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https://www.readbyqxmd.com/read/29124783/a-key-role-for-rac-and-pak-signaling-in-neutrophil-extracellular-traps-nets-formation-defines-a-new-potential-therapeutic-target
#1
M Gavillet, K Martinod, R Renella, D D Wagner, D A Williams
NET formation in mice (NETosis) is supported by reactive oxygen species (ROS) production by NADPH oxidase and histone hypercitrullination by peptidylarginine deiminase 4 (PAD4). Rac1 and Rac2, expressed in polymorphonuclear neutrophils (PMNs), regulate the cytoskeleton, cell shape, adhesion and migration and are also essential components of the NADPH oxidase complex. We aimed to explore the role of the Rac signaling pathway including the upstream guanosine exchange factor (GEF) activator, Vav, and a downstream effector, the p21-activated kinase, Pak, on NETosis in PMNs using a previously described flow-cytometry-based assay...
November 10, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29092026/copd-gwas-variant-at-19q13-2-in-relation-with-dna-methylation-and-gene-expression
#2
Ivana Nedeljkovic, Lies Lahousse, Elena Carnero Montoro, Alen Faiz, Judith M Vonk, Kim de Jong, Diana A van der Plaat, Cleo C van Diemen, Maarten van den Berge, Ma'en Obeidat, Yohan Bossé, David C Nickle, Andre G Uitterlinden, Joyce B J van Meurs, Bruno H C Stricker, Guy G Brusselle, Dirkje S Postma, H Marike Boezen, Cornelia M van Duijn, Najaf Amin
Chronic obstructive pulmonary disease (COPD) is among the major health burdens in adults. While cigarette smoking is the leading risk factor, a growing number of genetic variations have been discovered to influence disease susceptibility. Epigenetic modifications may mediate the response of the genome to smoking and regulate gene expression. Chromosome 19q13.2 region is associated with both smoking and COPD, yet its functional role is unclear. Our study aimed to determine whether rs7937 (RAB4B, EGLN2), a top genetic variant in 19q13...
October 28, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28942352/myo18a-an-unusual-myosin
#3
REVIEW
Matthew D Buschman, Seth J Field
MYO18A is a divergent member of the myosin family characterized by the presence of an amino-terminal PDZ domain. MYO18A has been found in a few different complexes involved in intracellular transport processes. MYO18A is found in a complex with LURAP1 and MRCK that functions in retrograde treadmilling of actin. It also has been found in a complex with PAK2, βPIX, and GIT1, functioning to transport that protein complex from focal adhesions to the leading edge. Finally, a high proportion of MYO18A is found in complex with GOLPH3 at the trans Golgi, where it functions to promote vesicle budding for Golgi-to-plasma membrane trafficking...
September 18, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/28789679/consensus-strategy-in-genes-prioritization-and-combined-bioinformatics-analysis-for-preeclampsia-pathogenesis
#4
Eduardo Tejera, Maykel Cruz-Monteagudo, Germán Burgos, María-Eugenia Sánchez, Aminael Sánchez-Rodríguez, Yunierkis Pérez-Castillo, Fernanda Borges, Maria Natália Dias Soeiro Cordeiro, César Paz-Y-Miño, Irene Rebelo
BACKGROUND: Preeclampsia is a multifactorial disease with unknown pathogenesis. Even when recent studies explored this disease using several bioinformatics tools, the main objective was not directed to pathogenesis. Additionally, consensus prioritization was proved to be highly efficient in the recognition of genes-disease association. However, not information is available about the consensus ability to early recognize genes directly involved in pathogenesis. Therefore our aim in this study is to apply several theoretical approaches to explore preeclampsia; specifically those genes directly involved in the pathogenesis...
August 8, 2017: BMC Medical Genomics
https://www.readbyqxmd.com/read/28765936/human-cytomegalovirus-mir-us4-5p-promotes-apoptosis-via-downregulation-of-p21-activated-kinase-2-in-cultured-cells
#5
Yaozhong Shao, Ying Qi, Yujing Huang, Zhongyang Liu, Yanping Ma, Xin Guo, Shujuan Jiang, Zhengrong Sun, Qiang Ruan
The human cytomegalovirus (HCMV) encodes ≥26 microRNAs (miRNAs). These miRNAs are utilized by HCMV to regulate its own genes in addition to the genes of the host cell, during infection. The present study first identified p21‑activated kinase 2 (PAK2) as a target of hcmv‑miR‑US4‑5p, via hybrid polymerase chain reaction, which was further verified using a luciferase reporter assay. The protein expression level of PAK2, detected via western blotting, was demonstrated to be directly downregulated by overexpression of hcmv‑miR‑US4‑5p in HEK293, HELF and THP‑1 cells...
