CDC42 Binds PAK4 Via an Extended Gtpase-Effector Interface
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Screening Differentially Expressed Genes of Pancreatic Cancer Between Mongolian and Han People Using Bioinformatics Technology
Screening differentially expressed genes of pancreatic cancer between Mongolian and Han people using bioinformatics technology Jiasheng Xu First Aliated Hospital of Nanchang University Kaili Liao Second Aliated Hospital of Nanchang University ZHONGHUA FU First Aliated Hospital of Nanchang University ZHENFANG XIONG ( [email protected] ) The First Aliated Hospital of Nanchang University https://orcid.org/0000-0003-2062-9204 Research article Keywords: Pancreatic ductal cell carcinoma; Affymetrix gene expression prole; Gene differential expression; GO analysis; Pathway analysis; Mongolian Posted Date: October 14th, 2019 DOI: https://doi.org/10.21203/rs.2.11118/v2 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published at BMC Cancer on April 9th, 2020. See the published version at https://doi.org/10.1186/s12885-020-06722-7. Page 1/19 Abstract Objective: To screen and analyze differentially expressed genes in pancreatic carcinoma tissues taken from Mongolian and Han patients by Affymetrix Genechip. Methods: Pancreatic ductal cell carcinoma tissues were collected from the Mongolian and Han patients undergoing resection in the Second Aliated Hospital of Nanchang University from March 2015 to May 2018 and the total RNA was extracted. Differentially expressed genes were selected from the total RNA qualied by Nanodrop 2000 and Agilent 2100 using Affymetrix and a cartogram was drawn; The gene ontology (GO) analysis and Pathway analysis were used for the collection and analysis of biological information of these differentially expressed genes. Finally, some differentially expressed genes were veried by real-time PCR. Results: Through the microarray analysis of gene expression, 970 differentially expressed genes were detected by comparing pancreatic cancer tissue samples between Mongolian and Han patients. -
An in Cellulo-Derived Structure of PAK4 in Complex with Its Inhibitor Inka1
ARTICLE Received 27 May 2015 | Accepted 21 Sep 2015 | Published 26 Nov 2015 DOI: 10.1038/ncomms9681 OPEN An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1 Yohendran Baskaran1,*, Khay C. Ang1,2,*, Praju V. Anekal1, Wee L. Chan1, Jonathan M. Grimes3,4, Ed Manser1,5,6 & Robert C. Robinson1,2 PAK4 is a metazoan-specific kinase acting downstream of Cdc42. Here we describe the structure of human PAK4 in complex with Inka1, a potent endogenous kinase inhibitor. Using single mammalian cells containing crystals 50 mm in length, we have determined the in cellulo crystal structure at 2.95 Å resolution, which reveals the details of how the PAK4 catalytic domain binds cellular ATP and the Inka1 inhibitor. The crystal lattice consists only of PAK4– PAK4 contacts, which form a hexagonal array with channels of 80 Å in diameter that run the length of the crystal. The crystal accommodates a variety of other proteins when fused to the kinase inhibitor. Inka1–GFP was used to monitor the process crystal formation in living cells. Similar derivatives of Inka1 will allow us to study the effects of PAK4 inhibition in cells and model organisms, to allow better validation of therapeutic agents targeting PAK4. 1 Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Biopolis, Proteos Building, 61 Biopolis Drive, 8-15, Singapore 138673, Singapore. 2 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore. 3 Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. -
Dysregulation of Rho Gtpases in the Apix/Arhgef6 Mouse Model of X
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2011 Dysregulation of Rho GTPases in the Pix/Arhgef6 mouse model of X-linked intellectual disability is paralleled by impaired structural and synaptic plasticity and cognitive deficits Ramakers, G J A ; Wolfer, D ; Rosenberger, G ; Kuchenbecker, K ; Kreienkamp, H J ; Prange-Kiel, J ; Rune, G ; Richter, K ; Langnaese, K ; Masneuf, S ; Bösl, M R ; Fischer, K D ; Krugers, H J ; Lipp, H P ; van Galen, E ; Kutsche, K Abstract: Mutations in the ARHGEF6 gene, encoding the guanine nucleotide exchange factor PIX/Cool- 2 for the Rho GTPases Rac1 and Cdc42, cause X-linked intellectual disability (ID) in