The Tumor Suppressor SCRIB Is a Negative Modulator of the Wnt/-Catenin Signaling Pathway
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Regulation of Cdc42 and Its Effectors in Epithelial Morphogenesis Franck Pichaud1,2,*, Rhian F
© 2019. Published by The Company of Biologists Ltd | Journal of Cell Science (2019) 132, jcs217869. doi:10.1242/jcs.217869 REVIEW SUBJECT COLLECTION: ADHESION Regulation of Cdc42 and its effectors in epithelial morphogenesis Franck Pichaud1,2,*, Rhian F. Walther1 and Francisca Nunes de Almeida1 ABSTRACT An overview of Cdc42 Cdc42 – a member of the small Rho GTPase family – regulates cell Cdc42 was discovered in yeast and belongs to a large family of small – polarity across organisms from yeast to humans. It is an essential (20 30 kDa) GTP-binding proteins (Adams et al., 1990; Johnson regulator of polarized morphogenesis in epithelial cells, through and Pringle, 1990). It is part of the Ras-homologous Rho subfamily coordination of apical membrane morphogenesis, lumen formation and of GTPases, of which there are 20 members in humans, including junction maturation. In parallel, work in yeast and Caenorhabditis elegans the RhoA and Rac GTPases, (Hall, 2012). Rho, Rac and Cdc42 has provided important clues as to how this molecular switch can homologues are found in all eukaryotes, except for plants, which do generate and regulate polarity through localized activation or inhibition, not have a clear homologue for Cdc42. Together, the function of and cytoskeleton regulation. Recent studies have revealed how Rho GTPases influences most, if not all, cellular processes. important and complex these regulations can be during epithelial In the early 1990s, seminal work from Alan Hall and his morphogenesis. This complexity is mirrored by the fact that Cdc42 can collaborators identified Rho, Rac and Cdc42 as main regulators of exert its function through many effector proteins. -
E-Cadherin Bridges Cell Polarity and Spindle Orientation to Ensure
bioRxiv preprint doi: https://doi.org/10.1101/245449; this version posted January 11, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. E-cadherin bridges cell polarity and spindle orientation to ensure prostate epithelial integrity and prevent carcinogenesis in vivo Xue Wang1,2, Kai Zhang2, Zhongzhong Ji2, Chaping Cheng2, Huifang Zhao2, Yaru Sheng2, Xiaoxia Li2, Liancheng Fan3, Baijun Dong3, Wei Xue3, Wei-Qiang Gao1,2, Helen He Zhu1 1State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, China; 2School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China; 3Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Correspondence*: Wei-Qiang Gao ([email protected]) or Helen He Zhu ([email protected]). Tel: 86-21-68383917, Fax: 86-21-68383916. Address: Stem Cell Research Center, Ren Ji Hospital, 160 Pujian Rd., School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. Conflict of Interest: We declare no conflict of interest. Short running title: Role of E-cad in cell polarity and spindle orientation 1 bioRxiv preprint doi: https://doi.org/10.1101/245449; this version posted January 11, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Cell polarity and correct mitotic spindle positioning are essential for the maintenance of a proper prostate epithelial architecture, and disruption of the two biological features occurs at early stages in prostate tumorigenesis. -
COVID-19—The Potential Beneficial Therapeutic Effects of Spironolactone During SARS-Cov-2 Infection
pharmaceuticals Review COVID-19—The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-2 Infection Katarzyna Kotfis 1,* , Kacper Lechowicz 1 , Sylwester Drozd˙ zal˙ 2 , Paulina Nied´zwiedzka-Rystwej 3 , Tomasz K. Wojdacz 4, Ewelina Grywalska 5 , Jowita Biernawska 6, Magda Wi´sniewska 7 and Miłosz Parczewski 8 1 Department of Anesthesiology, Intensive Therapy and Acute Intoxications, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; [email protected] 2 Department of Pharmacokinetics and Monitored Therapy, Pomeranian Medical University, 70-111 Szczecin, Poland; [email protected] 3 Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland; [email