October 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28707321/expansion-of-bcr-abl1-cells-requires-pak2-but-not-pak1
#6
Leo Edlinger, Angelika Berger-Becvar, Ingeborg Menzl, Gregor Hoermann, Georg Greiner, Eva Grundschober, Zsuzsanna Bago-Horvath, Wael Al-Zoughbi, Gerald Hoefler, Christine Brostjan, Lars Gille, Richard Moriggl, Andreas Spittler, Veronika Sexl, Andrea Hoelbl-Kovacic
The p21-activated kinases (PAKs) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers and is associated with poor prognosis. To date, PAK deregulation has mainly been studied in solid tumours, where PAK1 and PAK4 are the main isoforms deregulated. We show that PAK1 and PAK2 are the critical isoforms in a BCR/ABL1(+) haematopoietic malignancy. In suspension, leukaemic cells deficient for PAK1 and PAK2 undergo apoptosis, while the loss of either protein is well tolerated...
October 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28596968/piper-betle-l-modulates-senescence-associated-genes-expression-in-replicative-senescent-human-diploid-fibroblasts
#7
Lina Wati Durani, Shy Cian Khor, Jen Kit Tan, Kien Hui Chua, Yasmin Anum Mohd Yusof, Suzana Makpol
Piper betle (PB) is a traditional medicine that is widely used to treat different diseases around Asian region. The leaf extracts contain various bioactive compounds, which were reported to have antidiabetic, antibacterial, anti-inflammatory, antioxidant, and anticancer effects. In this study, the effect of PB aqueous extracts on replicative senescent human diploid fibroblasts (HDFs) was investigated by determining the expressions of senescence-associated genes using quantitative PCR. Our results showed that PB extracts at 0...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28596238/loss-of-%C3%AE-pix-inhibits-focal-adhesion-disassembly-and-promotes-keratinocyte-motility-via-myosin-light-chain-activation
#8
Sho Hiroyasu, Gregory P Stimac, Susan B Hopkinson, Jonathan C R Jones
During healing of the skin, the cytoskeleton of keratinocytes and their matrix adhesions, including focal adhesions (FAs), undergo reorganization. These changes are coordinated by small GTPases and their regulators, including the guanine nucleotide exchange factor β-PIX (also known as ARHGEF7). In fibroblasts, β-PIX activates small GTPases, thereby enhancing migration. In keratinocytes in vitro, β-PIX localizes to FAs. To study β-PIX functions, we generated β-PIX knockdown keratinocytes. During wound closure of β-PIX knockdown cell monolayers, disassembly of FAs is impaired, and their number and size are increased...
July 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28577469/the-interaction-between-hiv-1-nef-and-adaptor-protein-2-reduces-nef-mediated-cd4-t-cell-apoptosis
#9
Rajesh Abraham Jacob, Aaron L Johnson, Emily N Pawlak, Brennan S Dirk, Logan R Van Nynatten, S M Mansour Haeryfar, Jimmy D Dikeakos
Acquired Immune Deficiency Syndrome is characterized by a decline in CD4(+) T cells. Here, we elucidated the mechanism underlying apoptosis in Human Immunodeficiency Virus-1 (HIV-1) infection by examining host apoptotic pathways hijacked by the HIV-1 Nef protein in the CD4(+) T-cell line Sup-T1. Using a panel of Nef mutants unable to bind specific host proteins we uncovered that Nef generates pro- and anti-apoptotic signals. Apoptosis increased upon mutating the motifs involved in the interaction of Nef:AP-1 (NefM20A or NefEEEE62-65AAAA) or Nef:AP-2 (NefLL164/165AA), implying these interactions limit Nef-mediated apoptosis...
September 2017: Virology
https://www.readbyqxmd.com/read/28508421/subversion-of-host-kinases-a-key-network-in-cellular-signaling-hijacked-by-helicobacter-pylori-caga
#10
REVIEW
Nicole Tegtmeyer, Matthias Neddermann, Carmen Isabell Asche, Steffen Backert
Helicobacter pylori is a paradigm of persistent pathogens and major risk factor for developing severe diseases including adenocarcinoma in the human stomach. An important bacterial factor linked to gastric disease progression is the cag pathogenicity island-encoded type-IV secretion system (T4SS) effector protein CagA. Translocated CagA undergoes tyrosine phosphorylation at EPIYA-motifs and then activates or inactivates multiple host signaling proteins in a phosphorylation-dependent and phosphorylation-independent fashion...
