DOCSLIB.ORG

The Nebulin Family LIM and SH3 Proteins Regulate Postsynaptic Development and Function

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Research Articles: Cellular/Molecular The nebulin family LIM and SH3 proteins regulate postsynaptic development and function https://doi.org/10.1523/JNEUROSCI.0334-19.2019 Cite as: J. Neurosci 2019; 10.1523/JNEUROSCI.0334-19.2019 Received: 11 February 2019 Revised: 12 November 2019 Accepted: 15 November 2019 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 © 2019 the authors 1 The nebulin family LIM and SH3 proteins regulate postsynaptic 2 development and function 3 4 Kenneth R Myers1*, Kuai Yu1, Joachim Kremerskothen2, Elke Butt3, and James Q. Zheng1,4* 5 1 Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322. 6 2 Medizinische Klinik D, Abteilung für Molekulare Nephrologie, Universitätsklinikum Münster, 7 Münster, Germany. 8 3Institute of Experimental Biomedicine II, University Medical Clinic of Wuerzburg, Wuerzburg, 9 Germany. 10 4 Department of Neurology and Center for Neurodegenerative Diseases, Emory University School 11 of Medicine, Atlanta, GA 30322 12 13 Abbreviated title: LASP regulation of dendrite development 14 Keywords: Actin cytoskeleton, synapse, dendrite, spines, neuronal development 15 Correspondence: Dr. James Zheng, Department of Cell Biology, Emory University School of 16 Medicine, Atlanta, GA 30322. Email: [email protected]; Dr. Kenneth Myers, 17 Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322. Email: 18 [email protected]. 19 Number of pages: 41 20 Number of figures: 10 1 21 Number of words: Abstract (150), Introduction (650), and Discussion (1,188) 22 Conflict of interest statement: The authors declare no competing financial interests. 23 Acknowledgements: This work is supported in part by research grants from National Institutes 24 of Health to JQZ (MH104632 and GM083889), and a Ruth L. Kirschstein NRSA Postdoctoral 25 Fellowship to KRM (NS092342). We thank Jinny Yoo and Jenny Mai for help with image analysis, 26 and Madeline Morgan for helpful discussions. The authors declare no competing financial 27 interests. 28 29 30 31 32 33 34 35 36 37 38 39 2 40 ABSTRACT 41 Neuronal dendrites have specialized actin-rich structures called dendritic spines that 42 receive and integrate most excitatory synaptic inputs. The stabilization of dendrites and spines 43 during neuronal maturation is essential for proper neural circuit formation. Changes in dendritic 44 morphology and stability are largely mediated by regulation of the actin cytoskeleton, however 45 the underlying mechanisms remain to be fully elucidated. Here, we present evidence that the 46 nebulin family members LASP1 and LASP2 play an important role in the postsynaptic 47 development of rat hippocampal neurons from both sexes. We find that both LASP1 and LASP2 48 are enriched in dendritic spines, and their knockdown impairs spine development and synapse 49 formation. Furthermore, LASP2 exerts a distinct role in dendritic arbor and dendritic spine 50 stabilization. Importantly the actin-binding N-terminal LIM domain and nebulin repeats of 51 LASP2 are required for spine stability and dendritic arbor complexity. These findings identify 52 LASP1 and LASP2 as novel regulators of neuronal circuitry. 53 54 55 56 57 58 59 3 60 SIGNIFICANCE STATEMENT 61 Proper regulation of the actin cytoskeleton is essential for the structural stability of 62 dendrites and dendritic spines. Consequently, malformation of dendritic structures accompanies 63 numerous neurologic disorders, such as schizophrenia and autism. Nebulin family members are 64 best known for their role in regulating the stabilization and function of actin thin filaments in 65 muscle. The two smallest family members, LASP1 and LASP2, are more structurally diverse 66 and are expressed in a broader array of tissues. While both LASP1 and LASP2 are highly 67 expressed in the brain, little is currently known about their function in the nervous system. In this 68 study, we demonstrate the first evidence that LASP1 and LASP2 are involved in the formation 69 and long-term maintenance of dendrites and dendritic spines. 