protected] 4 Independent Clinical Epigenetics Laboratory, Pomeranian Medical University, 71-252 Szczecin, Poland; [email protected] 5 Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, 20-093 Lublin, Poland; [email protected] 6 Department of Anesthesiology and Intensive Therapy, Pomeranian Medical University in Szczecin, 71-252 Szczecin, Poland; [email protected] 7 Clinical Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, 70-111 Szczecin, Poland; [email protected] 8 Department of Infectious, Tropical Diseases and Immune Deficiency, Pomeranian Medical University in Szczecin, 71-455 Szczecin, Poland; [email protected] * Correspondence: katarzyna.kotfi[email protected]; Tel.: +48-91-466-11-44 Abstract: In March 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared Citation: Kotfis, K.; Lechowicz, K.; a global pandemic by the World Health Organization (WHO). The clinical course of the disease is Drozd˙ zal,˙ S.; Nied´zwiedzka-Rystwej, unpredictable but may lead to severe acute respiratory infection (SARI) and pneumonia leading to P.; Wojdacz, T.K.; Grywalska, E.; acute respiratory distress syndrome (ARDS). -
ARHGEF7 (B-PIX) Is Required for the Maintenance of Podocyte Architecture and Glomerular Function
BASIC RESEARCH www.jasn.org ARHGEF7 (b-PIX) Is Required for the Maintenance of Podocyte Architecture and Glomerular Function Jun Matsuda, Mirela Maier, Lamine Aoudjit, Cindy Baldwin, and Tomoko Takano Division of Nephrology, McGill University Health Centre, Montreal, Quebec, Canada ABSTRACT Background Previous studies showed that Cdc42, a member of the prototypical Rho family of small GTPases and a regulator of the actin cytoskeleton, is critical for the normal development and health of podocytes. However, upstream regulatory mechanisms for Cdc42 activity in podocytes are largely unknown. Methods We used a proximity-based ligation assay, BioID, to identify guanine nucleotide exchange fac- tors that activate Cdc42 in immortalized human podocytes. We generated podocyte-specificARHGEF7 (commonly known as b-PIX) knockout mice by crossing b-PIX floxed mice with Podocin-Cre mice. Using shRNA, we established cultured mouse podocytes with b-PIX knockdown and their controls. Results We identified b-PIX as a predominant guanine nucleotide exchange factor that interacts with Cdc42 in human podocytes. Podocyte-specific b-PIX knockout mice developed progressive proteinuria and kidney failure with global or segmental glomerulosclerosis in adulthood. Glomerular podocyte density gradually decreased in podocyte-specific b-PIX knockout mice, indicating podocyte loss. Compared with controls, glomeruli from podocyte-specific b-PIX knockout mice and cultured mouse podocytes with b-PIX knockdown exhibited significant reduction in Cdc42 activity. Loss of b-PIX promoted podocyte apoptosis, which was mediated by the reduced activity of the prosurvival transcriptional regulator Yes-associated protein. Conclusions These findings indicate that b-PIX is required for the maintenance of podocyte architecture and glomerular function via Cdc42 and its downstream Yes-associated protein activities. -
Molecular Expression of the Scribble Complex Genes, Dlg, Scrib and Lgl, in Silkworm, Bombyx Mori
Genes 2013, 4, 264-274; doi:10.3390/genes4020264 OPEN ACCESS genes ISSN 2073-4425 www.mdpi.com/journal/genes Article Molecular Expression of the Scribble Complex Genes, Dlg, Scrib and Lgl, in Silkworm, Bombyx mori Hai-Sheng Qi 1,2, Shu-Min Liu 2, Sheng Li 2,* and Zhao-Jun Wei 1,* 1 School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei 230009, China; E-Mail: [email protected] 2 Key Laboratory of Insect Developmental and Evolutionary Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China; E-Mail: [email protected] * Authors to whom correspondence should be addressed; E-Mails: [email protected] (S.L.); [email protected] (Z.-J.W.); Tel./Fax: +86-551-6291-9369 (Z.