May 15, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28408623/protein-kinase-d1-pkd1-phosphorylation-on-ser-203-by-type-i-p21-activated-kinase-pak-regulates-pkd1-localization
#11
Jen-Kuan Chang, Yang Ni, Liang Han, James Sinnett-Smith, Rodrigo Jacamo, Osvaldo Rey, Steven H Young, Enrique Rozengurt
Although PKC-mediated phosphorylation of protein kinase D1 (PKD1) has been extensively characterized, little is known about PKD1 regulation by other upstream kinases. Here we report that stimulation of epithelial or fibroblastic cells with G protein-coupled receptor agonists, including angiotensin II or bombesin, induced rapid and persistent PKD1 phosphorylation at Ser(203), a highly conserved residue located within the PKD1 N-terminal domain. Exposure to PKD or PKC family inhibitors did not prevent PKD1 phosphorylation at Ser(203), indicating that it is not mediated by autophosphorylation...
June 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28216158/resveratrol-regulates-neuronal-glucose-uptake-and-insulin-sensitivity-via-p21-activated-kinase-2-pak2
#12
Pallavi Varshney, Chinmoy Sankar Dey
We have recently reported P21-activated kinase 2 (PAK2), a serine/threonine kinase as a negative regulator of neuronal glucose uptake and insulin sensitivity. Resveratrol (RSV), a natural polyphenol with anti-oxidative, anti-inflammatory and anti-diabetic properties, regulates PAK2 activity in HepG2 and ESC-B5 cell apoptosis. However, regulation of PAK2 by RSV in neuronal insulin signaling pathway, if any, is still unknown. In the present study, RSV treatment significantly increased PAK2 activity under insulin-sensitive and insulin-resistant condition, along with a marked decrease in glucose uptake in differentiated N2A cells...
April 1, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28148733/dynamic-interaction-and-phospho-proteomics-reveal-lck-as-a-major-signaling-hub-of-cd147-in-t-cells
#13
Verena Supper, Ingrid Hartl, Cyril Boulègue, Anna Ohradanova-Repic, Hannes Stockinger
Numerous publications have addressed CD147 as a tumor marker and regulator of cytoskeleton, cell growth, stress response, or immune cell function; however, the molecular functionality of CD147 remains incompletely understood. Using affinity purification, mass spectrometry, and phosphopeptide enrichment of isotope-labeled peptides, we examined the dynamic of the CD147 microenvironment and the CD147-dependent phosphoproteome in the Jurkat T cell line upon treatment with T cell stimulating agents. We identified novel dynamic interaction partners of CD147 such as CD45, CD47, GNAI2, Lck, RAP1B, and VAT1 and, furthermore, found 76 CD147-dependent phosphorylation sites on 57 proteins...
March 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28065575/multiparametric-analysis-of-cell-shape-demonstrates-that-%C3%AE-pix-directly-couples-yap-activation-to-extracellular-matrix-adhesion
#14
Julia E Sero, Chris Bakal
Mechanical signals from the extracellular matrix (ECM) and cellular geometry regulate the nuclear translocation of transcriptional regulators such as Yes-associated protein (YAP). Elucidating how physical signals control the activity of mechanosensitive proteins poses a technical challenge, because perturbations that affect cell shape may also affect protein localization indirectly. Here, we present an approach that mitigates confounding effects of cell-shape changes, allowing us to identify direct regulators of YAP localization...
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28045132/a-second-generation-snp-and-ssr-integrated-linkage-map-and-qtl-mapping-for-the-chinese-mitten-crab-eriocheir-sinensis
#15
Gao-Feng Qiu, Liang-Wei Xiong, Zhi-Ke Han, Zhi-Qiang Liu, Jian-Bin Feng, Xu-Gan Wu, Yin-Long Yan, Hong Shen, Long Huang, Li Chen
The Chinese mitten crab Eriocheir sinensis is the most economically important cultivated crab species in China, and its genome has a high number of chromosomes (2n = 146). To obtain sufficient markers for construction of a dense genetic map for this species, we employed the recently developed specific-locus amplified fragment sequencing (SLAF-seq) method for large-scale SNPs screening and genotyping in a F1 full-sib family of 149 individuals. SLAF-seq generated 127,677 polymorphic SNP markers, of which 20,803 valid markers were assigned into five segregation types and were used together with previous SSR markers for linkage map construction...