70 71 72 73 74 75 76 77 78 79 80 4 81 INTRODUCTION 82 The structure of a neuron’s dendritic arbor is essential for neural circuit formation, 83 determining how synaptic inputs are received and integrated. In turn, presynaptic inputs 84 themselves can shape and stabilize the dendritic arbor (Parrish et al., 2007). The arbor is highly 85 dynamic during early development as numerous branches form, elongate, and retract (Scott 86 and Luo, 2001; Parrish et al., 2007; Koleske, 2013). However, as development proceeds 87 increased neuronal activity stabilizes individual branches, and less active branches retract (Van 88 Aelst and Cline, 2004; Cline and Haas, 2008). The majority of excitatory inputs are received at 89 glutamatergic synapses, which are formed between presynaptic axonal terminals and 90 specialized postsynaptic structures called dendritic spines (Nimchinsky et al., 2002; Bourne and 91 Harris, 2008; Rochefort and Konnerth, 2012). Spines are small membranous protrusions that 92 form on dendrites and function as the sites of signal integration and transduction downstream 93 of glutamate receptor activity (Chen and Sabatini, 2012). Dendritic spines are highly plastic, and 94 changes in their morphology underlie synapse formation and modification during learning and 95 memory (Segal, 2005; Bosch and Hayashi, 2012; Lai and Ip, 2013). The growth of the dendritic 96 arbor and dendritic spines are therefore closely linked, and both are essential for the 97 development and function of neuronal circuits (Koleske, 2013). However, as neurons mature, 98 the dendritic arbor typically stabilizes while spines retain a reduced level of plasticity. 99 Changes in spine morphology are largely driven by remodeling of the actin cytoskeleton 100 (Hotulainen and Hoogenraad, 2010; Lei et al., 2016). Actin filaments are remodeled by 101 regulatory proteins that arrange actin into distinct networks with different functions. These 102 regulatory proteins modify actin structures by crosslinking, severing, end capping, and bundling 5 103 actin filaments. The LIM and SH3 domain-containing proteins, LASP1 and LASP2, are small 104 multi-domain actin-binding proteins that have been implicated in the stabilization of actin 105 filaments (Grunewald and Butt, 2008; Pappas et al., 2011). Consequently, LASP1 and LASP2 106 localize to numerous sites of dynamic actin assembly and disassembly including; focal 107 adhesions, membrane ruffles, lamellipodia, and pseudopodia (Chew et al., 2002b). In non- 108 neuronal cells, both LASP proteins have been shown to regulate cell adhesion and cell migration 109 (Lin et al., 2004; Bliss et al., 2013). LASP1 and LASP2 are highly homologous, and are 110 differentiated from the other members of the Nebulin family of actin binding proteins by their 111 small size and the presence of an N-terminal LIM domain (Pappas et al., 2011). LIM domains 112 participate in a wide variety of cellular functions including the regulation of gene expression, 113 signal transduction, cell adhesion, and cell motility (Kadrmas and Beckerle, 2004). In addition, 114 LASP1 and LASP2 feature a C-terminal SRC homology region 3 (SH3) domain, a flexible non- 115 structured linker region, and either two or three 35-amino acid actin-binding nebulin-like 116 repeats, respectively (Grunewald and Butt, 2008). This unique domain architecture enables the 117 LASP proteins to serve as signaling hubs, linking numerous proteins to the actin cytoskeleton 118 (Orth et al., 2015). Studies have shown that both proteins are highly expressed in the central 119 nervous system, and that LASP1 is concentrated in the postsynaptic density (Phillips et al., 120 2004; Terasaki et al., 2004). In addition, LASP1 has been identified as a risk factor for both 121 autism and schizophrenia (Stone et al., 2007; Joo et al., 2013). However, little is currently 122 known about the physiological role of either LASP1 or LASP2 in the nervous system. 123 In this study, we present evidence that LASP1 and LASP2 play an important role in 124 dendritic spine development and stabilization, respectively. Furthermore, we demonstrate that 6 125 LASP2, but not LASP1, promotes dendritic complexity by stabilizing dendritic branches. LASP2, 126 but not LASP1 has been identified as an actin bundling protein (Chew et al., 2002a; Zieseniss et 127 al., 2008), and here we identify a role for the actin-binding LIM domain and Nebulin repeats in 128 LASP2-mediated dendritic stabilization. Our findings demonstrate an important new role for 129 nebulin family members in the stabilization of dendritic spines and dendritic arbor, and in 130 regulating synapse formation. 131 7 132 METHODS 133 Antibodies 134 The following commercial antibodies were used: rabbit anti-MAP2 (AB5622; EMD 135 Millipore; 1:1000), rabbit anti-RFP (600-401-279; Rockland; 1:1000), rabbit anti-GFP (A-11122; 136 Invitrogen; 1:1,000), mouse anti-PSD95 (MA1-045; ThermoFisher; 1:1,000), and mouse anti-SV2 137 (DSHB; 1:1000). To examine LASP localization, we used total-LASP antibody (recognizes both 138 LASP1 and LASP2) which was generated by immunizing rabbit with full-length GST-LASP1 (Butt 139 et al.,
Recommended publications
  • Paxillin: a Focal Adhesion-Associated Adaptor Protein

