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International Journal of Molecular Sciences Dual Specificity Phosphatases From Molecular Mechanisms to Biological Function Edited by Rafael Pulido and Roland Lang Printed Edition of the Special Issue Published in International Journal of Molecular Sciences www.mdpi.com/journal/ijms Dual Specificity Phosphatases Dual Specificity Phosphatases From Molecular Mechanisms to Biological Function Special Issue Editors Rafael Pulido Roland Lang MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editors Rafael Pulido Roland Lang Biocruces Health Research Institute University Hospital Erlangen Spain Germany Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal International Journal of Molecular Sciences (ISSN 1422-0067) from 2018 to 2019 (available at: https: //www.mdpi.com/journal/ijms/special issues/DUSPs). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03921-688-8 (Pbk) ISBN 978-3-03921-689-5 (PDF) c 2019 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Special Issue Editors ..................................... vii Rafael Pulido and Roland Lang Dual Specificity Phosphatases: From Molecular Mechanisms to Biological Function Reprinted from: Int. J. Mol. Sci. 2019, 20, 4372, doi:10.3390/ijms20184372 .............. 1 Gema Gonz´alez-Rubio, Teresa Fern´andez-Acero, Humberto Mart´ın and Mar´ıa Molina Mitogen-Activated Protein Kinase Phosphatases (MKPs) in Fungal Signaling: Conservation, Function, and Regulation Reprinted from: Int. J. Mol. Sci. 2019, 20, 1709, doi:10.3390/ijms20071709 .............. 5 Roland Lang and Faizal A.M. Raffi Dual-Specificity Phosphatases in Immunity and Infection: An Update Reprinted from: Int. J. Mol. Sci. 2019, 20, 2710, doi:10.3390/ijms20112710 .............. 21 Grace C. A. Manley, Lisa C. Parker and Yongliang Zhang Emerging Regulatory Roles of Dual-Specificity Phosphatases in Inflammatory Airway Disease Reprinted from: Int. J. Mol. Sci. 2019, 20, 678, doi:10.3390/ijms20030678 ............... 47 Yashwanth Subbannayya, Sneha M. Pinto, Korbinian B¨osl, T. S. Keshava Prasad and Richard K. Kandasamy Dynamics of Dual Specificity Phosphatases and Their Interplay with Protein Kinases in Immune Signaling Reprinted from: Int. J. Mol. Sci. 2019, 20, 2086, doi:10.3390/ijms20092086 .............. 70 Hsueh-Fen Chen, Huai-Chia Chuang and Tse-Hua Tan Regulation of Dual-Specificity Phosphatase (DUSP) Ubiquitination and Protein Stability Reprinted from: Int. J. Mol. Sci. 2019, 20, 2668, doi:10.3390/ijms20112668 .............. 92 Marta Jim´enez-Mart´ınez, Konstantinos Stamatakis and Manuel Fresno The Dual-Specificity Phosphatase 10 (DUSP10): Its Role in Cancer, Inflammation, and Immunity Reprinted from: Int. J. Mol. Sci. 2019, 20, 1626, doi:10.3390/ijms20071626 ..............109 Jinhui Li, Xiantao Wang, William E. Ackerman IV, Abel J. Batty, Sean G. Kirk, William M. White, Xianxi Wang, Dimitrios Anastasakis, Lobelia Samavati, Irina Buhimschi, and et al. Dysregulation of Lipid Metabolism in Mkp-1 Deficient Mice during Gram-Negative Sepsis Reprinted from: Int. J. Mol. Sci. 2018, 19, 3904, doi:10.3390/ijms19123904 ..............122 Thikryat Neamatallah, Shilan Jabbar, Rothwelle Tate, Juliane Schroeder, Muhannad Shweash, James Alexander and Robin Plevin Whole Genome Microarray Analysis of DUSP4-Deletion Reveals A Novel Role for MAP Kinase Phosphatase-2 (MKP-2) in Macrophage Gene Expression and Function Reprinted from: Int. J. Mol. Sci. 2019, 20, 3434, doi:10.3390/ijms20143434 ..............143 Fan Wu, Robert D. McCuaig, Christopher R. Sutton, Abel H. Y. Tan, Yoshni Jeelall, Elaine G. Bean, Jin Dai, Thiru Prasanna, Jacob Batham, Laeeq Malik, et