Neurology
Amanpreet Kaur, Oxana V Denisova, Xi Qiao, Mikael Jumppanen, Emilia Peuhu, Shafiq U Ahmed, Olayinka Raheem, Hannu Haapasalo, John Eriksson, Anthony J Chalmers, Pirjo Laakkonen, Jukka Westermarck
Glioblastoma multiforme lacks effective therapy options. Although deregulated kinase pathways are drivers of malignant progression in glioblastoma multiforme, glioma cells exhibit intrinsic resistance toward many kinase inhibitors, and the molecular basis of this resistance remains poorly understood. Here, we show that overexpression of the protein phosphatase 2A (PP2A) inhibitor protein PME-1 drives resistance of glioma cells to various multikinase inhibitors. The PME-1-elicited resistance was dependent on specific PP2A complexes and was mediated by a decrease in cytoplasmic HDAC4 activity...
December 1, 2016: Cancer Research
Lucía Perucho-González, Federico Sáenz-Francés, Laura Morales-Fernández, José María Martínez-de-la-Casa, Carmen D Méndez-Hernández, Enrique Santos-Bueso, John L Brookes, Julián García-Feijoó
PURPOSE: To determine whether a set of ocular morphometric and biomechanical variables are able to discriminate between healthy volunteers and patients suffering from primary congenital glaucoma (PCG). METHODS: Case-control study in which 66 patients with PCG and 94 age-matched healthy subjects were evaluated using ocular response analyser (ORA) to record corneal biomechanical properties. Topographic corneal variables were obtained using the Pentacam in both groups...
March 2017: Acta Ophthalmologica
Juyeon Hwang, Jocelyn A Lee, David C Pallas
The protein phosphatase 2A (PP2A) subfamily of phosphatases, PP2A, PP4, and PP6, are multifunctional serine/threonine protein phosphatases involved in many cellular processes. Carboxyl methylation of the PP2A catalytic subunit (PP2Ac) C-terminal leucine is regulated by the opposing activities of leucine carboxyl methyltransferase 1 (LCMT-1) and protein phosphatase methylesterase 1 (PME-1) and regulates PP2A holoenzyme formation. The site of methylation on PP2Ac is conserved in the catalytic subunits of PP4 and PP6, and PP4 is also methylated on that site, but the identities of the methyltransferase enzyme for PP4 are not known...
September 30, 2016: Journal of Biological Chemistry
Cheng-Di Liu, Qin Wang, De-Kang Zong, Shuang-Chao Pei, Yan Yan, Mei-Ling Yan, Lin-Lin Sun, Yang-Yang Hao, Meng Mao, Wen-Jing Xing, Huan Ren, Jing Ai
Reduction of protein phosphatase-2A (PP2A) activity is a common clinical feature of Alzheimer's disease and vascular dementia. In this study, we observed that chronic brain hypoperfusion induced by bilateral common carotid artery occlusion of rats led to PP2A inactivation based on the increase in tyrosine-307 phosphorylation and leucine-309 demethylation of PP2AC and the depression in PP2ABα. Knockdown of miR-195 using overexpression of its antisense molecule oligonucleotide (pre-AMO-miR-195) delivered by a lentivirus (lenti-pre-AMO-miR-195) increased tyrosine-307 phosphorylation and decreased both PP2ABα expression and leucine-309 methylation; these effects were prevented by the overexpression of miR-195 using lenti-pre-miR-195 and controlled by an increase in methylesterase (PME-1) and a decrease in leucine carboxyl methyltransferase-1...
September 2016: Neurobiology of Aging
Michelle Pusey, Sophie Bail, Yan Xu, Olesia Buiakova, Mariya Nestor, Jing-Jing Yang, Lyndi M Rice
Protein methylesterase 1 (PME-1) promotes cancerous phenotypes through the demethylation and inactivation of protein phosphatase 2A. We previously demonstrated that PME-1 overexpression promotes Akt, ERK, and may promote Wnt signaling and increases tumor burden in a xenograft model of endometrial cancer. Here, we show that covalent PME-1 inhibitors decrease cell proliferation and invasive growth in vitro but have no effect in vivo at the concentrations tested; however, depletion of PME-1 with shRNA in an endometrial cancer xenograft model significantly reduced tumor growth...
September 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Russell E Nicholls, Jean-Marie Sontag, Hong Zhang, Agnieszka Staniszewski, Shijun Yan, Carla Y Kim, Michael Yim, Caitlin M Woodruff, Erland Arning, Brandi Wasek, Deqi Yin, Teodoro Bottiglieri, Estelle Sontag, Eric R Kandel, Ottavio Arancio
Elevated levels of the β-amyloid peptide (Aβ) are thought to contribute to cognitive and behavioral impairments observed in Alzheimer's disease (AD). Protein phosphatase 2A (PP2A) participates in multiple molecular pathways implicated in AD, and its expression and activity are reduced in postmortem brains of AD patients. PP2A is regulated by protein methylation, and impaired PP2A methylation is thought to contribute to increased AD risk in hyperhomocysteinemic individuals. To examine further the link between PP2A and AD, we generated transgenic mice that overexpress the PP2A methylesterase, protein phosphatase methylesterase-1 (PME-1), or the PP2A methyltransferase, leucine carboxyl methyltransferase-1 (LCMT-1), and examined the sensitivity of these animals to behavioral and electrophysiological impairments caused by exogenous Aβ exposure...
March 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
Cui-cui Yang, Xue-xian Kuai, Wen-bin Gao, Jian-chun Yu, Qi Wang, Lin Li, Lan Zhang
BACKGROUND: An accumulation of hyperphosphorylated tau in the brain is a hallmark of Alzheimer's disease (AD). Deficits in protein phosphatase 2A (PP2A) are associated with tau hyperphosphorylation in AD. OBJECTIVE: To investigate the effects of morroniside (MOR), isolated from Cornus officinalis, on tau hyperphosphorylation and its underlying mechanisms related to PP2A. METHODS: SK-N-SH cells were pretreated with 50-200 μM MOR for 24 h followed by 20 nM okadaic acid (OA) for 6 h...
2016: Journal of Alzheimer's Disease: JAD
Sari Longin, Jozef Goris
PP2A has been shown to be methylated at the C-terminal leucine residue of the catalytic subunit by a specific 38 kDa methyltransferase (LCMT1) and demethylated by a specific 44-kDa methylesterase (PME-1). This reversible methylation does not seem to drastically change the PP2A activity but is shown to be a modulating factor in the binding of the third regulatory subunit. The structure of LCMT1 is solved and a model for the catalysis of the methylation reaction is presented. By purifying the PP2A-methylesterase, inactive dimeric (PP2AiD) and trimeric (PP2AiT55) holoenzymes were found to be associated with PME-1...
2006: Enzymes
Ryotaro Yabe, Akane Miura, Tatsuya Usui, Ingrid Mudrak, Egon Ogris, Takashi Ohama, Koichi Sato
Protein phosphatase 2A (PP2A) is a conserved essential enzyme that is implicated as a tumor suppressor based on its central role in phosphorylation-dependent signaling pathways. Protein phosphatase methyl esterase (PME-1) catalyzes specifically the demethylation of the C-terminal Leu309 residue of PP2A catalytic subunit (PP2Ac). It has been shown that PME-1 affects the activity of PP2A by demethylating PP2Ac, but also by directly binding to the phosphatase active site, suggesting loss of PME-1 in cells would enhance PP2A activity...
2015: PloS One
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