    Paxillin: a Focal Adhesion-Associated Adaptor Protein

    Oncogene (2001) 20, 6459 ± 6472 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Paxillin: a focal adhesion-associated adaptor protein Michael D Schaller*,1 1Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center and Comprehensive Center for In¯ammatory Disorders, University of North Carolina, Chapel Hill, North Carolina, NC 27599, USA Paxillin is a focal adhesion-associated, phosphotyrosine- The molecular cloning of paxillin revealed a number containing protein that may play a role in several of motifs that are now known to function in mediating signaling pathways. Paxillin contains a number of motifs protein ± protein interactions (see Figure 1) (Turner that mediate protein ± protein interactions, including LD and Miller, 1994; Salgia et al., 1995a). The N-terminal motifs, LIM domains, an SH3 domain-binding site and half of paxillin contains a proline-rich region that SH2 domain-binding sites. These motifs serve as docking could serve as an SH3 domain-binding site. Several sites for cytoskeletal proteins, tyrosine kinases, serine/ tyrosine residues conforming to SH2 domain binding threonine kinases, GTPase activating proteins and other sites were also noted. In addition, the N-terminal adaptor proteins that recruit additional enzymes into domain of paxillin contains ®ve copies of a peptide complex with paxillin. Thus paxillin itself serves as a sequence, called the LD motif, which are now known docking protein to recruit signaling molecules to a to function as binding sites for other proteins (see speci®c cellular compartment, the focal adhesions, and/ Table 1) (Brown et al., 1998a). The C-terminal half of or to recruit speci®c combinations of signaling molecules paxillin is comprised of four LIM domains, which are into a complex to coordinate downstream signaling.
  • The PX Domain Protein Interaction Network in Yeast