-J.W.). Received: 18 March 2013; in revised form: 7 May 2013 / Accepted: 15 May 2013 / Published: 30 May 2013 Abstract: The Scribble protein complex genes, consisting of lethal giant larvae (Lgl), discs large (Dlg) and scribble (Scrib) genes, are components of an evolutionarily conserved genetic pathway that links the cell polarity in cells of humans and Drosophila. The tissue expression and developmental changes of the Scribble protein complex genes were documented using qRT-RCR method. The Lgl and Scrib genes could be detected in all the experimental tissues, including fat body, midgut, testis/ovary, wingdisc, trachea, malpighian tubule, hemolymph, prothoracic gland and silk gland. The Dlg gene, mainly expressed only in testis/ovary, could not be detected in prothoracic gland and hemolymph. In fat body, there were two higher expression stages of the three genes. -
Redefining the Specificity of Phosphoinositide-Binding by Human
bioRxiv preprint doi: https://doi.org/10.1101/2020.06.20.163253; this version posted June 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Redefining the specificity of phosphoinositide-binding by human PH domain-containing proteins Nilmani Singh1†, Adriana Reyes-Ordoñez1†, Michael A. Compagnone1, Jesus F. Moreno Castillo1, Benjamin J. Leslie2, Taekjip Ha2,3,4,5, Jie Chen1* 1Department of Cell & Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; 2Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205; 3Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218; 4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205; 5Howard Hughes Medical Institute, Baltimore, MD 21205, USA †These authors contributed equally to this work. *Correspondence: [email protected]. bioRxiv preprint doi: https://doi.org/10.1101/2020.06.20.163253; this version posted June 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. ABSTRACT Pleckstrin homology (PH) domains are presumed to bind phosphoinositides (PIPs), but specific interaction with and regulation by PIPs for most PH domain-containing proteins are unclear. Here we employed a single-molecule pulldown assay to study interactions of lipid vesicles with full-length proteins in mammalian whole cell lysates. -
Deciphering the Nature of Trp73 Isoforms in Mouse
cancers Article Deciphering the Nature of Trp73 Isoforms in Mouse Embryonic Stem Cell Models: Generation of Isoform-Specific Deficient Cell Lines Using the CRISPR/Cas9 Gene Editing System Lorena López-Ferreras 1,2,†, Nicole Martínez-García 1,3,†, Laura Maeso-Alonso 1,2,‡, Marta Martín-López 1,4,‡, Ángela Díez-Matilla 1,‡ , Javier Villoch-Fernandez 1,2, Hugo Alonso-Olivares 1,2, Margarita M. Marques 3,5,* and Maria C. Marin 1,2,* 1 Instituto de Biomedicina (IBIOMED), Universidad de León, 24071 León, Spain; [email protected] (L.L.-F.); [email protected] (N.M.-G.); [email protected] (L.M.-A.); [email protected] (M.M.-L.); [email protected] (Á.D.-M.); [email protected] (J.V.-F.); [email protected] (H.A.-O.) 2 Departamento de Biología Molecular, Universidad de León, 24071 León, Spain 3 Departamento de Producción Animal, Universidad de León, 24071 León, Spain 4 Biomar Microbial Technologies, Parque Tecnológico de León, Armunia, 24009 León, Spain 5 Instituto de Desarrollo Ganadero y Sanidad Animal (INDEGSAL), Universidad de León, 24071 León, Spain * Correspondence: [email protected] (M.M.M.); [email protected] (M.C.M.); Tel.: +34-987-291757 Citation: López-Ferreras, L.; (M.M.M.); +34-987-291490 (M.C.M.) Martínez-García, N.; Maeso-Alonso, † Equal contribution. ‡ Equal contribution. L.; Martín-López, M.; Díez-Matilla, Á.; Villoch-Fernandez, J.; Simple Summary: The Trp73 gene is involved in the regulation of multiple biological processes Alonso-Olivares, H.; Marques, M.M.; Marin, M.C. Deciphering the Nature such as response to stress, differentiation and tissue architecture. -
Influence of Scribble Polarity Complex on Hematopoiesis and Leukemia – a Matter of Where, When and How
