DOCSLIB.ORG

RTK-RAS-MAPK Modulators As New Therapeutic Targets

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
RTK-RAS-MAPK Modulators As New Therapeutic Targets biomolecules Commentary Spotlight on Accessory Proteins: RTK-RAS-MAPK Modulators as New Therapeutic Targets Silke Pudewell and Mohammad Reza Ahmadian * Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, Germany; [email protected] * Correspondence: [email protected] Abstract: The RTK-RAS-MAPK axis is one of the most extensively studied signaling cascades and is related to the development of both cancers and RASopathies. In the last 30 years, many ideas and approaches have emerged for directly targeting constituent members of this cascade, predominantly in the context of cancer treatment. These approaches are still insufficient due to undesirable drug toxicity, resistance, and low efficacy. Significant advances have been made in understanding the spatiotemporal features of the constituent members of the RTK-RAS-MAPK axis, which are linked and modulated by many accessory proteins. Given that the majority of such modulators are now emerging as attractive therapeutic targets, a very small number of accessory inhibitors have yet to be discovered. Keywords: adaptor proteins; anchoring proteins; docking proteins; KRAS; scaffold proteins; RAF kinase; RTK; MEK; ERK Citation: Pudewell, S.; Ahmadian, External signals are sensed, integrated, and amplified by conserved signaling cassettes. M.R. Spotlight on Accessory Proteins: The activation of the RTK-RAS-MAPK signaling cascade is regulated by several different RTK-RAS-MAPK Modulators as New extracellular signals and intracellular proteins. Growth factors activate receptor tyrosine Therapeutic Targets. Biomolecules kinases (RTKs) at the plasma membrane, which in turn activate RAS via the GDP/GTP 2021, 11, 895. https://doi.org/ exchange reaction. These reactions are catalyzed by guanosine exchange factors (GEFs), 10.3390/biom11060895 such as SOS1 (son of sevenless 1). GTP-bound RAS initiates RAF dimerization and in- duces the phosphorylation cascade towards MEK and ERK [1]. Aberrant regulation or Academic Editor: Daniel Abankwa hyperactivation of the pathway leads to cancer and a group of developmental disorders with a mild gain-of-function of the RAS-MAPK pathway, which are collectively called Received: 10 May 2021 RASopathies [2,3]. Accepted: 15 June 2021 Targeting the constituent components of the RTK-RAS-MAPK signaling cascade often Published: 16 June 2021 leads to high toxicity and activation of backup mechanisms, lowering the treatment effi- cacy and increasing the burden of the therapy. In this context, we have to consider that Publisher’s Note: MDPI stays neutral RASopathies are caused by germline mutations, therefore, most patients are children. with regard to jurisdictional claims in Here, we highlight a group of proteins named “accessory proteins”, which are emerg- published maps and institutional affil- ing as new potential therapeutic targets for the treatment of RAS-MAPK-related diseases. iations. These proteins orchestrate the assembly and spatiotemporal localization of the constituent members of the cascade, without being part of the signaling pathway themselves [4]. Acces- sory proteins can be categorized into four distinct subgroups (see Figure1): (1) anchoring proteins that bind to the membrane and other effectors (mostly kinases); (2) docking pro- Copyright: © 2021 by the authors. teins that bind to receptors (e.g., RTKs and GPCRs) and more than one effector; (3) adaptor Licensee MDPI, Basel, Switzerland. proteins that simply link two signaling components (e.g., receptor and GEF); and (4) scaf- This article is an open access article fold proteins that bind two or more partners and provide a signaling platform. distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Biomolecules 2021, 11, 895. https://doi.org/10.3390/biom11060895 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, 895 2 of 4 Biomolecules 2021, 11, x FOR PEER REVIEW 2 of 4 Figure 1. AccessoryAccessory proteins proteins can can be be divided divided into into at atleast least four four subgroups: subgroups: anchoring, anchoring, docking, docking, adaptor, adaptor, and scaffold and scaffold pro- teins. All groups include