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Molecular Biology of the CellVolume 26, Issue 10, 15 May 2015, Pages 1845-1856

Preventing farnesylation of the dynein adaptor Spindly contributes to the mitotic defects caused by farnesyltransferase inhibitors(Article)

  • Holland, A.J.,
  • Reis, R.M.,
  • Niessen, S.,
  • Pereira, C.,
  • Andres, D.A.,
  • Spielmann, H.P.,
  • Cleveland, D.W.,
  • Desai, A.,
  • Gassmann, R.
  • View Correspondence (jump link)
  • aLudwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA 92093, United States
  • bInstituto de Biologia Molecular e Celular, Universidade do Porto, Porto, 4150-180, Portugal
  • cInstituto de Investigação e Inovação em Saúde-i3S, Universidade do Porto, Porto, 4150-180, Portugal
  • dSkaggs Institute for Chemical Biology, Department of Chemical Physiology, Center for Physiological Proteomics, San Diego, CA 92037, United States
  • eDepartment of Molecular and Cellular Biochemistry, Markey Cancer Center, Kentucky Center for Structural Biology, University of Kentucky, Lexington, KY 40536, United States
  • fDepartment of Chemistry, Markey Cancer Center, Kentucky Center for Structural Biology, University of Kentucky, Lexington, KY 40536, United States
  • gDepartment of Molecular Biology and Genetics, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, United States

Abstract

The clinical interest in farnesyltransferase inhibitors (FTIs) makes it important to understand how these compounds affect cellular processes involving farnesylated proteins. Mitotic abnormalities observed after treatment with FTIs have so far been attributed to defects in the farnesylation of the outer kinetochore proteins CENP-E and CENP-F, which are involved in chromosome congression and spindle assembly checkpoint signaling. Here we identify the cytoplasmic dynein adaptor Spindly as an additional component of the outer kinetochore that is modified by farnesyltransferase (FTase). We show that farnesylation of Spindly is essential for its localization, and thus for the proper localization of dynein and its cofactor dynactin, to prometaphase kinetochores and that Spindly kinetochore recruitment is more severely affected by FTase inhibition than kinetochore recruitment of CENP-E and CENP-F. Molecular replacement experiments show that both Spindly and CENP-E farnesylation are required for efficient chromosome congression. The identification of Spindly as a new mitotic substrate of FTase provides insight into the causes of the mitotic phenotypes observed with FTase inhibitors. © 2015 Holland et al.

Indexed keywords

EMTREE drug terms:dynactindynein adenosine triphosphataseprotein farnesyltransferaseprotein farnesyltransferase inhibitorspindlyunclassified drugcarrier proteincentromere protein Edynactindynein adenosine triphosphataseenzyme inhibitorfarnesyl trans transferasemicrotubule associated proteinnonhistone proteinspindly protein, human
EMTREE medical terms:Articlecentromerechromosomechromosome segregationcontrolled studyenzyme inhibitionfarnesylationfemalehumanhuman cellmitosisphenotypepriority journalprometaphaseprotein localizationanimalantagonists and inhibitorsdrug effectsmetabolismmitosisprotein prenylationXenopus
MeSH:AnimalsCarrier ProteinsChromosomal Proteins, Non-HistoneChromosome SegregationDynactin ComplexDyneinsEnzyme InhibitorsFarnesyltranstransferaseHumansKinetochoresMicrotubule-Associated ProteinsMitosisProtein PrenylationXenopus

Chemicals and CAS Registry Numbers:

dynein adenosine triphosphatase; protein farnesyltransferase; carrier protein, 80700-39-6; farnesyl trans transferase, 9032-58-0;

Carrier Proteins; centromere protein E; Chromosomal Proteins, Non-Histone; Dyneins; Enzyme Inhibitors; Farnesyltranstransferase; Microtubule-Associated Proteins; spindly protein, human

Funding details

Funding sponsor Funding number Acronym
European Research Council338410ERC
Fundação para a Ciência e a TecnologiaIF/01015/2013/CP1157/CT0006FCT
  • ISSN: 10591524
  • CODEN: MBCEE
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1091/mbc.E14-11-1560
  • PubMed ID: 25808490
  • Document Type: Article
  • Publisher: American Society for Cell Biology

  Gassmann, R.; Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal;
© Copyright 2018 Elsevier B.V., All rights reserved.

Cited by 16 documents

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Conte, C. , Griffis, E.R. , Hickson, I.
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