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Protein phosphatase

Peisheng Liang, Wangyong Zhu, Tianjun Lan, Qian Tao
Saliva secretion disorder is one of the most common symptoms in primary Sjögren syndrome (pSS). Salivary biomarkers related to saliva secretion disorder were identified in a pSS murine model, NOD/ShiLtJ mouse, using differential proteomic analysis. Candidate biomarkers were screened with Kyoto Encyclopedia of Genes and Genomes pathway analysis and validated in saliva and salivary glands by western blotting and immunohistochemistry (IHC). Biological functions were detected using ingenuity pathway analysis (IPA)...
March 12, 2018: Journal of Pharmaceutical and Biomedical Analysis
Yide Huang, Yafei Zhang, Lilin Ge, Yao Lin, Hang Fai Kwok
The protein tyrosine phosphatase (PTP) family is involved in multiple cellular functions and plays an important role in various pathological and physiological processes. In many chronic diseases, for example cancer, PTP is a potential therapeutic target for cancer treatment. In the last two decades, dozens of PTP inhibitors which specifically target individual PTP molecules were developed as therapeutic agents. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and is the second most lethal cancer worldwide due to a lack of effective therapies...
March 20, 2018: Cancers
Jin Liu, Yu Chen, Jing-Ya Li, Cheng Luo, Jia Li, Kai-Xian Chen, Xu-Wen Li, Yue-Wei Guo
Phidianidines A and B are two novel marine indole alkaloids bearing an uncommon 1,2,4-oxadiazole ring and exhibiting various biological activities. Our previous research showed that the synthesized phidianidine analogs had the potential to inhibit the activity of protein tyrosine phosphatase 1B (PTP1B), a validated target for Type II diabetes, which indicates that these analogs are worth further structural modification. Therefore, in this paper, a series of phidianidine derivatives were designed and rapidly synthesized with a function-oriented synthesis (FOS) strategy...
March 20, 2018: Marine Drugs
Ruoxing Lei, Jessica P Lee, Matthew B Francis, Sanjay Kumar
Intrinsically disordered proteins (IDPs) play central roles in numerous cellular processes. While IDP structure and function are often regulated by multisite phosphorylation, the biophysical mechanisms linking these post-translational modifications to IDP structure remain elusive. For example, the intrinsically disordered C-terminal sidearm domain of the neurofilament heavy subunit (NFH-SA) forms a dense brush along axonal NF backbones and is subject to extensive serine phosphorylation. Yet, biophysical insight into the relationship between phosphorylation and structure has been limited by the lack of paradigms in which NF brush conformational responses can be measured in the setting of controlled phosphorylation...
March 20, 2018: Biochemistry
Christopher B Lietz, Thomas Toneff, Charles Mosier, Sonia Podvin, Anthony J O'Donoghue, Vivian Hook
Neuropeptides are vital for cell-cell communication and function in the regulation of the nervous and endocrine systems. They are generated by post-translational modification (PTM) steps resulting in small active peptides generated from prohormone precursors. Phosphorylation is a significant PTM for the bioactivity of neuropeptides. From the known diversity of distinct neuropeptide functions, it is hypothesized that the extent of phosphorylation varies among different neuropeptides. To assess this hypothesis, neuropeptide-containing dense core secretory vesicles from bovine adrenal medullary chromaffin cells were subjected to global phosphopeptidomics analyses by liquid chromatography (LC)-mass spectrometry (MS/MS)...
March 19, 2018: Journal of the American Society for Mass Spectrometry
Jun Liu, Lei Huang, Pengxiao Su, Tao Song, Wentao Zhang, Jinzhu Fan, Yang Liu
A number of studies have attempted to elucidate the association between mircoRNAs (miRNAs/miRs) and cancer-associated processes. The aim of the present study was to determine how miR-499a-5p intervenes in human osteosarcoma cell proliferation and differentiation. The cancerous tissues and adjacent non-cancerous tissues of 62 patients with osteosarcoma (OS) were collected. miRNA microarray analysis revealed that 29 miRNAs were upregulated while 26 were downregulated, among which miR-499a-5p expression was the most decreased...
April 2018: Oncology Letters
Siddhant Bhoir, Althaf Shaik, Vijay Thiruvenkatam, Sivapriya Kirubakaran
Human Tousled-like kinases (TLKs) are highly conserved serine/threonine protein kinases responsible for cell proliferation, DNA repair, and genome surveillance. Their possible involvement in cancer via efficient DNA repair mechanisms have made them clinically relevant molecular targets for anticancer therapy. Innovative approaches in chemical biology have played a key role in validating the importance of kinases as molecular targets. However, the detailed understanding of the protein structure and the mechanisms of protein-drug interaction through biochemical and biophysical techniques demands a method for the production of an active protein of exceptional stability and purity on a large scale...