humans. We show here that Pix/Arhgef6 is primarily expressed in neuropil regions of the hippocampus. To study the role of Pix/Arhgef6 in neuronal development and plasticity and gain insight into the pathogenic mechanisms underlying ID, we generated Pix/Arhgef6-deficient mice. Gross brain structure in these mice appeared to be normal; however, analysis of Golgi-Cox-stained pyramidal neurons revealed an increase in both dendritic length and spine density in the hippocampus, accompanied by an overall loss in spine synapses. Early-phase long-term potentiation was reduced and long-term depression was increased in the CA1 hippocampal area of Pix/Arhgef6-deficient animals. Knockout animals exhibited impaired spatial and complex learning and less behavioral control in mildly stressful situations, suggesting that this model mimics the human ID phenotype. The structural and electrophysiological alterations in the hippocampus were accompanied by a significant reduction in active Rac1 and Cdc42, but not RhoA. -
The Mental Retardation Protein PAK3 Contributes to Synapse Formation and Plasticity in Hippocampus
10816 • The Journal of Neuroscience, December 1, 2004 • 24(48):10816–10825 Development/Plasticity/Repair The Mental Retardation Protein PAK3 Contributes to Synapse Formation and Plasticity in Hippocampus Bernadett Boda, Stefano Alberi, Irina Nikonenko, Roxanne Node-Langlois, Pascal Jourdain, Marlyse Moosmayer, Lorena Parisi-Jourdain, and Dominique Muller Department of Basic Neuroscience, Centre Medical Universitaire, 1211 Geneva 4, Switzerland Mutations of the gene coding for PAK3 (p21-activated kinase 3) are associated with X-linked, nonsyndromic forms of mental retardation (MRX) in which the only distinctive clinical feature is the cognitive deficit. The mechanisms through which PAK3 mutation produces the mental handicap remain unclear, although an involvement in the mechanisms that regulate the formation or plasticity of synaptic networks has been proposed. Here we show, using a transient transfection approach, that antisense and small interfering RNA-mediated suppression of PAK3 or expression of a dominant-negative PAK3 carrying the human MRX30 mutation in rat hippocampal organotypic slice cultures results in the formation of abnormally elongated dendritic spines and filopodia-like protrusions and a decrease in mature spine synapses. Ultrastructural analysis of the changes induced by expression of PAK3 carrying the MRX30 mutation reveals that many elongated spines fail to express postsynaptic densities or contact presynaptic terminals. These defects are associated with a reduced spontaneous activity, altered expression of AMPA-type glutamate receptors, and defective long-term potentiation. Together, these data identify PAK3 as a key regulator of synapse formation and plasticity in the hippocampus and support interpretations that these defects might contribute to the cognitive deficits underlying this form of mental retardation. -
Phospho-PAK4 (Ser474)/PAK5 (Ser602)/PAK6 (Ser560) Antibody Detects Endogenous 12
Revision 1 C 0 2 - t Phospho-PAK4 (Ser474)/PAK5 a e r o t (Ser602)/PAK6 (Ser560) Antibody S Orders: 877-616-CELL (2355) [email protected] Support: 877-678-TECH (8324) 1 4 Web: [email protected] 2 www.cellsignal.com 3 # 3 Trask Lane Danvers Massachusetts 01923 USA For Research Use Only. Not For Use In Diagnostic Procedures. Applications: Reactivity: Sensitivity: MW (kDa): Source: UniProt ID: Entrez-Gene Id: WB H M GP Endogenous 72 (PAK4). 82 Rabbit Q9NQU5, Q9P286, O96013 56924, 57144, 10298 (PAK6). 90 (PAK5). p y g y p y Product Usage Information pivotal role in regulating the activity and function of PAK4 (10). PAK family members are widely expressed, and often overexpressed in human cancer (11,12). Application Dilution 1. Knaus, U.G. and Bokoch, G.M. (1998) Int. J. Biochem. Cell Biol. 30, 857-62. 2. Daniels, R.H. et al. (1998) EMBO J. 17, 754-64. Western Blotting 1:1000 3. King, C.C. et al. (2000) J. Biol. Chem. 275, 41201-9. 4. Manser, E. et al. (1997) Mol. Cell. Biol. 17, 1129-43. Storage 5. Gatti, A. et al. (1999) J. Biol. Chem. 274, 8022-8. 6. Lei, M. et al. (2000) Cell 102, 387-97. Supplied in 10 mM sodium HEPES (pH 7.5), 150 mM NaCl, 100 µg/ml BSA and 50% 7. Chong, C. et al. (2001) J. Biol. Chem. 276, 17347-53. glycerol. Store at –20°C. Do not aliquot the antibody. 8. Zhao, Z. et al. (2000) Mol. Cell. Biol. 20, 3906-17. 9. -