several different binders of the RTK-RAS-MAPK signaling pathway, such as RAF, MEK, and/or proteins. All groups include several different binders of the RTK-RAS-MAPK signaling pathway, such as RAF, MEK, and/or ERK, and often share common domains. Anchoring proteins include membrane-associated domains, such as pleckstrin ERK, and often share common domains. Anchoring proteins include membrane-associated domains, such as pleckstrin homology (PH) and transmembrane (TM) domains or a posttranslational modification, (e.g., myristoylation in FLOT2) to determinehomology a (PH) special and subcellular transmembrane localization (TM) domains and increase or a posttranslationalthe dwell time of the modification, proteins at (e.g., the membrane. myristoylation Docking in FLOT2) proteins to connectdetermine receptors a special with subcellular downstream localization effectors and and increase feature the recept dwellor binding time ofthe domains, proteins such at the as PTBs membrane. (phosphotyrosine Docking proteins bind- ingconnect domains). receptors FRS2, with for downstream example, interact effectorss with and featurethe FGFR receptor (fibroblast binding growth domains, fact suchor receptor) as PTBs and (phosphotyrosine links activated binding RTKs (receptordomains). tyrosine FRS2, for kinases) example, with interacts adaptor with proteins the FGFR such (fibroblast as GRB2 and growth SHC, factor and receptor)with other and effe linksctors, activated such as SOS1. RTKs (receptorAdaptor proteinstyrosine kinases)can simply with connect adaptor two proteins proteins such and asoften GRB2 exhibit and SH SHC, (SRC and homology) with other 2 effectors, and SH3 suchdomains. as SOS1. GRB2 Adaptor is a well-known proteins adaptorcan simply protein connect of RTKs two proteins and SOS1 and but often can exhibitalso, as SH mentioned (SRC homology) before, bind 2 and to SH3other domains. accessor GRB2y proteins is a well-known and RTKs and adaptor fine- proteintune the of signaling RTKs and machinery SOS1 but an cand the also, cross-talk as mentioned of different before, pathways. bind to other Scaffold accessory proteins proteins can simultaneously and RTKs and fine-tunebind several the signaling components. They can contribute to clustering events by oligomerization via special domains or intrinsically signaling machinery and the cross-talk of different pathways. Scaffold proteins can simultaneously bind several signaling disordered regions (such as galectin 1 and 3), recruit proteins to the site of action (such as SPRED1), or determine RAS components. They can contribute to clustering events by oligomerization via special domains or intrinsically disordered signaling at a specific subcellular localization (such as MP1, which binds MEK1 and ERK1 on late endosomes). Scaffold proteinsregions (such are also as galectinable to bind 1 and ot 3),her recruit accessory proteins proteins to the and site allow of action tight (suchcontrol as of SPRED1), the RAS-MAPK or determine pathway. RAS signaling at a specific subcellular localization (such as MP1, which binds MEK1 and ERK1 on late endosomes). Scaffold proteins are also able to bind other accessory proteinsAs modulators and allow tight of the control RTK-RAS-MAPK of the RAS-MAPK axis pathway., accessory proteins are multidomain pro- teins that bind several interaction partners and connect them as a functional unit. Accord- As modulators of the RTK-RAS-MAPK axis, accessory proteins are multidomain ingly, they contribute to liquid–liquid phase separation (LLPS) events, which are crucial proteins that bind several interaction partners and connect them as a functional unit. for a directed assembly of the respective signaling machinery[5,6]. Furthermore, they can Accordingly, they contribute to liquid–liquid phase separation (LLPS) events, which are fine-tune the crosstalk between signaling pathways, increase the dwell time of proteins crucial for a directed assembly of the respective signaling machinery [5,6]. Furthermore, on the membrane, induce nanoclustering, sequester effectors, and shield them from acti- they can fine-tune the crosstalk between signaling pathways, increase the dwell time of vation, or determine the cell type specificity and subcellular localization of signaling cas- proteins