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https://www.readbyqxmd.com/read/29121083/structural-and-biochemical-analysis-of-atypically-low-dephosphorylating-activity-of-human-dual-specificity-phosphatase-28
#1
Bonsu Ku, Won Hong, Chae Won Keum, Myeongbin Kim, Hyunyeol Ryu, Donghwan Jeon, Ho-Chul Shin, Jae Hoon Kim, Seung Jun Kim, Seong Eon Ryu
Dual-specificity phosphatases (DUSPs) constitute a subfamily of protein tyrosine phosphatases, and are intimately involved in the regulation of diverse parameters of cellular signaling and essential biological processes. DUSP28 is one of the DUSP subfamily members that is known to be implicated in the progression of hepatocellular and pancreatic cancers, and its biological functions and enzymatic characteristics are mostly unknown. Herein, we present the crystal structure of human DUSP28 determined to 2.1 Å resolution...
2017: PloS One
https://www.readbyqxmd.com/read/29106959/two-intermediate-states-of-the-conformational-switch-in-dual-specificity-phosphatase-13a
#2
Chun Hwa Wei, Hee Gyeong Min, Myeongbin Kim, Gwan Hee Kim, Ha-Jung Chun, Seong Eon Ryu
Dual specificity phosphatases (DUSPs) include MAP kinase phosphatases and atypical dual specificity phosphatases and mediate cell growth and differentiation, brain function, and immune responses. They serve as targets for drug development against cancers, diabetes and depression. Several DUSPs have non-canonical conformation of the central β-sheet and active site loops, suggesting that they may have conformational switch that is related to the regulation of enzyme activity. Here, we determined the crystal structure of DUSP13a, and identified two different structures that represent intermediates of the postulated conformational switch...
October 26, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29062315/dual-specificity-phosphatase-12-targets-p38-map-kinase-to-regulate-macrophage-response-to-intracellular-bacterial-infection
#3
Sharol Su Lei Cho, Jian Han, Sharmy J James, Chin Wen Png, Madhushanee Weerasooriya, Sylvie Alonso, Yongliang Zhang
The mitogen-activated protein kinase (MAPK) cascades are activated in innate immune cells such as macrophages upon the detection of microbial infection, critically regulating the expression of proinflammatory cytokines and chemokines such as TNF-α, IL-6, and MCP-1. As a result, activation of MAPKs is tightly regulated to ensure appropriate and adequate immune responses. Dual-specificity phosphatases (DUSPs) are a family of proteins which specifically dephosphorylates threonine and tyrosine residues essential for MAPK activation to negatively regulate their activation...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29018280/dusp5-functions-as-a-feedback-regulator-of-tnf%C3%AE-induced-erk1-2-dephosphorylation-and-inflammatory-gene-expression-in-adipocytes
#4
Justine S Habibian, Mitra Jefic, Rushita A Bagchi, Robert H Lane, Robert A McKnight, Timothy A McKinsey, Ron F Morrison, Bradley S Ferguson
Adipose tissue inflammation is a central pathological element that regulates obesity-mediated insulin resistance and type II diabetes. Evidence demonstrates that extracellular signal-regulated kinase (ERK 1/2) activation (i.e. phosphorylation) links tumor necrosis factor α (TNFα) to pro-inflammatory gene expression in the nucleus. Dual specificity phosphatases (DUSPs) inactivate ERK 1/2 through dephosphorylation and can thus inhibit inflammatory gene expression. We report that DUSP5, an ERK1/2 phosphatase, was induced in epididymal white adipose tissue (WAT) in response to diet-induced obesity...
October 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28915331/dual-specificity-phosphatase-5-substrate-interaction-a-mechanistic-perspective
#5
Raman G Kutty, Marat R Talipov, Robert D Bongard, Rachel A Jones Lipinski, Noreena L Sweeney, Daniel S Sem, Rajendra Rathore, Ramani Ramchandran
The mammalian genome contains approximately 200 phosphatases that are responsible for catalytically removing phosphate groups from proteins. In this review, we discuss dual specificity phosphatase 5 (DUSP5). DUSP5 belongs to the dual specificity phosphatase (DUSP) family, so named after the family members' abilities to remove phosphate groups from serine/threonine and tyrosine residues. We provide a comparison of DUSP5's structure to other DUSPs and, using molecular modeling studies, provide an explanation for DUSP5's mechanistic interaction and specificity toward phospho-extracellular regulated kinase, its only known substrate...