    The PX Domain Protein Interaction Network in Yeast

    The PX domain protein interaction network in yeast Zur Erlangung des akademischen Grades eines DOKTORS DER NATURWISSENSCHAFTEN (Dr. rer. nat.) der Fakultät für Chemie und Biowissenschaften der Universität Karlsruhe (TH) vorgelegte DISSERTATION von Dipl. Biol. Carolina S. Müller aus Buenos Aires Dekan: Prof. Dr. Manfred Kappes Referent: Dr. Nils Johnsson Korreferent: HD. Dr. Adam Bertl Tag der mündlichen Prüfung: 17.02.2005 I dedicate this work to my Parents and Alex TABLE OF CONTENTS Table of contents Introduction 1 Yeast as a model organism in proteome analysis 1 Protein-protein interactions 2 Protein Domains in Yeast 3 Classification of protein interaction domains 3 Phosphoinositides 5 Function 5 Structure 5 Biochemistry 6 Localization 7 Lipid Binding Domains 8 The PX domain 10 Function of PX domain containing proteins 10 PX domain structure and PI binding affinities 10 Yeast PX domain containing proteins 13 PX domain and protein-protein interactions 13 Lipid binding domains and protein-protein interactions 14 The PX-only proteins Grd19p and Ypt35p and their phenotypes 15 Aim of my PhD work 16 Project outline 16 Searching for interacting partners 16 Confirmation of obtained interactions via a 16 second independent method Mapping the interacting region 16 The Two-Hybrid System 17 Definition 17 Basic Principle of the classical Yeast-Two Hybrid System 17 Peptide Synthesis 18 SPOT synthesis technique 18 Analysis of protein- peptide contact sites based on SPOT synthesis 19 TABLE OF CONTENTS Experimental procedures 21 Yeast two-hybrid assay
  • (LASP1) in the Metastatic Dissemination of Medulloblastoma

    (LASP1) in the Metastatic Dissemination of Medulloblastoma

    Published OnlineFirst October 5, 2010; DOI: 10.1158/0008-5472.CAN-10-0592 Published OnlineFirst on October 5, 2010 as 10.1158/0008-5472.CAN-10-0592 Therapeutics, Targets, and Chemical Biology Cancer Research Role of LIM and SH3 Protein 1 (LASP1) in the Metastatic Dissemination of Medulloblastoma Christopher Traenka1, Marc Remke2,5, Andrey Korshunov4,6, Sebastian Bender2,5, Thomas Hielscher3, Paul A. Northcott7, Hendrik Witt2,5, Marina Ryzhova8, Jörg Felsberg9, Axel Benner3, Stephanie Riester2, Wolfram Scheurlen10, Thomas G.P. Grunewald11, Andreas von Deimling6, Andreas E. Kulozik5, Guido Reifenberger9, Michael D. Taylor7, Peter Lichter2, Elke Butt1, and Stefan M. Pfister2,5 Abstract Medulloblastoma is the most common malignant pediatric brain tumor and is one of the leading causes of cancer-related mortality in children. Treatment failure mainly occurs in children harboring metastatic tumors, which typically carry an isochromosome 17 or gain of 17q, a common hallmark of intermediate and high-risk medulloblastoma. Through mRNA expression profiling, we identified LIM and SH3 protein 1 (LASP1) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. In an independent validation cohort of 101 medulloblastoma samples, the abundance of LASP1 mRNA was significantly associated with 17q gain, metastatic dissemination, and unfavorable outcome. LASP1 protein expression was analyzed by immuno- histochemistry in a large cohort of patients (n = 207), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival. In vitro experiments in medulloblastoma cell lines showed a strong reduction of cell migration, increased adhesion, and decreased proliferation upon LASP1 knockdown by small interfering RNA–mediated silencing, further indicating a functional role for LASP1 in the progression and metastatic dissemination of medullo- blastoma.
  • A Dissertation Entitled Characterization of the CXCR4