Screening of Potential Genes and Transcription Factors Of
ANIMAL STUDY e-ISSN 1643-3750 © Med Sci Monit, 2018; 24: 503-510 DOI: 10.12659/MSM.907445 Received: 2017.10.08 Accepted: 2018.01.01 Screening of Potential Genes and Transcription Published: 2018.01.25 Factors of Postoperative Cognitive Dysfunction via Bioinformatics Methods Authors’ Contribution: ABE 1 Yafeng Wang 1 Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical Study Design A AB 1 Ailan Huang University, Nanning, Guangxi, P.R. China Data Collection B 2 Department of Gynecology, People’s Hospital of Guangxi Zhuang Autonomous Statistical Analysis C BEF 1 Lixia Gan Region, The First Affiliated Hospital of Guangxi Medical University, Nanning, Data Interpretation D BCF 1 Yanli Bao Guangxi, P.R. China Manuscript Preparation E BDF 1 Weilin Zhu 3 Department of Anesthesiology, The First Affiliated Hospital of Guangxi Medical Literature Search F University, Nanning, Guangxi, P.R. China Funds Collection G EF 1 Yanyan Hu AE 1 Li Ma CF 2 Shiyang Wei DE 3 Yuyan Lan Corresponding Author: Yafeng Wang, e-mail: [email protected] Source of support: Departmental sources Background: The aim of this study was to explore the potential genes and transcription factors involved in postoperative cognitive dysfunction (POCD) via bioinformatics analysis. Material/Methods: GSE95070 miRNA expression profiles were downloaded from Gene Expression Omnibus database, which in- cluded five hippocampal tissues from POCD mice and controls. Moreover, the differentially expressed miRNAs (DEMs) between the two groups were identified. In addition, the target genes of DEMs were predicted using Targetscan 7.1, followed by protein-protein interaction (PPI) network construction, functional enrichment anal- ysis, pathway analysis, and prediction of transcription factors (TFs) targeting the potential targets. -
A De Novo Mutation in the X-Linked PAK3 Gene Is the Underlying Cause of Intellectual Disability and Macrocephaly in Monozygotic Twins
European Journal of Medical Genetics xxx (2017) 1e5 Contents lists available at ScienceDirect European Journal of Medical Genetics journal homepage: http://www.elsevier.com/locate/ejmg A de novo mutation in the X-linked PAK3 gene is the underlying cause of intellectual disability and macrocephaly in monozygotic twins Jozef Hertecant a, b, Makanko Komara c, Aslam Nagi a, Olfat Al-Zaabi d, Waseem Fathallah e, Hong Cui f, Yaping Yang f, Christine M. Eng f, Mohammad Al Sorkhy g, * Mohammad A. Ghattas g, Lihadh Al-Gazali b, Bassam R. Ali c, a Department of Paediatrics, Tawam Hospital, Al-Ain, United Arab Emirates b Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates c Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates d Fujairah Hospital, Fujairah, United Arab Emirates e Mafraq Hospital, Abu Dhabi, United Arab Emirates f Department of Molecular and Human Genetics, Baylor College of Medicine, Baylor Miraca Genetics Laboratories, Houston, TX 77030, USA g College of Pharmacy, Al Ain University of Science and Technology, Al-Ain, United Arab Emirates article info abstract Article history: Pathogenic variants in theP21 protein (Cdc42/Rac)-activated kinase 3gene (PAK3) lead to a rare non Received 29 May 2016 syndromic X-linked intellectual disability. The protein encoded by this gene forms an activated complex Received in revised form with GTP-bound RAS-like (P21), CDC2 and RAC1 proteins which then mediates a variety of cellular 17 January 2017 processes. So far, mutations in PAK3 gene have been reported in few families affected with intellectual Accepted 18 January 2017 disability associated with neurological manifestations such as speech defect, behavioral problem, brain Available online xxx structural abnormalities, microcephaly and cerebral palsy. -
Transcriptome Analysis of Human Diabetic Kidney Disease