September 12, 2017: Comprehensive Physiology
https://www.readbyqxmd.com/read/28910386/dusp5-and-dusp6-two-erk-specific-phosphatases-are-markers-of-a-higher-mapk-signaling-activation-in-braf-mutated-thyroid-cancers
#6
Camille Buffet, Karine Hecale-Perlemoine, Léopoldine Bricaire, Florent Dumont, Camille Baudry, Frédérique Tissier, Jérôme Bertherat, Beatrix Cochand-Priollet, Marie-Laure Raffin-Sanson, Françoise Cormier, Lionel Groussin
BACKGROUND: Molecular alterations of the MAPK pathway are frequently observed in papillary thyroid carcinomas (PTCs). It leads to a constitutive activation of the signalling pathway through an increase in MEK and ERK phosphorylation. ERK is negatively feedback-regulated by Dual Specificity Phosphatases (DUSPs), especially two ERK-specific DUSPs, DUSP5 (nuclear) and DUSP6 (cytosolic). These negative MAPK regulators may play a role in thyroid carcinogenesis. METHODS: MAPK pathway activation was analyzed in 11 human thyroid cancer cell lines...
2017: PloS One
https://www.readbyqxmd.com/read/28822081/expression-profiling-of-the-map-kinase-phosphatase-family-reveals-a-role-for-dusp1-in-the-glioblastoma-stem-cell-niche
#7
Bradley N Mills, George P Albert, Marc W Halterman
The dual specificity phosphatases (DUSPs) constitute a family of stress-induced enzymes that provide feedback inhibition on mitogen-activated protein kinases (MAPKs) critical in key aspects of oncogenic signaling. While described in other tumor types, the landscape of DUSP mRNA expression in glioblastoma (GB) remains largely unexplored. Interrogation of the REpository for Molecular BRAin Neoplasia DaTa (REMBRANDT) revealed induction (DUSP4, DUSP6), repression (DUSP2, DUSP7-9), or mixed (DUSP1, DUSP5, DUSP10, DUSP15) DUSP transcription of select DUSPs in bulk tumor specimens...
August 18, 2017: Cancer Microenvironment: Official Journal of the International Cancer Microenvironment Society
https://www.readbyqxmd.com/read/28819544/hypoxia-downregulates-mapk-erk-but-not-stat3-signaling-in-ros-dependent-and-hif-1-independent-manners-in-mouse-embryonic-stem-cells
#8
Jan Kučera, Julie Netušilová, Stanislava Sladeček, Martina Lánová, Ondřej Vašíček, Kateřina Štefková, Jarmila Navrátilová, Lukáš Kubala, Jiří Pacherník
Hypoxia is involved in the regulation of stem cell fate, and hypoxia-inducible factor 1 (HIF-1) is the master regulator of hypoxic response. Here, we focus on the effect of hypoxia on intracellular signaling pathways responsible for mouse embryonic stem (ES) cell maintenance. We employed wild-type and HIF-1α-deficient ES cells to investigate hypoxic response in the ERK, Akt, and STAT3 pathways. Cultivation in 1% O2 for 24 h resulted in the strong dephosphorylation of ERK and its upstream kinases and to a lesser extent of Akt in an HIF-1-independent manner, while STAT3 phosphorylation remained unaffected...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28797290/role-and-regulation-of-mkp-1-in-airway-inflammation
#9
REVIEW
Seyed M Moosavi, Pavan Prabhala, Alaina J Ammit
Mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is a protein with anti-inflammatory properties and the archetypal member of the dual-specificity phosphatases (DUSPs) family that have emerged over the past decade as playing an instrumental role in the regulation of airway inflammation. Not only does MKP-1 serve a critical role as a negative feedback effector, controlling the extent and duration of pro-inflammatory MAPK signalling in airway cells, upregulation of this endogenous phosphatase has also emerged as being one of the key cellular mechanism responsible for the beneficial actions of clinically-used respiratory medicines, including β2-agonists, phosphodiesterase inhibitors and corticosteroids...
August 10, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28743632/comparative-analysis-of-dual-specificity-protein-phosphatase-genes-1-2-and-5-in-response-to-immune-challenges-in-japanese-flounder-paralichthys-olivaceus
#10
Shuo Li, Gaixiang Hao, Jiafang Li, Weijiao Peng, Xuyun Geng, Jinsheng Sun
Dual-specificity MAP kinase (MAPK) phosphatases (DUSPs) are well-established negative modulators in regulating MAPK signaling in mammalian cells and tissues. Our previous studies have shown the involvement of DUSP6 in regulating innate immunity in Japanese flounder Paralichthys olivaceus. In order to gain a better understanding of the role of DUSPs in fish innate immunity, in the present study we identified and characterized three additional DUSP genes including DUSP1, 2 and 5 in P. olivaceus. The three Japanese flounder DUSP proteins share common domain structures composed of a conserved N-terminal Rhodanase/CDC25 domain and a C-terminal catalytic phosphatase domain, while they show only less than 26% sequence identities, indicating that they may have different substrate selectivity...
