PAK Signaling in Oncogenesis
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The Role of P21-Activated Protein Kinase 1 in Metabolic Homeostasis
THE ROLE OF P21-ACTIVATED PROTEIN KINASE 1 IN METABOLIC HOMEOSTASIS by YU-TING CHIANG A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Physiology University of Toronto © Copyright by Yu-ting Chiang 2014 The Role of P21-Activated Protein Kinase 1 in Metabolic Homeostasis Yu-ting Chiang Doctor of Philosophy Department of Physiology University of Toronto 2014 Abstract Our laboratory has demonstrated previously that the proglucagon gene (gcg), which encodes the incretin hormone GLP-1, is among the downstream targets of the Wnt signaling pathway; and that Pak1 mediates the stimulatory effect of insulin on Wnt target gene expression in mouse gut non- endocrine cells. Here, I asked whether Pak1 controls gut gcg expression and GLP-1 production, and whether Pak1 deletion leads to impaired metabolic homeostasis in mice. I detected the expression of Pak1 and two other group I Paks in the gut endocrine L cell line GLUTag, and co- localized Pak1 and GLP-1 in the mouse gut. Insulin was shown to stimulate Pak1 Thr423 and β-cat Ser675 phosphorylation. The stimulation of insulin on β-cat Ser675 phosphorylation, gcg promoter activity and gcg mRNA expression could be attenuated by the Pak inhibitor IPA3. Male Pak1-/- mice showed significant reduction in both gut and brain gcg expression levels, and attenuated elevation of plasma GLP-1 levels in response to oral glucose challenge. Notably, the Pak1-/- mice were intolerant to both intraperitoneal and oral glucose administration. Aged Pak1-/- mice showed a severe defect in response to intraperitoneal pyruvate challenge (IPPTT). -
Human T-Cell Lymphotropic Virus Type II Infection (Letter to the Editor)
HUMAN T-CELL L YMPHOTROPIC VIRUSES 1. Exposure Data 1.1 Structure, taxonomy and biology 1.1.1 Structure The structure of retroviruses is reviewed in the monograph on human immuno- deficiency viruses (HIV) in this volume. The human T-cell lymphotropic (T-cell Ieu- kaemia/lymphoma) viruses (HTL V) are enveloped viruses with a diameter of approxi- mately 80-100 nm (Figure 1). The HTLV virions contain two covalently bound genomic RNA strands, which are complexed with the viral enzymes reverse transcriptase (RT; with associated RNase H activity), integrase and protease and the capsid proteins. The outer part of the virions consists of a membrane-associated matrix protein and a lipid Iayer intersected by the envelope proteins (GeIderbIom, 1991). Figure 1. An electron micrograph of HTL V -1 virus Courtes y of Dr Bernard Kramarsky, Advanced Biotechnologies, Inc., Columbia, MD, USA 1.1.2 T axonomy and phylogeny Traditionally, retroviruses (family Retroviridae) have been cIassified according to a combination of criteria incIuding disease association, morphoIogy and cytopathic effects in vitro. On this basis three subfamiIies were defined. The oncoviruses (Greek, onkos = mass, swelling) consist of four morphological subtypes which are associated with tumours in naturally or experimentally infected animaIs, and non-oncogenic related viruses. The second group, the Ientiviruses (Latin, lentus = slow), cause a variety of diseases including immunodeficiency and wasting syndromes, usually after a long period -261- 262 IARC MONOGRAPHS VOLUME 67 of clinical latency. The third subfamily, the spumaviruses (Latin, spuma = foam), so called because of the characteristic 'foamy' appearance induced in infected cells in vitro, have not been conclusively 1inked to any disease. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Merlin Inhibits Wnt/Β-Catenin Signaling by Blocking LRP6 Phosphorylation
Cell Death and Differentiation (2016) 23, 1638–1647 & 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1350-9047/16 www.nature.com/cdd Merlin inhibits Wnt/β-catenin signaling by blocking LRP6 phosphorylation M Kim1,6, S Kim1,6, S-H Lee2,3,6, W Kim1, M-J Sohn4, H-S Kim5, J Kim*,2 and E-H Jho*,1 Merlin, encoded by the NF2 gene, is a tumor suppressor that acts by inhibiting mitogenic signaling and is mutated in Neurofibromatosis type II (NF2) disease, although its molecular mechanism is not fully understood. Here, we observed that Merlin inhibited Wnt/β-catenin signaling by blocking phosphorylation of LRP6, which is necessary for Wnt signal transduction, whereas mutated Merlin in NF2 patients did not. Treatment with Wnt3a enhanced phosphorylation of Ser518 in Merlin via activation of PAK1 in a PIP2-dependent manner. Phosphorylated Merlin dissociated from LRP6, allowing for phosphorylation of LRP6. Tissues from NF2 patients exhibited higher levels of β-catenin, and proliferation of RT4-D6P2T rat schwannoma cells was significantly reduced by treatment with chemical inhibitors of Wnt/β-catenin signaling. Taken together, our findings suggest that sustained activation of Wnt/β-catenin signaling due to abrogation of Merlin-mediated inhibition of LRP6 phosphorylation may be a cause of NF2 disease. Cell Death and Differentiation (2016) 23, 1638–1647; doi:10.1038/cdd.2016.54; published online 10 June 2016 Wnt/β-catenin signaling has essential roles in the regulation of β-catenin is then translocated into nuclei to activate -