on the membrane, induce nanoclustering, sequester effectors, and shield them from settes [7]. These modulating abilities turn accessory proteins into incredibly flexible and activation, or determine the cell type specificity and subcellular localization of signaling importantcassettes [ 7proteins]. These within modulating a very abilitiesspecific contex turn accessoryt. In fact, proteinsit is easy intoto understand incredibly why flexible the dysregulationand important of proteins accessory within proteins a very not specific only leads context. to cancer In fact, development it is easy to understand and cancer whypro- gressionthe dysregulation in RAS-mutant of accessory tumors proteins but also not contributes only leads to toRASopathies. cancer development and cancer progressionThe last in30 RAS-mutant years of research tumors have but led also to contributessignificant discoveries to RASopathies. and improvements in cancerThe treatment, last 30 years but new of research therapeutic have ledapproa to
Load more

Recommended publications
  • Adaptive Stress Signaling in Targeted Cancer Therapy Resistance
    Oncogene (2015) 34, 5599–5606 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc REVIEW Adaptive stress signaling in targeted cancer therapy resistance E Pazarentzos1,2 and TG Bivona1,2 The identification of specific genetic alterations that drive the initiation and progression of cancer and the development of targeted drugs that act against these driver alterations has revolutionized the treatment of many human cancers. Although substantial progress has been achieved with the use of such targeted cancer therapies, resistance remains a major challenge that limits the overall clinical impact. Hence, despite progress, new strategies are needed to enhance response and eliminate resistance to targeted cancer therapies in order to achieve durable or curative responses in patients. To date, efforts to characterize mechanisms of resistance have primarily focused on molecular events that mediate primary or secondary resistance in patients. Less is known about the initial molecular response and adaptation that may occur in tumor cells early upon exposure to a targeted agent. Although understudied, emerging evidence indicates that the early adaptive changes by which tumor cells respond to the stress of a targeted therapy may be crucial for tumo r cell survival during treatment and the development of resistance. Here we review recent data illuminating the molecular architecture underlying adaptive stress signaling in tumor cells. We highlight how leveraging this knowledge could catalyze novel strategies to minimize
    [Show full text]
  • Mutation Analysis of Son of Sevenless in Juvenile Myelomonocytic Leukemia
    Letters to the Editor 1108 3 Licht JD. Reconstructing a disease: what essential features of the the development of acute promyelocytic leukemia in transgenic retinoic acid receptor fusion oncoproteins generate acute promye- mice. Proc Natl Acad Sci USA 2000; 97: 13306–13311. locytic leukemia? Cancer Cell 2006; 9: 73–74. 10 Sternsdorf T, Phan VT, Maunakea ML, Ocampo CB, Sohal J, 4 Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J et al. Silletto A et al. Forced retinoic acid receptor alpha homodimers A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 prime mice for APL-like leukemia. Cancer Cell 2006; 9: 81–94. genes as a therapeutic target of imatinib in idiopathic hypereosino- 11 Kwok C, Zeisig BB, Dong S, So CW. Forced homo-oligomerization philic syndrome. N Engl J Med 2003; 348: 1201–1214. of RARalpha leads to transformation of primary hematopoietic 5 Kaufmann I, Martin G, Friedlein A, Langen H, Keller W. Human cells. Cancer Cell 2006; 9: 95–108. Fip1 is a subunit of CPSF that binds to U-rich RNA elements and 12 Palaniswamy V, Moraes KC, Wilusz CJ, Wilusz J. Nucleophosmin stimulates poly(A) polymerase. EMBO J 2004; 23: 616–626. is selectively deposited on mRNA during polyadenylation. Nat 6 Sainty D, Liso V, Cantu-Rajnoldi A, Head D, Mozziconacci MJ, Struct Mol Biol 2006; 13: 429–435. Arnoulet C et al. A new morphologic classification system for acute 13 Rego EM, Ruggero D, Tribioli C, Cattoretti G, Kogan S, Redner RL promyelocytic leukemia distinguishes cases with underlying PLZF/ et al.