ORIGINAL ARTICLE Transcriptome Analysis of Human Diabetic Kidney Disease Karolina I. Woroniecka,1 Ae Seo Deok Park,1 Davoud Mohtat,2 David B. Thomas,3 James M. Pullman,4 and Katalin Susztak1,5 OBJECTIVE—Diabetic kidney disease (DKD) is the single cases, mild and then moderate mesangial expansion can be leading cause of kidney failure in the U.S., for which a cure has observed. In general, diabetic kidney disease (DKD) is not yet been found. The aim of our study was to provide an considered a nonimmune-mediated degenerative disease unbiased catalog of gene-expression changes in human diabetic of the glomerulus; however, it has long been noted that kidney biopsy samples. complement and immunoglobulins sometimes can be de- — tected in diseased glomeruli, although their role and sig- RESEARCH DESIGN AND METHODS Affymetrix expression fi arrays were used to identify differentially regulated transcripts in ni cance is not clear (4). 44 microdissected human kidney samples. The DKD samples were The understanding of DKD has been challenged by multi- significant for their racial diversity and decreased glomerular ple issues. First, the diagnosis of DKD usually is made using filtration rate (~20–30 mL/min). Stringent statistical analysis, using clinical criteria, and kidney biopsy often is not performed. the Benjamini-Hochberg corrected two-tailed t test, was used to According to current clinical practice, the development of identify differentially expressed transcripts in control and diseased albuminuria in patients with diabetes is sufficient to make the glomeruli and tubuli. Two different Web-based algorithms were fi diagnosis of DKD (5). We do not understand the correlation used to de ne differentially regulated pathways. -
Proximity Proteomics Identifies PAK4 As a Component of Afadin–Nectin
ARTICLE https://doi.org/10.1038/s41467-021-25011-w OPEN Proximity proteomics identifies PAK4 as a component of Afadin–Nectin junctions Yohendran Baskaran 1,5, Felicia Pei-Ling Tay2,5, Elsa Yuen Wai Ng1, Claire Lee Foon Swa 3, Sheena Wee 3, ✉ Jayantha Gunaratne3 & Edward Manser 1,4 Human PAK4 is an ubiquitously expressed p21-activated kinase which acts downstream of Cdc42. Since PAK4 is enriched in cell-cell junctions, we probed the local protein environment 1234567890():,; around the kinase with a view to understanding its location and substrates. We report that U2OS cells expressing PAK4-BirA-GFP identify a subset of 27 PAK4-proximal proteins that are primarily cell-cell junction components. Afadin/AF6 showed the highest relative biotin labelling and links to the nectin family of homophilic junctional proteins. Reciprocally >50% of the PAK4-proximal proteins were identified by Afadin BioID. Co-precipitation experiments failed to identify junctional proteins, emphasizing the advantage of the BioID method. Mechanistically PAK4 depended on Afadin for its junctional localization, which is similar to the situation in Drosophila. A highly ranked PAK4-proximal protein LZTS2 was immuno- localized with Afadin at cell-cell junctions. Though PAK4 and Cdc42 are junctional, BioID analysis did not yield conventional cadherins, indicating their spatial segregation. To identify cellular PAK4 substrates we then assessed rapid changes (12’) in phospho-proteome after treatment with two PAK inhibitors. Among the PAK4-proximal junctional proteins seventeen PAK4 sites were identified. We anticipate mammalian group II PAKs are selective for the Afadin/nectin sub-compartment, with a demonstrably distinct localization from tight and cadherin junctions. -
Whole Exome Sequencing of Thymic Neuroendocrine Tumor With
176:2 Y Li, Y Peng and others Sequencing thymic 176:2 187–194 Clinical Study neuroendocrine tumor Whole exome sequencing of thymic neuroendocrine tumor with ectopic ACTH syndrome Yanli Li1,*, Ying Peng1,*, Xiuli Jiang1, Yulong Cheng3, Weiwei Zhou1, Tingwei Su1, Jing Xie2, Xu Zhong1, Dalong Song1, Luming Wu1, Liwen Fan1, Min Li1, Jie Hong1, Weiqing Wang1, Guang Ning1,3 and Yanan Cao1 1Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors and 2Department of Pathology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China, and 3Laboratory of Endocrinology and Metabolism, Institute of Health Correspondence Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & should be addressed Shanghai Jiao-Tong University School of Medicine (SJTUSM), Shanghai, China to Y Cao *(Y Li and Y Peng contributed equally to this work) Email [email protected] Abstract Objective: Thymic neuroendocrine tumor is the second-most prevalent cause of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), which is a rare disease characterized by ectopic ACTH oversecretion from nonpituitary tumors. However, the genetic abnormalities of thymic neuroendocrine tumors with EAS remain largely unknown. We aim to elucidate the genetic abnormalities and identify the somatic mutations of potential tumor-related genes of thymic neuroendocrine tumors with EAS by whole exome sequencing. Design and methods: Nine patients with thymic neuroendocrine tumors with EAS who were diagnosed at Shanghai Clinical Center for Endocrine and Metabolic Diseases in Ruijin Hospital between 2002 and 2014 were enrolled. We performed whole exome sequencing on the DNA obtained from thymic neuroendocrine tumors and matched peripheral blood using the Hiseq2000 platform. -