al. Nuclear-Biased DUSP6 Expression is Associated with Cancer Spreading Including Brain Metastasis in Triple-Negative Breast Cancer Reprinted from: Int. J. Mol. Sci. 2019, 20, 3080, doi:10.3390/ijms20123080 ..............160 v Yuming Cao, Dallas A. Banks, Andrew M. Mattei, Alexys T. Riddick, Kirstin M. Reed, Ashley M. Zhang, Emily S. Pickering and Shant´a D. Hinton Pseudophosphatase MK-STYX Alters Histone Deacetylase 6 Cytoplasmic Localization, Decreases Its Phosphorylation, and Increases Detyrosination of Tubulin Reprinted from: Int. J. Mol. Sci. 2019, 20, 1455, doi:10.3390/ijms20061455 ..............173 Caroline E. Nunes-Xavier, Laura Zaldumbide, Olaia Aurtenetxe, Ricardo L´opez-Almaraz, Jos´eI.L´opez and Rafael Pulido Dual-Specificity Phosphatases in Neuroblastoma Cell Growth and Differentiation Reprinted from: Int. J. Mol. Sci. 2019, 20, 1170, doi:10.3390/ijms20051170 ..............189 Raquel P´erez-Sen, Mar´ıa Jos´e Queipo, Juan Carlos Gil-Redondo, Felipe Ortega, Rosa G´omez-Villafuertes, Mar´ıa Teresa Miras-Portugal and Esmerilda G. Delicado Dual-Specificity Phosphatase Regulation in Neurons and Glial Cells Reprinted from: Int. J. Mol. Sci. 2019, 20, 1999, doi:10.3390/ijms20081999 ..............208 vi About the Special Issue Editors Rafael Pulido is an Ikerbasque Research Professor at Biocruces Bizkaia Health Research Institute (Barakaldo, Bilbao, Spain). His laboratory investigates the role of protein tyrosine phosphatases in human disease, and studies the involvement of phosphatases and kinases in human cancer and cancer-associated hereditary syndromes, with a focus on the PTEN tumor suppressor. His professional interest is the identification, characterization, and validation of new molecular biomarkers and targets for anti-cancer precision therapies. Roland Lang is an MD specialized in Medical Microbiology and an Associate Professor of Innate Immunity at the Institute of Clinical Microbiology, Immunology and Hygiene at the University Hospital Erlangen, Germany. He studied medicine in Regensburg and at the TU Munich, where he was trained in Medical Microbiology. From 1999–2002 he was a postdoctoral fellow at St. Jude Children’s Research Hospital in Memphis, TN. From 2002–2008 he was an established junior investigator at the Institute of Medical Microbiology at TUM. In 2008 he was recruited to Erlangen. His main research interests are innate immune receptors and pathways of pathogen recognition, how innate immune activation is regulated by cytokines and modulators of intracellular signaling, and the implications of these interactions on inflammation and infection, and during immunization. vii International Journal of Molecular Sciences Editorial Dual Specificity Phosphatases: From Molecular Mechanisms to Biological Function Rafael Pulido 1,2,* and Roland Lang 3,* 1 Biomarkers in Cancer Unit, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain 2 IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain 3 Institute of Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany * Correspondence: [email protected] or [email protected] (R.P.); [email protected] (R.L.) Received: 3 September 2019; Accepted: 4 September 2019; Published: 6 September 2019 Dual specificity phosphatases (DUSPs) constitute a heterogeneous group of enzymes, relevant in human disease, which belong to the class I Cys-based group of protein tyrosine phosphatase (PTP) gene superfamily [1–4]. DUSPs possess the capability to dephosphorylate Ser/Thr and Tyr residues from proteins as well as to remove phosphates from other non-proteinaceous substrates, including signaling lipids [5]. Catalytically inactive pseudophosphatase DUSPs also exist