    [Show full text]
  • Figure S1. HAEC ROS Production and ML090 NOX5-Inhibition
    Figure S1. HAEC ROS production and ML090 NOX5-inhibition. (a) Extracellular H2O2 production in HAEC treated with ML090 at different concentrations and 24 h after being infected with GFP and NOX5-β adenoviruses (MOI 100). **p< 0.01, and ****p< 0.0001 vs control NOX5-β-infected cells (ML090, 0 nM). Results expressed as mean ± SEM. Fold increase vs GFP-infected cells with 0 nM of ML090. n= 6. (b) NOX5-β overexpression and DHE oxidation in HAEC. Representative images from three experiments are shown. Intracellular superoxide anion production of HAEC 24 h after infection with GFP and NOX5-β adenoviruses at different MOIs treated or not with ML090 (10 nM). MOI: Multiplicity of infection. Figure S2. Ontology analysis of HAEC infected with NOX5-β. Ontology analysis shows that the response to unfolded protein is the most relevant. Figure S3. UPR mRNA expression in heart of infarcted transgenic mice. n= 12-13. Results expressed as mean ± SEM. Table S1: Altered gene expression due to NOX5-β expression at 12 h (bold, highlighted in yellow). N12hvsG12h N18hvsG18h N24hvsG24h GeneName GeneDescription TranscriptID logFC p-value logFC p-value logFC p-value family with sequence similarity NM_052966 1.45 1.20E-17 2.44 3.27E-19 2.96 6.24E-21 FAM129A 129. member A DnaJ (Hsp40) homolog. NM_001130182 2.19 9.83E-20 2.94 2.90E-19 3.01 1.68E-19 DNAJA4 subfamily A. member 4 phorbol-12-myristate-13-acetate- NM_021127 0.93 1.84E-12 2.41 1.32E-17 2.69 1.43E-18 PMAIP1 induced protein 1 E2F7 E2F transcription factor 7 NM_203394 0.71 8.35E-11 2.20 2.21E-17 2.48 1.84E-18 DnaJ (Hsp40) homolog.
    [Show full text]
  • Structural Analysis of Autoinhibition in the Ras-Specific Exchange Factor
    RESEARCH ARTICLE elife.elifesciences.org Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1 Jeffrey S Iwig1,2, Yvonne Vercoulen3†, Rahul Das1,2†, Tiago Barros1,2,4, Andre Limnander3, Yan Che1,2, Jeffrey G Pelton2, David E Wemmer2,5,6, Jeroen P Roose3*, John Kuriyan1,2,4,5,6* 1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; 2California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States; 3Department of Anatomy, University of California, San Francisco, San Francisco, United States; 4Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; 5Department of Chemistry, University of California, Berkeley, Berkeley, United States; 6Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, United States Abstract RasGRP1 and SOS are Ras-specific nucleotide exchange factors that have distinct roles in lymphocyte development. RasGRP1 is important in some cancers and autoimmune diseases but, in contrast to SOS, its regulatory mechanisms are poorly understood. Activating signals lead to the membrane recruitment of RasGRP1 and Ras engagement, but it is unclear how interactions between RasGRP1 and Ras are suppressed in the absence of such signals. We present a crystal structure of a fragment of RasGRP1 in which the Ras-binding site is blocked by an interdomain linker and the membrane-interaction surface of RasGRP1 is hidden within a dimerization interface that may be stabilized by the C-terminal oligomerization domain. NMR data demonstrate that calcium binding to the regulatory module generates substantial conformational changes that are incompatible with the inactive assembly. These features allow RasGRP1 to be maintained in an inactive state that is poised for activation by calcium and membrane-localization signals.