September 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28652251/hypoxia-induced-downregulation-of-dusp-2-phosphatase-drives-colon-cancer-stemness
#11
Pei-Chi Hou, Yo-Hua Li, Shih-Chieh Lin, Shau-Chieh Lin, Jenq-Chang Lee, Bo-Wen Lin, Jing-Ping Liou, Jang-Yang Chang, Ching-Chuan Kuo, Yi-Min Liu, H Sunny Sun, Shaw-Jenq Tsai
Cancer stem-like cells (CSC) evolve to overcome the pressures of reduced oxygen, nutrients or chemically induced cell death, but the mechanisms driving this evolution are incompletely understood. Here, we report that hypoxia-mediated downregulation of the dual specificity phosphatase 2 (DUSP2) is critical for the accumulation of CSC in colorectal cancer. Reduced expression of DUSP2 led to overproduction of COX-2-derived prostaglandin E2, which promoted cancer stemness via the EP2/EP4 signaling pathways. Genetic and pharmacological inhibition of PGE2 biosynthesis or signal transduction ameliorated loss-of-DUSP2-induced tumor growth and cancer stemness...
August 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28642802/perk-dependent-defective-tcr-mediated-activation-of-cd4-t-cells-in-end-stage-renal-disease-patients
#12
Ling Huang, Nicolle H R Litjens, Nynke M Kannegieter, Mariska Klepper, Carla C Baan, Michiel G H Betjes
BACKGROUND: Patients with end-stage renal disease (ESRD) have an impaired immune response with a prematurely aged T-cell system. Mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK) and p38, regulate diverse cellular programs by transferring extracellular signals into an intracellular response. T cell receptor (TCR)-induced phosphorylation of ERK (pERK) may show an age-associated decline, which can be reversed by inhibiting dual specific phosphatase (DUSP) 6, a cytoplasmic phosphatase with substrate specificity to dephosphorylate pERK...
2017: Immunity & Ageing: I & A
https://www.readbyqxmd.com/read/28631302/l-hcy-induced-cathepsin-v-mediates-the-vascular-endothelial-inflammation-in-hyperhomocysteinemia
#13
Yi-Ping Leng, Ye-Shuo Ma, Xiao-Gang Li, Rui-Fang Chen, Ping-Yu Zeng, Xiao-Hui Li, Cheng-Feng Qiu, Ya-Pei Li, Zhen Zhang, Alex F Chen
BACKGROUND AND PURPOSE: Vascular inflammation, including the expression of inflammatory cytokines in endothelial cells, plays a critical role in hyperhomocysteinemia-associated vascular diseases. Cathepsin V, specifically expressed in humans, is involved in vascular diseases through its elastolytic and collagenolytic activities. The aim of this study was to determine the effects of cathepsin V on the L-homocysteine (L-Hcy)-induced vascular inflammation. EXPERIMENTAL APPROACH: A high methionine diet-induced hyperhomocysteinemic mice model was used to assess the cathepsin V expression and vascular inflammation...
June 20, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28550735/clarithromycin-inhibits-tnf-%C3%AE-induced-muc5ac-mucin-gene-expression-via-the-mkp-1-p38mapk-dependent-pathway
#14
Said Ahmad Shah, Hajime Ishinaga, Kazuhiko Takeuchi
Clarithromycin is a 14-membered macrolide antibiotic. Low-dose, long-term macrolide therapy is effective in patients with chronic airway diseases, such as diffuse panbronchitis, chronic bronchitis, and chronic sinusitis. However, the mechanism underlying this clinical efficacy remains unclear. The dual specificity phosphatase MKP-1 (MAPK phosphatase-1), also called DUSP (dual specificity phosphatase-1), was initially identified as an in vitro ERK-specific phosphatase, but depending on the cell type, it can also dephosphorylate other members of the MAPK family, such as p38 and JNK, and thus suppress downstream signaling of these kinases...
May 24, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28460125/how-protein-kinase-a-activates-canonical-tyrosine-kinase-signaling-pathways-to-promote-granulosa-cell-differentiation
#15
Nathan C Law, Elyse M Donaubauer, Anthony J Zeleznik, Mary Hunzicker-Dunn
Protein kinase A (PKA) has recently been shown to mimic the actions of follicle-stimulating hormone (FSH) by activating signaling pathways that promote granulosa cell (GC) differentiation, such as phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). We sought to elucidate the mechanism by which PKA, a Ser/Thr kinase, intersected the PI3K/AKT and MAPK/ERK pathways that are canonically activated by receptor tyrosine kinases (RTKs). Our results show that for both of these pathways, the RTK is active in the absence of FSH yet signaling down the pathways to commence transcriptional responses requires FSH-stimulated PKA activation...