which regulate phosphorylation-related cell signaling [6]. DUSPs include, among others, mitogen-activated protein kinase (MAPK) phosphatases (MKPs) and small-size atypical DUSPs. These proteins are non-transmembrane enzymes displaying variable substrate specificity and harboring a single PTP catalytic domain with a HCXXGXXR consensus catalytic motif [7,8]. MKPs are enzymes specialized in regulating the catalytic activity and subcellular location of MAPKs, whereas the functions of small-size atypical DUSPs are more diversified. DUSPs have emerged as key players in the regulation of cell growth, differentiation, stress responses and apoptosis. In physiology, DUSPs regulate essential processes, including immunity, neurobiology and metabolic homeostasis, and have been involved in tumorigenesis, pathological inflammation and metabolic disorders [9–11]. Accordingly, alterations in the expression or function of MKPs and small-size atypical DUSPs have important consequences in human disease, making these enzymes potential biological markers and therapeutic targets. Although major biochemical, structural, functional and physiological properties of many DUSPs are currently known, their developmental stage- and tissue-specific involvement in different human pathologies is only starting to be disclosed. This Special Issue provides original research and review articles focused on the involvement of specific MKPs and small-size atypical DUSPs in human
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  • Hyperactive and Impulsive Behaviors of LMTK1 Knockout Mice

    Hyperactive and Impulsive Behaviors of LMTK1 Knockout Mice

    www.nature.com/scientificreports OPEN Hyperactive and impulsive behaviors of LMTK1 knockout mice Miyuki Takahashi1,7, Arika Sugiyama1, Ran Wei1, Shizuka Kobayashi2, Kimiko Fukuda3, Hironori Nishino1, Roka Takahashi1, Koji Tsutsumi1,8, Ichiro Kita4, Kanae Ando1, Toshiya Manabe2, Hiroyuki Kamiguchi5, Mineko Tomomura6 & Shin‑ichi Hisanaga1* Lemur tail kinase 1 (LMTK1), previously called Apoptosis‑Associated Tyrosine Kinase (AATYK), remains an uncharacterized Ser/Thr protein kinase that is predominantly expressed in the brain. It is recently reported that LMTK1A, an isoform of LMTK1, binds to recycling endosomes through its palmitoylation and regulates endosomal trafcking by suppressing the activity of Rab11 small GTPase. In neurons, knockdown or knockout of LMTK1 results in longer axons, greater branching of dendrites and increased number of spines, suggesting that LMTK1 plays a role in neuronal circuit formation. However, its in vivo function remained to be investigated. Here, we examined the brain structures and behaviors of LMTK1 knockout (KO) mice. LMTK1 was expressed in most neurons throughout the brain. The overall brain structure appeared to be normal in LMTK1 KO mice, but the numbers of synapses were increased. LMTK1 KO mice had a slight impairment in memory formation and exhibited distinct psychiatric behaviors such as hyperactivity, impulsiveness and high motor coordination without social interaction defcits. Some of these abnormal behaviors represent core features of attention defcit hyperactive disorder (ADHD), suggesting the possible involvement of LMTK1 in the pathogenesis of ADHD. Abbreviations AATYK1 Apoptosis-Associated Tyrosine Kinase ADHD Attention defcit hyperactive disorder Cx Cerebral cortex Cb Cerebellum CS Conditioned stimulus ISH In situ hybridization KO Knockout LMTK Lemur tail kinase PPF Paired-pulse facilitation US Unconditioned stimulus WT Wildtype Neuronal circuit wiring is the structural and functional basis of higher brain activities such as recognition and behaviors.