    [Show full text]
  • Snapshot: Mtorc1 Signaling at the Lysosomal Surface Liron Bar-Peled and David M
    1390 Cell SnapShot: mTORC1 Signaling at the 151 , December 7,2012©2012 ElsevierInc. DOI http://dx.doi.org/10.1016/j.cell.2012.11.038 Lysosomal Surface Liron Bar-Peled and David M. Sabatini Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA Nutrient signaling Wnt Growth Leu signaling factor signaling TNF signaling Amino Gln Wnt Tyrosine acids Frizzled IGF kinase TNFD receptor TNF receptor DNA Energy levels O levels SLC1A5 SLC7A5 2 damage ATP/AMP PIP2 Pten Amino acid mTORC1 Dsh1 IRS1 transporter Gln (inactive) GRB2 SOS PI3K PIP3 Gln Redd1 p53 LKB1 GEF GSK3 activity Leu GTP Ras NF1 PDK1 GAP Sestrin Movement to the activity RagAGTP lysosomal surface Movement AMPK Raf GDP away from Rapamycin RagA the lysosomal surface FKBP12 Mek Erk1/2 Rsk1 Akt1 IKK` v-ATPase GEF activity CYTOPLASM RagAGTP mTORC1 Ragulator GTP GAP activity GDP TSC complex RagC (active) Rheb Tumor suppressor Oncogene mTORC1 substrate ? Growth DOWNSTREAM CELLULAR PROGRAMS REGULATED BY mTORC1 ACTIVITY See online version for legend and references. S6K1 Amino acids LYSOSOME Protein synthesis 4EBP1 COMPLEXES AT THE LYSOSOMAL SURFACE HIF1_ Energy metabolism A B A E E G G pras40 deptor Lysosome biogenesis A BB MP1 HBXIP TSC1 TBC1D7 TFEB p14 C7orf59 raptor H mLST8 Lipin-1 D C Lipid p18 biosynthesis a d F mTOR TSC2 SREBP1/2 c cc ATG13 FIP200 Autophagy Lysosomal v-ATPase Ragulator complex mTORC1 TSC complex ULK1 SnapShot: mTORC1 Signaling at the Lysosomal Surface Liron Bar-Peled and David M. Sabatini Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA In mammals, the mTOR complex 1 (mTORC1) ser/thr kinase regulates cellular and organismal growth in response to a variety of environmental and intracellular stimuli.
    [Show full text]
  • Regulation of Ras Exchange Factors and Cellular Localization of Ras Activation by Lipid Messengers Int Cells
    REVIEW ARTICLE published: 04 September 2013 doi: 10.3389/fimmu.2013.00239 Regulation of Ras exchange factors and cellular localization of Ras activation by lipid messengers inT cells Jesse E. Jun1, Ignacio Rubio2 and Jeroen P.Roose 1* 1 Department of Anatomy, University of California San Francisco, San Francisco, CA, USA 2 Institute for Molecular Cell Biology, Center for Sepsis Control and Care (CSCC), University Hospital, Friedrich-Schiller-University, Jena, Germany Edited by: The Ras-MAPK signaling pathway is highly conserved throughout evolution and is acti- Karsten Sauer, The Scripps Research vated downstream of a wide range of receptor stimuli. Ras guanine nucleotide exchange Institute, USA factors (RasGEFs) catalyze GTP loading of Ras and play a pivotal role in regulating receptor- Reviewed by: Kjetil Taskén, University of Oslo, ligand induced Ras activity. In T cells, three families of functionally important RasGEFs are Norway expressed: RasGRF,RasGRP,and Son of Sevenless (SOS)-family GEFs. Early on it was rec- Balbino Alarcon, Consejo Superior de ognized that Ras activation is critical for T cell development and that the RasGEFs play an Investigaciones Cientificas, Spain important role herein. More recent work has revealed that nuances in Ras activation appear *Correspondence: to significantly impactT cell development and selection.These nuances include distinct bio- Jeroen P.Roose, Department of Anatomy, University of California San chemical patterns of analog versus digital Ras activation, differences in cellular localization Francisco, 513 Parnassus Avenue, of Ras activation, and intricate interplays between the RasGEFs during distinctT cell devel- Room HSW-1326, San Francisco, CA opmental stages as revealed by various new mouse models.
