title: Preventing farnesylation of the dynein adaptor Spindly contributes to the mitotic defects caused by farnesyltransferase inhibitors.
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.
authors: Ludwig Institute for Cancer Research/Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093.
authors: Andrew J
authors: AJ
authors: Holland
authors: Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto 4150-180, Portugal Instituto de Investigação e Inovação em Saúde-i3S, Universidade do Porto, Porto 4150-180, Portugal.
authors: Rita M
authors: RM
authors: Reis
authors: Skaggs Institute for Chemical Biology and Department of Chemical Physiology, Center for Physiological Proteomics, Scripps Research Institute, La Jolla, CA 92037.
authors: Sherry
authors: S
authors: Niessen
authors: Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto 4150-180, Portugal Instituto de Investigação e Inovação em Saúde-i3S, Universidade do Porto, Porto 4150-180, Portugal.
authors: Cláudia
authors: C
authors: Pereira
authors: Department of Molecular and Cellular Biochemistry, Kentucky Center for Structural Biology, University of Kentucky, Lexington, KY 40536.
authors: Douglas A
authors: DA
authors: Andres
authors: Department of Molecular and Cellular Biochemistry, Kentucky Center for Structural Biology, University of Kentucky, Lexington, KY 40536 Department of Chemistry, Markey Cancer Center, Kentucky Center for Structural Biology, University of Kentucky, Lexington, KY 40536.
authors: H Peter
authors: HP
authors: Spielmann
authors: Ludwig Institute for Cancer Research/Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093.
authors: Don W
authors: DW
authors: Cleveland
authors: Ludwig Institute for Cancer Research/Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093.
authors: Arshad
authors: A
authors: Desai
authors: Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto 4150-180, Portugal Instituto de Investigação e Inovação em Saúde-i3S, Universidade do Porto, Porto 4150-180, Portugal rgassmann@ibmc.up.pt.
authors: Reto
authors: R
authors: Gassmann
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D020090:Chromosome Segregation / Q000187:drug effects; D000072159:Dynactin Complex; D004398:Dyneins / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D018386:Kinetochores / Q000187:drug effects* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects*; D017368:Protein Prenylation; D014981:Xenopus
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D000072159:Dynactin Complex; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; C549402:SPDL1 protein, human; C068688:centromere protein E; D051231:Farnesyltranstransferase; D004398:Dyneins