www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 78), pp: 34642-34643 Editorial Influence of Scribble polarity complex on hematopoiesis and leukemia – a matter of where, when and how Florian H. Heidel and Sarah Ellis A key characteristic of hematopoietic stem cells inactivation of Dlg promotes the development of BCR- (HSC) is their ability to self-renew. Several evolutionarily ABL and p53 driven B cell leukemia/lymphoma [6], conserved genes and pathways control the fine balance indicating a conserved role of Dlg as a tumor suppressor between self-renewal and differentiation in HSC and in the B-lymphoid lineage. potentially also in leukemic stem cells (LSC). In vivo Similarly to Lgl1, the influence of Scrib on RNAi screens have identified polarity regulators that lymphoid cells is cell context dependent. Whilst Scrib enhanced (e.g. Prox1) or diminished (e.g. Pard6a, Prkcz, is not required for mature B-cell function and humoral Msi2) the repopulation potential of HSCs in vivo [1]. immunity [7], its inactivation affects immature T-cell However, few of these genes and proteins have been polarization and function [8]. investigated in detail. In their recent paper, Mohr and colleagues revealed The Scribble complex, which was discovered and loss of self-renewal in adult murine HSCs following characterized in Drosophila melanogaster, consists of genetic inactivation of Scrib [9]. Comparable to the role three proteins: Scribble (Scrib), Discs large (Dlg) and of Llgl1 in HSC function, this effect was restricted to LT- Lethal giant larvae (Lgl). These complex members serve HSC. While steady state hematopoiesis was not affected, as scaffolding proteins and regulate cell polarity, motility serial transplantation and application of cell stress resulted and growth mainly through protein–protein interactions. -
Cdc42 Mediates Cancer Cell Chemotaxis in Perineural Invasion
Author Manuscript Published OnlineFirst on February 21, 2020; DOI: 10.1158/1541-7786.MCR-19-0726 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Cdc42 mediates cancer cell chemotaxis in perineural invasion ______________________________________________________________________ Natalya Chernichenko1, Tatiana Omelchenko2, Sylvie Deborde1, Richard Bakst3, Shizhi He1, Chun-Hao Chen1, Laxmi Gusain1, Efsevia Vakiani4, Nora Katabi4, Alan Hall2*, Richard J Wong1 ______________________________________________________________________ 1Department of Surgery, 2Cell Biology Program, 4Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10021 3Department of Radiation Oncology Mount Sinai Hospital, New York, NY, 10029 * Deceased The authors declare that they each do not have any conflict of interest with the material in this manuscript. Correspondence: Richard J. Wong, MD Memorial Sloan-Kettering Cancer Center 1275 York Avenue, C-1069 New York, NY 10021 Office: (212) 639-7638 FAX: (212) 717-3302 Email: [email protected] Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on February 21, 2020; DOI: 10.1158/1541-7786.MCR-19-0726 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 2 Abstract Perineural invasion (PNI) is an ominous form of cancer progression along nerves associated with poor clinical outcome. Glial derived neurotrophic factor (GDNF) interacts with cancer cell RET receptors to enable PNI, but downstream events remain undefined. We demonstrate that GDNF leads to early activation of the GTPase Cdc42 in pancreatic cancer cells, but only delayed activation of RhoA and does not affect Rac1. Depletion of Cdc42 impairs pancreatic cancer cell chemotaxis towards GDNF and nerves. -
Changes in Presynaptic Gene Expression During Homeostatic Compensation at a Central Synapse
Research Articles: Cellular/Molecular Changes in presynaptic gene expression during homeostatic compensation at a central synapse https://doi.org/10.1523/JNEUROSCI.2979-20.2021 Cite as: J. Neurosci 2021; 10.1523/JNEUROSCI.2979-20.2021 Received: 25 November 2020 Revised: 27 January 2021 Accepted: 28 January 2021 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2021 Harrell et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 Changes in presynaptic gene expression during homeostatic compensation 2 at a central synapse 3 4 Abbreviated title: Trans-synaptic regulation of gene expression 5 6 Evan R. Harrell1,2,*, Diogo Pimentel1, Gero Miesenböck1,* 7 8 1 Centre for Neural Circuits and Behaviour, University of Oxford, Tinsley Building, 9 Mansfield Road, Oxford, OX1 3SR, United Kingdom. 10 2 Present address: Institute Pasteur, INSERM, Hearing Institute, 63 rue de Charenton, F- 11 75012 Paris, France. 12 13 * [email protected], [email protected] 14 15 24 pages of text; 5 Figures; 12 Tables. 16 Word counts: abstract 207; introduction 541; discussion 1495 17 18 Acknowledgments: This work was supported by grants from the Wellcome Trust 19 (209235/Z/17/Z, 106988/Z/15/Z, 090309/Z/09/Z, 089270/Z/09/Z), the Gatsby Charitable 20 Foundation (GAT3237), and the European Research Council (832467). -