March 19, 2018: Scientific Reports
Michael Perron, H Saragovi
Src-family kinases (SFK) govern cellular proliferation of bone marrow derived cells. SFKs are regulated by the protein tyrosine phosphatase enzymatic activity of CD45. All lymphoid cells express CD45 but only proliferating cells are dependent on CD45 activity. We postulated that a selective inhibitor of CD45 phosphatase activity, compound 211, could preferentially affect actively proliferating cells, but spare resting lymphoid cells. Compound 211 inhibited CD45 and induced inappropriate SFK signalling, leading to a G2/M cell cycle arrest and apoptotic cell death...
March 19, 2018: Molecular Pharmacology
Hee Kyoung Chung, Shelley R Wang, Lan Xiao, Navneeta Rathor, Douglas J Turner, Peixin Yang, Myriam Gorospe, Jaladanki N Rao, Jian-Ying Wang
The mammalian intestinal epithelium is a rapidly self-renewing tissue in the body and its homeostasis depends on a dynamic balance among proliferation, migration, apoptosis, and differentiation of intestinal epithelial cells (IECs). The PP2A-associated protein α4 controls the activity and specificity of serine/threonine phosphatases and is thus implicated in many cellular processes. Here we investigated the mechanisms whereby α4 controls the homeostasis of the intestinal epithelium using a genetic approach...
March 19, 2018: Molecular and Cellular Biology
Frank Zach, Franziska Polzer, Alexandra Mueller, André Gessner
The sequestosome 1 gene encodes the p62 protein and is the major genetic risk factor associated with Paget's disease of bone. In 2004, p62 was reported to up-regulate osteoclast differentiation by activating the transcription factors Nfatc1 and NF-κB. Here, we characterized the osteoclastogenic potential of murine p62-/- -derived cells compared with WT cells. Our data confirmed previous findings indicating that that p62 is induced during murine osteoclast differentiation. Surprisingly, an indispensable role for p62 in i n vitro osteoclast differentiation was not reproducible, since p62-deficient osteoclasts exhibited robust activation of Nfatc1, NF-κB, and osteoclast marker enzymes...
March 19, 2018: Journal of Biological Chemistry
Nesly Dotan, Vera Gayder, Itai Bloch, Maayan Gal
Calcineurin is a phosphatase that targets the transcription factor, nuclear factor of activated T-cells (NFAT) dephosphorylates multiple sites along NFAT's regulatory domain. The calcineurin-NFAT complex interaction is mediated through two conserved binding motifs known as the PxIxIT and LxVP, which are located at the N- and C- terminus to the phosphorylation sites. The vast range of cellular processes regulated by the calcineurin-NFAT interaction has aroused great interest in the investigation of the structural aspects that govern their complex formation and in the discovery of protein-protein interaction inhibitors; the latter interfere with calcineurin-NFAT complex formation while keeping calcineurin's catalytic site free...
March 16, 2018: Analytical Biochemistry
Małgorzata Jakubowicz, Witold Nowak, Łukasz Gałgański, Danuta Babula-Skowrońska
In this report, the members of PP2C, SnRK2a and Rboh oxidase families from Arabidopsis and poplar were studied in silico, and the expression profiles of the some of them were specified in Populus tremula buds and adult leaves. In poplars, the counterparts of ABI1- and ABI2-like protein phosphatases are lacking, but poplar genomes encode three HAB-like proteins denoted in this work as HAB1, HAB3a and HAB3b, and the counterparts of the two latter ones are absent in Arabidopsis. Nonetheless, they may be present in other species...
March 7, 2018: Journal of Plant Physiology
Sheila A Kitchen, Angela Z Poole, Virginia M Weis
In host-microbe interactions, signaling lipids function in interpartner communication during both the establishment and maintenance of associations. Previous evidence suggests that sphingolipids play a role in the mutualistic cnidarian-Symbiodinium symbiosis. Exogenously applied sphingolipids have been shown to alter this partnership, though endogenous host regulation of sphingolipids by the sphingosine rheostat under different symbiotic conditions has not been characterized. The rheostat regulates levels of pro-survival sphingosine-1-phosphate (S1P) and pro-apoptotic sphingosine (Sph) through catalytic activities of sphingosine kinase (SPHK) and S1P phosphatase (SGPP)...
December 2017: Biological Bulletin
Seeyoung Choi, Paul E Love
Oxidative inactivation of cysteine-dependent Protein Tyrosine Phosphatases (PTPs) by cellular reactive oxygen species (ROS) plays a critical role in regulating signal transduction in multiple cell types. The phosphatase activity of most PTPs depends upon a 'signature' cysteine residue within the catalytic domain that is maintained in the de-protonated state at physiological pH rendering it susceptible to ROS-mediated oxidation. Direct and indirect techniques for detection of PTP oxidation have been developed (Karisch and Neel, 2013)...