January 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/27920252/group-i-paks-promote-skeletal-myoblast-differentiation-in-vivo-and-in-vitro
#16
Giselle A Joseph, Min Lu, Maria Radu, Jennifer K Lee, Steven J Burden, Jonathan Chernoff, Robert S Krauss
Skeletal myogenesis is regulated by signal transduction, but the factors and mechanisms involved are not well understood. The group I Paks Pak1 and Pak2 are related protein kinases and direct effectors of Cdc42 and Rac1. Group I Paks are ubiquitously expressed and specifically required for myoblast fusion in Drosophila We report that both Pak1 and Pak2 are activated during mammalian myoblast differentiation. One pathway of activation is initiated by N-cadherin ligation and involves the cadherin coreceptor Cdo with its downstream effector, Cdc42...
February 15, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27914105/genetic-variants-in-the-integrin-signaling-pathway-genes-predict-cutaneous-melanoma-survival
#17
Hongyu Li, Yanru Wang, Hongliang Liu, Qiong Shi, Yinghui Xu, Wenting Wu, Dakai Zhu, Christopher I Amos, Shenying Fang, Jeffrey E Lee, Jiali Han, Qingyi Wei
To identify genetic variants involved in prognosis of cutaneous melanoma (CM), we investigated associations of single nucleotide polymorphisms (SNPs) of genes in the integrin signaling pathway with CM survival by re-analyzing a published genome-wide association study (GWAS) from The University of Texas M.D. Anderson Cancer Center (MDACC) and then validated significant SNPs in another GWAS from Harvard University. In the MDACC study, 1,148 SNPs were significantly associated with CM-specific survival (CMSS) (p ≤ 0...
March 15, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27889207/dual-site-phosphorylation-of-caspase-7-by-pak2-blocks-apoptotic-activity-by-two-distinct-mechanisms
#18
Scott J Eron, Kishore Raghupathi, Jeanne A Hardy
Caspases, the cysteine proteases that execute apoptosis, are tightly regulated via phosphorylation by a series of kinases. Although all apoptotic caspases work in concert to promote apoptosis, different kinases regulate individual caspases. Several sites of caspase-7 phosphorylation have been reported, but without knowing the molecular details, it has been impossible to exploit or control these complex interactions, which normally prevent unwanted proliferation. During dysregulation, PAK2 kinase plays an alternative anti-apoptotic role, phosphorylating caspase-7 and promoting unfettered cell growth and chemotherapeutic resistance...
January 3, 2017: Structure
https://www.readbyqxmd.com/read/27648129/pak2-promotes-migration-and-proliferation-of-salivary-gland-adenoid-cystic-carcinoma
#19
Wei-Wei Deng, Lei Wu, Lin-Lin Bu, Jian-Feng Liu, Yi-Cun Li, Si-Rui Ma, Guang-Tao Yu, Liang Mao, Wen-Feng Zhang, Zhi-Jun Sun
P21 activated kinase 2 (PAK2) is a member of Group I PAKs family and highly expressed in various cancers. Current studies have demonstrated that PAK2 played a pivotal role in tumor progression. However, the role of PAK2 in salivary adenoid cystic carcinoma is still unclear. This study aims to explore the expression and the function of PAK2 in AdCC. Human salivary gland tissue microarray, including 18 normal salivary glands (NSG), 12 pleomorphic adenoma (PMA) and 72 AdCC, and immunohistochemistry were used to evaluate the expression of PAK2...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27560372/d186-d190-is-an-allele-dependent-determinant-of-hiv-1-nef-function
#20
Andrea Imle, Bettina Stolp, Verena Böhmer, Matthias Geyer, Erez Raz, Oliver T Fackler
The HIV-1 pathogenesis factor Nef interacts with numerous ligands to affect cellular vesicular transport, signal transduction and cytoskeletal dynamics. While most Nef functions depend on multivalent protein interaction motifs, disrupting actin dynamics requires a motif that specifically recruits the host kinase PAK2. An adjacent aspartate was recently predicted to mediate Nef-β-catenin interactions. We report here that β-catenin can be co-immunoprecipitated with Nef.GFP from Jurkat T cell lysates. This association is conserved among lentiviral Nef proteins but does not involve classical Nef protein interaction motifs, including the critical aspartate...
November 2016: Virology
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