    A Dissertation Entitled Characterization of the CXCR4

    A Dissertation entitled Characterization of the CXCR4-LASP1-eIF4F Axis in Triple-Negative Breast Cancer by Cory M Howard Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences ___________________________________________ Dayanidhi Raman, B.V.Sc., Ph.D., Committee Chair ___________________________________________ Amit Tiwari, Ph.D., Committee Member ___________________________________________ Ritu Chakravarti, Ph.D., Committee Member ___________________________________________ Nagalakshmi Nadiminty, Ph.D., Committee Member ___________________________________________ Saori Furuta, Ph.D., Committee Member ___________________________________________ Shi-He Liu, M.D., Committee Member ___________________________________________ Amanda C. Bryant-Friedrich, Ph.D., Dean College of Graduate Studies The University of Toledo August 2020 © 2020 Cory M. Howard This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Characterization of the CXCR4-LASP1-eIF4F Axis in Triple-Negative Breast Cancer by Cory M. Howard Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Doctor of Philosophy Degree in Biomedical Sciences The University of Toledo August 2020 Triple-negative breast cancer (TNBC) remains clinically challenging as effective targeted therapies are still lacking. In addition, patient mortality mainly results from the metastasized
  • Insulin Receptor Tyrosine Kinase Substrate Links the E. Coli O157:H7

    Insulin Receptor Tyrosine Kinase Substrate Links the E. Coli O157:H7

    Insulin receptor tyrosine kinase substrate links the E. coli O157:H7 actin assembly effectors Tir and EspFU during pedestal formation Didier Vingadassaloma, Arunas Kazlauskasb, Brian Skehana, Hui-Chun Chengc, Loranne Magouna, Douglas Robbinsa, Michael K. Rosenc, Kalle Sakselab, and John M. Leonga,1 aDepartment of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655; bDepartment of Virology, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital, FIN-00014, Helsinki, Finland; and cDepartment of Biochemistry and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390 Edited by R. John Collier, Harvard Medical School, Boston, MA, and approved March 2, 2009 (received for review September 12, 2008) Enterohemorrhagic Escherichia coli O157:H7 translocates 2 effec- host cell plasma membrane with N- and C-terminal intracellular tors to trigger localized actin assembly in mammalian cells, result- domains and a central extracellular domain that binds to the ing in filamentous actin ‘‘pedestals.’’ One effector, the translocated bacterial outer membrane protein intimin. Clustering of Tir in the intimin receptor (Tir), is localized in the plasma membrane and host cell membrane upon intimin binding initiates a signaling clustered upon binding the bacterial outer membrane protein cascade, ultimately leading to actin pedestal formation. intimin. The second, the proline-rich effector EspFU (aka TccP) For the canonical EPEC strain, serotype O127:H6, Tir is the activates the actin nucleation-promoting factor WASP/N-WASP, only translocated effector required for pedestal formation, and and is recruited to sites of bacterial attachment by a mechanism after becoming phosphorylated on tyrosine residue 474 (Y474) dependent on an Asn-Pro-Tyr (NPY458) sequence in the Tir C- by mammalian kinases, recruits the SH2 domain-containing terminal cytoplasmic domain.
  • The Role of Non-Coding Rnas in Uveal Melanoma

    The Role of Non-Coding Rnas in Uveal Melanoma

    cancers Review The Role of Non-Coding RNAs in Uveal Melanoma Manuel Bande 1,2,*, Daniel Fernandez-Diaz 1,2, Beatriz Fernandez-Marta 1, Cristina Rodriguez-Vidal 3, Nerea Lago-Baameiro 4, Paula Silva-Rodríguez 2,5, Laura Paniagua 6, María José Blanco-Teijeiro 1,2, María Pardo 2,4 and Antonio Piñeiro 1,2 1 Department of Ophthalmology, University Hospital of Santiago de Compostela, Ramon Baltar S/N, 15706 Santiago de Compostela, Spain; [email protected] (D.F.-D.); [email protected] (B.F.-M.); [email protected] (M.J.B.-T.); [email protected] (A.P.) 2 Tumores Intraoculares en el Adulto, Instituto de Investigación Sanitaria de Santiago (IDIS), 15706 Santiago de Compostela, Spain; [email protected] (P.S.-R.); [email protected] (M.P.) 3 Department of Ophthalmology, University Hospital of Cruces, Cruces Plaza, S/N, 48903 Barakaldo, Vizcaya, Spain; [email protected] 4 Grupo Obesidómica, Instituto de Investigación Sanitaria de Santiago (IDIS), 15706 Santiago de Compostela, Spain; [email protected] 5 Fundación Pública Galega de Medicina Xenómica, Clinical University Hospital, SERGAS, 15706 Santiago de Compostela, Spain 6 Department of Ophthalmology, University Hospital of Coruña, Praza Parrote, S/N, 15006 La Coruña, Spain; [email protected] * Correspondence: [email protected]; Tel.: +34-981951756; Fax: +34-981956189 Received: 13 September 2020; Accepted: 9 October 2020; Published: 12 October 2020 Simple Summary: The development of uveal melanoma is a multifactorial and multi-step process, in which abnormal gene expression plays a key role.
  • From Src Homology Domains to Other Signaling Modules: Proposal of the `Protein Recognition Code'