Viewer 4.0 Software [73]
BMC Genomics BioMed Central Research Open Access Bioinformatic search of plant microtubule-and cell cycle related serine-threonine protein kinases Pavel A Karpov1, Elena S Nadezhdina2,3,AllaIYemets1, Vadym G Matusov1, Alexey Yu Nyporko1,NadezhdaYuShashina3 and Yaroslav B Blume*1 Addresses: 1Institute of Food Biotechnology and Genomics, National Academy of Sciences of Ukraine, 04123 Kyiv, Ukraine, 2Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russian Federation and 3AN Belozersky Institute of Physical- Chemical Biology, Moscow State University, Leninsky Gory, 119992 Moscow, Russian Federation E-mail: Pavel A Karpov - [email protected]; Elena S Nadezhdina - [email protected]; Alla I Yemets - [email protected]; Vadym G Matusov - [email protected]; Alexey Yu Nyporko - [email protected]; Nadezhda Yu Shashina - [email protected]; Yaroslav B Blume* - [email protected] *Corresponding author from International Workshop on Computational Systems Biology Approaches to Analysis of Genome Complexity and Regulatory Gene Networks Singapore 20-25 November 2008 Published: 10 February 2010 BMC Genomics 2010, 11(Suppl 1):S14 doi: 10.1186/1471-2164-11-S1-S14 This article is available from: http://www.biomedcentral.com/1471-2164/11/S1/S14 Publication of this supplement was made possible with help from the Bioinformatics Agency for Science, Technology and Research of Singapore and the Institute for Mathematical Sciences at the National University of Singapore. © 2010 Karpov et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. -
Identification of Potential Key Genes and Pathway Linked with Sporadic Creutzfeldt-Jakob Disease Based on Integrated Bioinformatics Analyses
medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Identification of potential key genes and pathway linked with sporadic Creutzfeldt-Jakob disease based on integrated bioinformatics analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 , Iranna Kotturshetti 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. 3. Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka 562209, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.12.21.20248688; this version posted December 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Abstract Sporadic Creutzfeldt-Jakob disease (sCJD) is neurodegenerative disease also called prion disease linked with poor prognosis. The aim of the current study was to illuminate the underlying molecular mechanisms of sCJD. The mRNA microarray dataset GSE124571 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened. -
Supplementary Materials
Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine -
The Role of the Rho Gtpases in Neuronal Development
Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW The role of the Rho GTPases in neuronal development Eve-Ellen Govek,1,2, Sarah E. Newey,1 and Linda Van Aelst1,2,3 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 11724, USA; 2Molecular and Cellular Biology Program, State University of New York at Stony Brook, Stony Brook, New York, 11794, USA Our brain serves as a center for cognitive function and and an inactive GDP-bound state. Their activity is de- neurons within the brain relay and store information termined by the ratio of GTP to GDP in the cell and can about our surroundings and experiences. Modulation of be influenced by a number of different regulatory mol- this complex neuronal circuitry allows us to process that ecules. Guanine nucleotide exchange factors (GEFs) ac- information and respond appropriately. Proper develop- tivate GTPases by enhancing the exchange of bound ment of neurons is therefore vital to the mental health of GDP for GTP (Schmidt and Hall 2002); GTPase activat- an individual, and perturbations in their signaling or ing proteins (GAPs) act as negative regulators of GTPases morphology are likely to result in cognitive impairment. by enhancing the intrinsic rate of GTP hydrolysis of a The development of a neuron requires a series of steps GTPase (Bernards 2003; Bernards and Settleman 2004); that begins with migration from its birth place and ini- and guanine nucleotide dissociation inhibitors (GDIs) tiation of process outgrowth, and ultimately leads to dif- prevent exchange of GDP for GTP and also inhibit the ferentiation and the formation of connections that allow intrinsic GTPase activity of GTP-bound GTPases (Zalc- it to communicate with appropriate targets. -
The Role of the C-Terminus Merlin in Its Tumor Suppressor Function Vinay Mandati