SHOC2–MRAS–PP1 Complex Positively Regulates RAF Activity and Contributes to Noonan Syndrome Pathogenesis
SHOC2–MRAS–PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis Lucy C. Younga,1, Nicole Hartiga,2, Isabel Boned del Ríoa, Sibel Saria, Benjamin Ringham-Terrya, Joshua R. Wainwrighta, Greg G. Jonesa, Frank McCormickb,3, and Pablo Rodriguez-Vicianaa,3 aUniversity College London Cancer Institute, University College London, London WC1E 6DD, United Kingdom; and bHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158 Contributed by Frank McCormick, September 18, 2018 (sent for review November 22, 2017; reviewed by Deborah K. Morrison and Marc Therrien) Dephosphorylation of the inhibitory “S259” site on RAF kinases CRAF/RAF1 mutations are also frequently found in NS and (S259 on CRAF, S365 on BRAF) plays a key role in RAF activation. cluster around the S259 14-3-3 binding site, enhancing CRAF ac- The MRAS GTPase, a close relative of RAS oncoproteins, interacts tivity through disruption of 14-3-3 binding (8) and highlighting the with SHOC2 and protein phosphatase 1 (PP1) to form a heterotri- key role of this regulatory step in RAF–ERK pathway activation. meric holoenzyme that dephosphorylates this S259 RAF site. MRAS is a very close relative of the classical RAS oncoproteins MRAS and SHOC2 function as PP1 regulatory subunits providing (H-, N-, and KRAS, hereafter referred to collectively as “RAS”) the complex with striking specificity against RAF. MRAS also func- and shares most regulatory and effector interactions as well as tions as a targeting subunit as membrane localization is required transforming ability (9–11). However, MRAS also has specific for efficient RAF dephosphorylation and ERK pathway regulation functions of its own, and uniquely among RAS family GTPases, it in cells. -
In Vivo Sensitivity of Human Melanoma to Tumor Necrosis Factor
[CANCER RESEARCH 59, 205–212, January 1, 1999] In Vivo Sensitivity of Human Melanoma to Tumor Necrosis Factor (TNF)-␣ Is Determined by Tumor Production of the Novel Cytokine Endothelial-Monocyte Activating Polypeptide II (EMAPII) Peter C. Wu, H. Richard Alexander, James Huang, Patrick Hwu, Michael Gnant, Adam C. Berger, Ewa Turner, Olga Wilson, and Steven K. Libutti1 Surgical Metabolism Section, Surgery Branch, National Cancer Institute [P. C. W., H. R. A., J. H., P. H., M. G., A. C. B., E. T., S. K. L.], and Hematology Section, Clinical Pathology, Clinical Center [O. W.], NIH, Bethesda, Maryland 20892 ABSTRACT of different tumor histologies (3). However, the results were disap- pointing because TNF resulted in significant systemic toxicity and no ␣ Tumor necrosis factor (TNF)- is a potent anticancer agent that seems significant antitumor effects at the maximally tolerated doses. The to selectively target tumor-associated vasculature resulting in hemor- clinical use of TNF was largely abandoned until Lienard et al. (4) rhagic necrosis of tumors without injury to surrounding tissues. The major limitation in the clinical use of TNF has been severe dose-limiting reported their initial results of isolated limb perfusion as a means of toxicity when administered systemically. However, when administered in delivering high concentrations to the extremity in patients with in isolated organ perfusion it results in regression of advanced bulky tumors. transit melanoma or unresectable sarcoma, while minimizing systemic A better understanding of the mechanisms of TNF-induced antitumor exposure. We and others have used isolated organ perfusion of the effects may provide valuable information into how its clinical use in limb or liver using TNF plus chemotherapeutic agents to treat unre- cancer treatment may be expanded.