    From Src Homology Domains to Other Signaling Modules: Proposal of the `Protein Recognition Code'

    Oncogene (1998) 17, 1469 ± 1474 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 http://www.stockton-press.co.uk/onc From Src Homology domains to other signaling modules: proposal of the `protein recognition code' Marius Sudol The Department of Biochemistry, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA The study of oncogenes has illuminated many aspects of domains have identi®ed a set of common features cellular signaling. The delineation and characterization which aids in their description. The domains are of protein modules exempli®ed by Src Homology composed of 40 ± 150 amino acids which fold to domains has revolutionized our understanding of the generate one or more ligand-binding surfaces, known molecular events underlying signal transduction path- as `recognition pockets'. Generally, conserved residues ways. Several well characterized intracellular modules of the domain are directly involved in mediating which mediate protein-protein interactions, namely SH2, contacts with the amino acids of the ligand and in SH3, PH, PTB, EH, PDZ, EVH1 and WW domains, maintaining the structure of the domain. Ligands are directly involved in the multitude of membrane, interact with their complementary domains through cytoplasmic and nuclear processes in multicellular and/or short sequence motifs (also called core motifs), unicellular organisms. The modular character of these composed of only 3 ± 6 amino acids (Figure 1). The protein domains and their cognate motifs, the univers- sequence of the core determines the selection of the ality of their molecular function, their widespread domains (Songyang and Cantley, 1995). The most occurrence, and the speci®city as well as the degeneracy `important' amino acid within the core is traditionally of their interactions have prompted us to propose the designated `0' and the remaining amino acids are concept of the `protein recognition code'.
  • Meltrin a Cytoplasmic Domain Interacts with SH3 Domains of Src and Grb2 and Is Phosphorylated by V-Src

    Meltrin a Cytoplasmic Domain Interacts with SH3 Domains of Src and Grb2 and Is Phosphorylated by V-Src

    Oncogene (2000) 19, 5842 ± 5850 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Meltrin a cytoplasmic domain interacts with SH3 domains of Src and Grb2 and is phosphorylated by v-Src Akiko Suzuki1, Nae Kadota1, Tomokazu Hara1, Yoshiko Nakagami1, Toshiaki Izumi1, Tadaomi Takenawa2, Hisataka Sabe3 and Takeshi Endo*,1 1Department of Biology, Faculty of Science, Chiba University, Yayoicho, Inageku, Chiba, Chiba 263-8522, Japan; 2Department of Biochemistry, Institute of Medical Science, University of Tokyo, Shirokanedai, Minatoku, Tokyo 108-8639, Japan; 3Department of Molecular Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan Meltrin a/ADAM12 is a member of the ADAM/MDC receptor tyrosine kinases, tyrosine kinase-coupled family proteins characterized by the presence of cytokine receptors, TGF-b family receptor serine/ metalloprotease and disintegrin domains. This protein threonine kinases, and seven-pass G protein-coupled also contains a single transmembrane domain and a receptors. Integrins and cadherins not only serve as relatively long cytoplasmic domain containing several transmembrane adhesion molecules but also participate proline-rich sequences. These sequences are compatible in intracellular and extracellular signaling (Schwartz et with the consensus sequences for binding the Src al., 1995; Ben-Ze'ev, 1997; Yamada and Geiger, 1997). homology 3 (SH3) domains. To determine whether the ADAM/MDC family proteins have emerged as proline-rich sequences interact with SH3 domains in candidate molecules for proteolytic processing, cell ± several proteins, binding of recombinant SH3 domains to cell attachment, and cell fusion (Wolfsberg et al., 1995; the meltrin a cytoplasmic domain was analysed by pull- Wolfsberg and White, 1996; Huovila et al., 1996; Black down assays.
  • Phosphorylation-Dependent Differences in CXCR4-LASP1