    [Show full text]
  • Regulation of Son of Sevenless by the Membrane-Actin Linker Protein Ezrin
    Regulation of Son of sevenless by the membrane-actin linker protein ezrin Katja J. Geißlera, M. Juliane Junga, Lars Björn Rieckena, Tobias Sperkab,1, Yan Cuia, Stephan Schackea, Ulrike Merkela, Robby Markwartc, Ignacio Rubioc, Manuel E. Thand, Constanze Breithaupte, Sebastian Peukerf, Reinhard Seifertf, Ulrich Benjamin Kauppf, Peter Herrlichb, and Helen Morrisona,2 aH.M. Laboratory, bP.H. Laboratory, and dM.E.T. Laboratory, Leibniz Institute for Age Research – Fritz Lipmann Institute, 07745 Jena, Germany; cResearch Group ANERGY, Center for Sepsis Control and Care, University Hospital, Friedrich Schiller University, 07747 Jena, Germany; eAbteilung Physikalische Biotechnologie, Martin Luther University of Halle-Wittenberg, 06120 Halle (Saale), Germany; and fDepartment of Molecular Sensory Systems, Center of Advanced European Studies and Research, 53175 Bonn, Germany Edited by Michael Karin, University of California, San Diego School of Medicine, La Jolla, CA, and approved October 28, 2013 (received for review December 18, 2012) Receptor tyrosine kinases participate in several signaling path- comprises Ras, SOS, filamentous actin, and coreceptors such as ways through small G proteins such as Ras (rat sarcoma). An im- β1-integrin. Coreceptors focus these complexes to relevant sites of portant component in the activation of these G proteins is Son of RTK activity at the plasma membrane/F-actin interface. We de- sevenless (SOS), which catalyzes the nucleotide exchange on Ras. fined binding sites on ezrin for both Ras and SOS, mutations of For optimal activity, a second Ras molecule acts as an allosteric which destroy the interactions and inhibit the activation of Ras. activator by binding to a second Ras-binding site within SOS.
    [Show full text]
  • Understanding SOS (Son of Sevenless) Stéphane Pierre, Anne-Sophie Bats, Xavier Coumoul
    Understanding SOS (Son of Sevenless) Stéphane Pierre, Anne-Sophie Bats, Xavier Coumoul To cite this version: Stéphane Pierre, Anne-Sophie Bats, Xavier Coumoul. Understanding SOS (Son of Sevenless). Bio- chemical Pharmacology, Elsevier, 2011, 82 (9), pp.1049-1056. 10.1016/j.bcp.2011.07.072. hal- 02190799 HAL Id: hal-02190799 https://hal.archives-ouvertes.fr/hal-02190799 Submitted on 22 Jul 2019 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. *Manuscript Click here to view linked References Understanding SOS (Son of Sevenless). 1 1,2,‡ 1,2,3,‡ 1,2, † 2 Stéphane PIERRE , Anne-Sophie BATS , Xavier COUMOUL 3 4 5 1 6 INSERM UMR-S 747, Toxicologie Pharmacologie et Signalisation Cellulaire, 45 rue des 7 Saints Pères, 75006 Paris France 8 9 10 2 Université Paris Descartes, Centre universitaire des Saints-Pères, 45 rue des Saints Pères, 11 12 75006 Paris France 13 14 3 15 AP-HP, Hôpital Européen Georges Pompidou, Service de Chirurgie Gynécologique 16 17 Cancérologique, 75015 Paris France 18 19 ‡ These authors contributed equally to this work. 20 21 † 22 Address correspondence to: Xavier Coumoul, INSERM UMR-S 747, 45 rue des Saints-Pères 23 24 75006 Paris France; Phone: +33 1 42 86 33 59; Fax: +33 1 42 86 38 68; E-mail: 25 26 [email protected] 27 28 29 30 31 Key words: Son of Sevenless.