July 1, 2017: Endocrinology
https://www.readbyqxmd.com/read/28413926/dusp-1-gene-expression-is-not-regulated-by-promoter-methylation-in-diabetes-associated-cardiac-hypertrophy
#16
Gurinder Bir Singh, Sanskriti Khanna, Satish K Raut, Saurabh Sharma, Rajni Sharma, Madhu Khullar
BACKGROUND: The exact mechanism causing decreased expression of the dual specific phosphatase-1 ( DUSP-1) gene in diabetes-associated cardiac hypertrophy is not known. DNA promoter methylation is often associated with decreased gene expression in many diseases including cardiovascular diseases. So, we investigated whether epigenetic silencing via promoter methylation is involved in the decreased expression of DUSP-1 in diabetes-associated cardiac hypertrophy. METHODS: Real-time polymerase chain reaction (PCR) and Western blotting confirmed the down regulation of the DUSP-1 gene at transcriptional and translational levels...
May 2017: Therapeutic Advances in Cardiovascular Disease
https://www.readbyqxmd.com/read/28389334/loss-of-dusp3-activity-radiosensitizes-human-tumor-cell-lines-via-attenuation-of-dna-repair-pathways
#17
Thompson E P Torres, Lilian C Russo, Alexsandro Santos, Gabriela R Marques, Yuli T Magalhaes, Sartaj Tabassum, Fabio L Forti
BACKGROUND: Radiotherapy causes the regression of many human tumors by increasing DNA damage, and the novel molecular mechanisms underlying the genomic instability leading to cancer progression and metastasis must be elucidated. Atypical dual-specificity phosphatase 3 (DUSP3) has been shown to down-regulate mitogen-activated protein kinases (MAPKs) to control the proliferation and apoptosis of human cancer cells. We have recently identified novel molecular targets of DUSP3 that function in DNA damage response and repair; however, whether DUSP3 affects these processes remains unknown...
July 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28384165/ramadan-fasting-in-saudi-arabia-is-associated-with-altered-expression-of-clock-dusp-and-il-1alpha-genes-as-well-as-changes-in-cardiometabolic-risk-factors
#18
Ghada M A Ajabnoor, Suhad Bahijri, Noor Ahmad Shaik, Anwar Borai, Aliaa A Alamoudi, Jumana Y Al-Aama, George P Chrousos
BACKGROUND: During the fasting month of Ramadan, practicing Saudis develop severe disturbances in sleeping and feeding patterns. Concomitantly, cortisol circadian rhythm is abolished, diurnal cortisol levels are elevated and circulating levels of several adipokines are altered favouring insulin resistance. AIM: To examine changes in the expression of CLOCK and glucocorticoid-controlled genes, such as DUSP1 and IL-1α in Saudi adults before and during Ramadan, and to investigate possible associations with selected cardiometabolic risk factors...
2017: PloS One
https://www.readbyqxmd.com/read/28283554/impaired-dual-specificity-protein-phosphatase-dusp4-reduces-corticosteroid-sensitivity
#19
Yoshiki Kobayashi, Kazuhiro Ito, Akira Kanda, Koich Tomoda, Nicolas Mercado, Peter J Barnes
We have reported that phosphorylation of the glucocorticoid receptor (GR) at Ser(226) reduces GR nuclear translocation, resulting in corticosteroid insensitivity in patients with severe asthmas. A serine/threonine protein phosphatase 2A, which regulates c-Jun N-terminal kinase (JNK) 1 and GR-Ser(226) signaling, is involved in this mechanism. Here, we further explored protein kinase dual-specificity phosphatases (DUSPs) with the ability to dephosphorylate JNK, and identified DUSP4 as a phosphatase involved in the regulation of corticosteroid sensitivity...
May 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28245560/the-regulations-of-deubiquitinase-usp15-and-its-pathophysiological-mechanisms-in-diseases
#20
REVIEW
Chon-Kit Chou, Yu-Ting Chang, Michal Korinek, Yei-Tsung Chen, Ya-Ting Yang, Steve Leu, I-Ling Lin, Chin-Ju Tang, Chien-Chih Chiu
Deubiquitinases (DUBs) play a critical role in ubiquitin-directed signaling by catalytically removing the ubiquitin from substrate proteins. Ubiquitin-specific protease 15 (USP15), a member of the largest subfamily of cysteine protease DUBs, contains two conservative cysteine (Cys) and histidine (His) boxes. USP15 harbors two zinc-binding motifs that are essential for recognition of poly-ubiquitin chains. USP15 is grouped into the same category with USP4 and USP11 due to high degree of homology in an N-terminal region consisting of domains present in ubiquitin-specific proteases (DUSP) domain and ubiquitin-like (UBL) domain...
February 24, 2017: International Journal of Molecular Sciences
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