    Phosphorylation-Dependent Differences in CXCR4-LASP1

    cells Article Phosphorylation-Dependent Differences in CXCR4-LASP1-AKT1 Interaction between Breast Cancer and Chronic Myeloid Leukemia Elke Butt 1,*, Katrin Stempfle 1, Lorenz Lister 1, Felix Wolf 1,2, Marcella Kraft 1, Andreas B. Herrmann 1 , Cristina Perpina Viciano 2,3, Christian Weber 4,5,6 , Andreas Hochhaus 7, Thomas Ernst 7, Carsten Hoffmann 2,3, Alma Zernecke 1 and Jochen J. Frietsch 7 1 Institute of Experimental Biomedicine, University Hospital Wuerzburg, Josef-Schneider-Straße 2, 97080 Wuerzburg, Germany; katrin.stempfl[email protected] (K.S.); [email protected] (L.L.); [email protected] (F.W.); [email protected] (M.K.); [email protected] (A.B.H.); [email protected] (A.Z.) 2 Institute of Molecular Cell Biology, CMB-Center for Molecular Biomedicine, University Hospital Jena, Hans-Knöll-Straße 2, 07745 Jena, Germany; [email protected] (C.P.V.); Carsten.Hoff[email protected] (C.H.) 3 Rudolf Virchow Center for Experimental Biomedicine, University of Wuerzburg, Josef-Schneider-Str. 5, 97080 Wuerzburg, Germany 4 Institute for Cardiovascular Prevention, LMU Munich, 80336 Munich, Germany; ipek.offi[email protected] 5 Cardiovascular Research Institute Maastricht, Department of Biochemistry, Maastricht University, 6229 ER Maastricht, The Netherlands 6 DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany 7 Klinik für Innere Medizin II, Abteilung für Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Am Klinikum 1, 07747 Jena, Germany; [email protected] (A.H.); [email protected] (T.E.); [email protected] (J.J.F.) * Correspondence: [email protected] Received: 3 December 2019; Accepted: 11 February 2020; Published: 14 February 2020 Abstract: The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival.
  • C-Abl: Activation and Nuclear Targets

    C-Abl: Activation and Nuclear Targets

    Cell Death and Differentiation (2000) 7, 10 ± 16 ã 2000 Macmillan Publishers Ltd All rights reserved 1350-9047/00 $15.00 www.nature.com/cdd Review c-Abl: activation and nuclear targets Y Shaul*,1 fibroblasts it resides predominantly in the nucleus while in primary haematopoietic cells and neurons c-Abl is more 1 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot cytoplasmic. In sharp contrast, all the transforming Abl 76100, Israel variants are exclusively cytoplasmic. The cellular subcellular * Corresponding author: Y Shaul, Department of Molecular Genetics, Weizmann localization of c-Abl is controlled by NLSs (nuclear localization Institute of Science, Rehovot 76100, Israel. Tel: 972-8-934-2320; signals) and an NES (nuclear export signal). This pattern of Fax: 972-8-934-4108; E-mail: [email protected] cellular distribution of c-Abl hints at its possible involvement in multiple molecular pathways, and indeed various nuclear and Received 30.9.99; accepted 26.10.99 cytoplasmic functions have been attributed to c-Abl (reviewed 1 Edited by R Knight in ). Cellular processes involving the nuclear c-Abl will be discussed below. Some of the functional domains of c-Abl have been Abstract characterized (Figure 1). Common features to this family are the myristoylation site (found at the N terminus of the The c-Abl tyrosine kinase and its transforming variants have alternatively spliced human Ib and mouse IV transcripts), been implicated in tumorigenesis and in many important the tyrosine kinase domain with substrate specificity,2 the cellular processes. c-Abl is localized in the nucleus and the Src homology 2 (SH2) and 3 (SH3), both regulating c-Abl cytoplasm, where it plays distinct roles.
  • Proteomic Shifts in Embryonic Stem Cells with Gene Dose Modifications Suggest the Presence of Balancer Proteins in Protein Regulatory Networks