    [Show full text]
  • The Sevenless Signaling Pathway: Variations of a Common Theme
    Biochimica et Biophysica Acta 1496 (2000) 151^163 www.elsevier.com/locate/bba Review The Sevenless signaling pathway: variations of a common theme Thomas Raabe * Department of Genetics, University of Wu«rzburg, Biozentrum, Am Hubland, D-97074 Wu«rzburg, Germany Received 26 November 1999; accepted 24 January 2000 Abstract Many developmental processes are regulated by intercellular signaling mechanisms that employ the activation of receptor tyrosine kinases. One model system that has been particular useful in determining the role of receptor tyrosine kinase- mediated signaling processes in cell fate determination is the developing Drosophila eye. The specification of the R7 photoreceptor cell in each ommatidium of the developing Drosophila eye is dependent on activation of the Sevenless receptor tyrosine kinase. This review will focus on the genetic and biochemical approaches that have identified signaling molecules acting downstream of the Sevenless receptor tyrosine kinase which ultimately trigger differentiation of the R7 photoreceptor cell. ß 2000 Elsevier Science B.V. All rights reserved. 1. Receptor tyrosine kinases in eye development: maining undi¡erentiated cells have undergone a last an overview round of mitosis, photoreceptors R1/R6, and ¢nally R7, are recruited. Addition of the nonneuronal cone Each of the 800 single eye units (ommatidia) of the and pigment cells completes ommatidial development Drosophila eye contains a stereotypic arrangement of [1]. Di¡erentiation of the di¡erent cell types in each eight photoreceptor cells (R1^R8), four lens secreting ommatidium is controlled by at least two receptor cone cells and a number of accessory cells (Fig. tyrosine kinases (RTKs), the Drosophila EGF recep- 1A,E).
    [Show full text]
  • The Interdependent Activation of Son-Of-Sevenless and Ras
    Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press The Interdependent Activation of Son-of-Sevenless and Ras Pradeep Bandaru,1 Yasushi Kondo,1 and John Kuriyan2 1Department of Molecular and Cell Biology, California Institute for Quantitative Biosciences, Howard Hughes Medical Institute, University of California, Berkeley, California 94720 2Departments of Molecular and Cell Biology and of Chemistry, California Institute for Quantitative Biosciences, Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Howard Hughes Medical Institute, University of California, Berkeley, California 94720 Correspondence: [email protected] The guanine-nucleotide exchange factor (GEF) Son-of-Sevenless (SOS) plays a critical role in metazoan signaling by converting Ras•GDP (guanosine diphosphate) to Ras•GTP (guano- sine triphosphate) in response to tyrosine kinase activation. Structural studies have shown that SOS differs from other Ras-specific GEFs in that SOS is itself activated by Ras•GTP binding to an allosteric site, distal to the site of nucleotide exchange. The activation of SOS involves membrane recruitment and conformational changes, triggered by lipid binding, that open the allosteric binding site for Ras•GTP. This is in contrast to other Ras-specific GEFs, which are activated by second messengers that more directly affect the active site. Allosteric Ras•GTP binding stabilizes SOS at the membrane, where it can turn over other Ras molecules processively, leading to an ultrasensitive response that is distinct from that of other Ras-specific GEFs. n evolutionary innovation in metazoans is 2007). Instead, SOS is recruited to the mem- Athe coupling of Ras activation to the phos- brane by tyrosine phosphorylation of receptors phorylation of tyrosine residues on cell-surface or scaffold proteins and, in addition, the activa- receptors.