Identification and Bioinformatics Analysis of Overlapping Differentially Expressed Genes in Depression, Papillary Thyroid Cancer and Uterine Fibroids
4810 EXPERIMENTAL AND THERAPEUTIC MEDICINE 15: 4810-4816, 2018 Identification and bioinformatics analysis of overlapping differentially expressed genes in depression, papillary thyroid cancer and uterine fibroids HANXIAO TANG1 and YONGSHENG ZHANG2 1Department of Pharmacy, Affiliated Tongde Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310012; 2The Diagnostic Institute of Chinese Medicine, School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China Received May 9, 2017; Accepted October 26, 2017 DOI: 10.3892/etm.2018.6023 Abstract. It is hypothesized that there may be common potential genetic interconnections between depression, PTC and characteristics between the genetic regulatory networks of UF, which may be beneficial for understanding their underlying different diseases. To identify these potential similarities, coregulatory mechanisms and contributing to the development analysis of overlapping differentially expressed genes (DEGs) of homeotherapy based on bioinformatics prediction. in several diseases, which are believed to be associated in traditional Chinese medicine (TCM) was performed in the Introduction present study. The gene expression profiles associated with depression, papillary thyroid carcinoma (PTC) and uterine Molecular biology methods, including DNA microarrays, fibroids (UF) were preliminarily analyzed using Gene are being increasingly used for high-throughput gene expres- Expression Omnibus 2R tools. Gene Ontology enrichment sion analysis and to assess -
Gene Networks Activated by Specific Patterns of Action Potentials in Dorsal Root Ganglia Neurons Received: 10 August 2016 Philip R
www.nature.com/scientificreports OPEN Gene networks activated by specific patterns of action potentials in dorsal root ganglia neurons Received: 10 August 2016 Philip R. Lee1,*, Jonathan E. Cohen1,*, Dumitru A. Iacobas2,3, Sanda Iacobas2 & Accepted: 23 January 2017 R. Douglas Fields1 Published: 03 March 2017 Gene regulatory networks underlie the long-term changes in cell specification, growth of synaptic connections, and adaptation that occur throughout neonatal and postnatal life. Here we show that the transcriptional response in neurons is exquisitely sensitive to the temporal nature of action potential firing patterns. Neurons were electrically stimulated with the same number of action potentials, but with different inter-burst intervals. We found that these subtle alterations in the timing of action potential firing differentially regulates hundreds of genes, across many functional categories, through the activation or repression of distinct transcriptional networks. Our results demonstrate that the transcriptional response in neurons to environmental stimuli, coded in the pattern of action potential firing, can be very sensitive to the temporal nature of action potential delivery rather than the intensity of stimulation or the total number of action potentials delivered. These data identify temporal kinetics of action potential firing as critical components regulating intracellular signalling pathways and gene expression in neurons to extracellular cues during early development and throughout life. Adaptation in the nervous system in response to external stimuli requires synthesis of new gene products in order to elicit long lasting changes in processes such as development, response to injury, learning, and memory1. Information in the environment is coded in the pattern of action-potential firing, therefore gene transcription must be regulated by the pattern of neuronal firing.