January 5, 2018: Bio-protocol
Álvaro Sebastián-Serrano, Laura de Diego-García, David C Henshall, Tobías Engel, Miguel Díaz-Hernández
Hypophosphatasia (HPP) is a rare heritable metabolic bone disease caused by hypomorphic mutations in the ALPL (in human) or Akp2 (in mouse) gene, encoding the tissue-nonspecific alkaline phosphatase (TNAP) enzyme. In addition to skeletal and dental malformations, severe forms of HPP are also characterized by the presence of spontaneous seizures. Initially, these seizures were attributed to an impairment of GABAergic neurotransmission caused by altered vitamin B6 metabolism. However, recent work by our group using knockout mice null for TNAP (TNAP-/-), a well-described model of infantile HPP, has revealed a deregulation of purinergic signaling contributing to the seizure phenotype...
2018: Frontiers in Pharmacology
Gang Xiao, Lai N Chan, Lars Klemm, Daniel Braas, Zhengshan Chen, Huimin Geng, Qiuyi Chen Zhang, Ali Aghajanirefah, Kadriye Nehir Cosgun, Teresa Sadras, Jaewoong Lee, Tamara Mirzapoiazova, Ravi Salgia, Thomas Ernst, Andreas Hochhaus, Hassan Jumaa, Xiaoyan Jiang, David M Weinstock, Thomas G Graeber, Markus Müschen
B cell activation during normal immune responses and oncogenic transformation impose increased metabolic demands on B cells and their ability to retain redox homeostasis. While the serine/threonine-protein phosphatase 2A (PP2A) was identified as a tumor suppressor in multiple types of cancer, our genetic studies revealed an essential role of PP2A in B cell tumors. Thereby, PP2A redirects glucose carbon utilization from glycolysis to the pentose phosphate pathway (PPP) to salvage oxidative stress. This unique vulnerability reflects constitutively low PPP activity in B cells and transcriptional repression of G6PD and other key PPP enzymes by the B cell transcription factors PAX5 and IKZF1...
March 6, 2018: Cell
Palani Dinesh, MahaboobKhan Rasool
The current study investigated the therapeutic effect of berberine (BBR), an alkaloid derivative against IL-21/IL-21R mediated phosphotidyl inositol 3 kinase/protein kinase B (PI3K/Akt) signaling in adjuvant induced arthritic fibroblast-like synoviocytes (AA-FLS) isolated from rats and IL-21 mediated osteoclastogenesis in bone-marrow derived monocytes (BMMs). BBR (15-45 µM) treatment attenuated the gene and protein levels of IL-21R complex. BBR suppressed the levels of IL-21 (20 ng/ml) mediated production of inflammatory cytokines such as: tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and interleukin 23 (IL-23) in AA-FLS cells...
March 14, 2018: Cytokine
Hung-Wei Kan, Jung-Hsien Hsieh, Hsiung-Fei Chien, Yea-Huey Lin, Ti-Yen Yeh, Chi-Chao Chao, Sung-Tsang Hsieh
To understand the pathology and molecular signatures of microangiopathy in diabetic neuropathy, we systemically and quantitatively examined the morphometry of microvascular and nerve pathologies of sural nerves. In the endoneurium of diabetic nerves, prominent microangiopathy evidenced by reduced capillary luminal area, increased capillary basement membrane thickness, and increased proportion of fibrin(+) blood vessels. Furthermore, capillary basement membrane thickness and the proportion of fibrin(+) blood vessels were correlated with small myelinated fiber density in diabetic nerves...
March 16, 2018: Disease Models & Mechanisms
Anna King, Anna Brain, Kelsey Hanson, Justin Dittmann, James Vickers, Carmen Fernandez-Martos
Disruption of leptin signalling has been implicated as playing a role in the development of Alzheimer's disease (AD). Leptin has previously been shown to be affected by amyloid-beta (Aβ)-related signalling; however, pathways that link leptin to the disease pathogenesis have not been determined. To characterize the association between increasing age-dependent Aβ levels with leptin signalling and the vulnerable brain regions in AD, we assessed the mRNA and protein expression profile of leptin and leptin receptor (Ob-Rb) at 9 and 18-month-age in APP/PS1 mice...
March 15, 2018: Metabolic Brain Disease
Xin Li, Di Wang, Chun Yang, Qi Zhou, Suo-Lang Zhuoga, Li-Qiang Wang, Han-Xin Yao, Qin Zhang, Qing Ai, Chen-Xi Yang, Jian-Cheng Xu
BACKGROUND: The development and growth of children influence values of liver function tests. This study aims to establish age- and gender-specific pediatric reference intervals of liver function among Han children in Changchun, China. METHODS: A total of 1394 healthy Han children, aged 2-14 years, were recruited from communities and schools with informed parental consent in Changchun. The levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), alkaline phosphatase (ALP), total protein (TP), albumin (ALB), total bilirubin (TBIL) and direct bilirubin (DBIL) were measured on Hitachi 7600-210 automatic biochemical analyzer...
March 15, 2018: World Journal of Pediatrics: WJP
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