    [Show full text]
  • NMR-Based Functional Profiling of Rasopathies and Oncogenic RAS
    NMR-based functional profiling of RASopathies and oncogenic RAS mutations Matthew J. Smitha, Benjamin G. Neela, and Mitsuhiko Ikuraa,b,1 aCampbell Family Cancer Research Institute, Ontario Cancer Institute, and bDepartment of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 1L7 Edited by Peter E. Wright, The Scripps Research Institute, La Jolla, CA, and approved February 1, 2013 (received for review October 17, 2012) Defects in the RAS small G protein or its associated network of reg- K-RAS mutations is highly codon-dependent (11, 12). This finding ulatory proteins that disrupt GTPase cycling are a major cause of directly correlates underlying RAS biochemical defects with can- cancer and developmental RASopathy disorders. Lack of robust func- cer pathology, and a better appreciation of the intrinsic properties tional assays has been a major hurdle in RAS pathway-targeted drug of RAS and its surrounding regulatory network could facilitate the development. We used NMR to obtain detailed mechanistic data on design of specific, mechanism-based therapeutic approaches for RAS cycling defects conferred by oncogenic mutations, or full-length patients carrying these mutations. RASopathy-derived regulatory proteins. By monitoring the confor- RASopathies are a group of hereditary developmental syn- mation of wild-type and oncogenic RAS in real-time, we show that dromes triggered by germ-line mutations in genes encoding com- opposing properties integrate with regulators to hyperactivate on- ponents of the RAS/MAPK pathway (1, 13). Neurofibromatosis cogenic RAS mutants. Q61L and G13D exhibited rapid nucleotide type 1 (NF1), resulting from deficiency in the RASGAP neuro- exchange and an unexpected susceptibility to GAP-mediated hydro- fibromin (NF1) (14, 15), and Noonan Syndrome (NS), caused by lysis, in direct contrast with G12V, indicating different approaches gain-of-function mutations in the RASGEF SOS1 (in addition to must be taken to inhibit these oncoproteins.
    [Show full text]
  • Guanine Nucleotide Exchange Factors for Rho Gtpases: Turning on the Switch
    Downloaded from genesdev.cshlp.org on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Guanine nucleotide exchange factors for Rho GTPases: turning on the switch Anja Schmidt1,3 and Alan Hall1,2 1MRC Laboratory for Molecular Cell Biology, Cancer Research UK Oncogene and Signal Transduction Group, and 2Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, UK Rho GTPases control many aspects of cell behavior Structural features through the regulation of multiple signal transduction The first mammalian GEF, Dbl, isolated in 1985 as an pathways (Van Aelst and D’Souza-Schorey 1997; Hall oncogene in an NIH 3T3 focus formation assay using 1998). Rho, Rac, and Cdc42were first recognized in the DNA from a human diffuse B-cell lymphoma (Eva and early 1990s for their unique ability to induce specific ∼ filamentous actin structures in fibroblasts; stress fibers, Aaronson 1985), was found to contain a region of 180 lamellipodia/membrane ruffles, and filopodia, respec- amino acids that showed significant sequence similarity tively (Hall 1998). Over the intervening years, evidence to CDC24, a protein identified genetically as an up- has accumulated to show that in all eukaryotic cells, stream activator of CDC42in yeast (Bender and Pringle Rho GTPases are involved in most, if not all, actin-de- 1989; Ron et al. 1991). Dbl was subsequently shown to pendent processes such as those involved in migration, catalyze nucleotide exchange on human Cdc42in vitro adhesion, morphogenesis, axon guidance, and phagocy- (Hart et al. 1991), and a conserved domain in Dbl and tosis (Kaibuchi et al. 1999; Chimini and Chavrier 2000; CDC24, now known as the DH (Dbl homology) domain, Luo 2000).
    [Show full text]