The role of the C-terminus Merlin in its tumor suppressor function Vinay Mandati To cite this version: Vinay Mandati. The role of the C-terminus Merlin in its tumor suppressor function. Agricultural sciences. Université Paris Sud - Paris XI, 2013. English. NNT : 2013PA112140. tel-01124131 HAL Id: tel-01124131 https://tel.archives-ouvertes.fr/tel-01124131 Submitted on 19 Mar 2015 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 1 TABLE OF CONTENTS Abbreviations ……………………………………………………………………………...... 8 Resume …………………………………………………………………………………… 10 Abstract …………………………………………………………………………………….. 11 1. Introduction ………………………………………………………………………………12 1.1 Neurofibromatoses ……………………………………………………………………….14 1.2 NF2 disease ………………………………………………………………………………15 1.3 The NF2 gene …………………………………………………………………………….17 1.4 Mutational spectrum of NF2 gene ………………………………………………………..18 1.5 NF2 in other cancers ……………………………………………………………………...20 2. ERM proteins and Merlin ……………………………………………………………….21 2.1 ERMs ……………………………………………………………………………………..21 2.1.1 Band 4.1 Proteins and ERMs …………………………………………………………...21 2.1.2 ERMs structure ………………………………………………………………………....23 2.1.3 Sub-cellular localization and tissue distribution of ERMs ……………………………..25 2.1.4 ERM proteins and their binding partners ……………………………………………….25 2.1.5 Assimilation of ERMs into signaling pathways ………………………………………...26 2.1.5. A. ERMs and Ras signaling …………………………………………………...26 2.1.5. B. ERMs in membrane transport ………………………………………………29 2.1.6 ERM functions in metastasis …………………………………………………………...30 2.1.7 Regulation of ERM proteins activity …………………………………………………...31 2.1.7. -
Phosphorylation Sites in Protein Kinases and Phosphatases Regulated by Formyl Peptide Receptor 2 Signaling
International Journal of Molecular Sciences Review Phosphorylation Sites in Protein Kinases and Phosphatases Regulated by Formyl Peptide Receptor 2 Signaling Maria Carmela Annunziata 1, Melania Parisi 1, Gabriella Esposito 2 , Gabriella Fabbrocini 1, Rosario Ammendola 2 and Fabio Cattaneo 2,* 1 Department of Clinical Medicine and Surgery, School of Medicine, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; [email protected] (M.C.A.); [email protected] (M.P.); [email protected] (G.F.) 2 Department of Molecular Medicine and Medical Biotechnology, School of Medicine,, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy; [email protected] (G.E.); [email protected] (R.A.) * Correspondence: [email protected]; Fax: +39-081-7464-359 Received: 5 May 2020; Accepted: 25 May 2020; Published: 27 May 2020 Abstract: FPR1, FPR2, and FPR3 are members of Formyl Peptides Receptors (FPRs) family belonging to the GPCR superfamily. FPR2 is a low affinity receptor for formyl peptides and it is considered the most promiscuous member of this family. Intracellular signaling cascades triggered by FPRs include the activation of different protein kinases and phosphatase, as well as tyrosine kinase receptors transactivation. Protein kinases and phosphatases act coordinately and any impairment of their activation or regulation represents one of the most common causes of several human diseases. Several phospho-sites has been identified in protein kinases and phosphatases, whose role may be to expand the repertoire of molecular mechanisms of regulation or may be necessary for fine-tuning of switch properties. We previously performed a phospho-proteomic analysis in FPR2-stimulated cells that revealed, among other things, not yet identified phospho-sites on six protein kinases and one protein phosphatase. -
Characterisation of a Protein Kinase B Inhibitor in Vitro and in Insulin Treated Liver Cells
Diabetes In Press, published online June 11, 2007 Characterisation of a protein kinase B inhibitor in vitro and in insulin treated liver cells. Received for publication 17 March 2007 and accepted in revised form 5 June 2007. Additional information for this article can be viewed in an online appendix at http://diabetes.diabetesjournals.org Lisa Logie, Antonio J. Ruiz-Alcaraz, Michael Keane*$, Yvonne L. Woods*, Jennifer Bain*, Rudolfo Marquez$, Dario R. Alessi* and Calum Sutherland. Division of Pathology and Neuroscience, *MRC Protein Phosphorylation Unit, $Division of Biological Chemistry, University of Dundee, Dundee, Scotland. Corresponding author Dr Calum Sutherland Pathology and Neurosciences University of Dundee, Ninewells Hospital Dundee, Scotland, UK, DD1 9SY email: [email protected] Word Count: 3978, Tables: 2, Figures: 6. Keywords: PKB, AKT, PEPCK, insulin, Akti-1/2, diabetes. Abbreviations: PKB, protein kinase B; G6Pase, glucose-6-phosphatase; PEPCK, phosphoenolpyruvate carboxykinase; IGFBP1, IGF binding protein-1; TIRE, thymine-rich insulin response element; PRAS40, proline rich akt substrate of 40kDa; Akti, Akt inhibitor. Running Title: PKB inhibition and insulin action. Copyright American Diabetes Association, Inc., 2007 Abstract: Objective: Abnormal expression of the hepatic gluconeogenic genes (glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK)) contributes to hyperglycemia. These genes are repressed by insulin but this process is defective in diabetes. Protein kinase B (PKB) is implicated in this action of insulin. An inhibitor of PKB, termed Akti-1/2, was recently reported, however the specificity and efficacy against insulin induced PKB was not reported. Our aim was to characterise the specificity and efficacy of Akti-1/2 in cells exposed to insulin and then establish whether inhibition of PKB is sufficient to prevent regulation of hepatic gene expression by insulin. -
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.