    Proteomic Shifts in Embryonic Stem Cells with Gene Dose Modifications Suggest the Presence of Balancer Proteins in Protein Regulatory Networks

    Proteomic shifts in embryonic stem cells with gene dose modifications suggest the presence of balancer proteins in protein regulatory networks. Lei Mao, Claus Zabel, Marion Herrmann, Tobias Nolden, Florian Mertes, Laetitia Magnol, Caroline Chabert, Daniela Hartl, Yann Herault, Jean Maurice Delabar, et al. To cite this version: Lei Mao, Claus Zabel, Marion Herrmann, Tobias Nolden, Florian Mertes, et al.. Proteomic shifts in embryonic stem cells with gene dose modifications suggest the presence of balancer proteins in protein regulatory networks.. PLoS ONE, Public Library of Science, 2007, 2 (11), pp.e1218. 10.1371/jour- nal.pone.0001218. hal-00408296 HAL Id: hal-00408296 https://hal.archives-ouvertes.fr/hal-00408296 Submitted on 31 May 2020 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. Proteomic Shifts in Embryonic Stem Cells with Gene Dose Modifications Suggest the Presence of Balancer Proteins in Protein Regulatory Networks Lei Mao1,2*, Claus Zabel1, Marion Herrmann1, Tobias Nolden2, Florian Mertes2, Laetitia Magnol3, Caroline Chabert4, Daniela
  • Novel Roles of SH2 and SH3 Domains in Lipid Binding

    Novel Roles of SH2 and SH3 Domains in Lipid Binding

    cells Review Novel Roles of SH2 and SH3 Domains in Lipid Binding Szabolcs Sipeki 1,†, Kitti Koprivanacz 2,†, Tamás Takács 2, Anita Kurilla 2, Loretta László 2, Virag Vas 2 and László Buday 1,2,* 1 Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis University Medical School, 1094 Budapest, Hungary; [email protected] 2 Institute of Enzymology, Research Centre for Natural Sciences, 1117 Budapest, Hungary; [email protected] (K.K.); [email protected] (T.T.); [email protected] (A.K.); [email protected] (L.L.); [email protected] (V.V.) * Correspondence: [email protected] † Both authors contributed equally to this work. Abstract: Signal transduction, the ability of cells to perceive information from the surroundings and alter behavior in response, is an essential property of life. Studies on tyrosine kinase action fundamentally changed our concept of cellular regulation. The induced assembly of subcellular hubs via the recognition of local protein or lipid modifications by modular protein interactions is now a central paradigm in signaling. Such molecular interactions are mediated by specific protein interaction domains. The first such domain identified was the SH2 domain, which was postulated to be a reader capable of finding and binding protein partners displaying phosphorylated tyrosine side chains. The SH3 domain was found to be involved in the formation of stable protein sub-complexes by constitutively attaching to proline-rich surfaces on its binding partners. The SH2 and SH3 domains have thus served as the prototypes for a diverse collection of interaction domains that recognize not only proteins but also lipids, nucleic acids, and small molecules.