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

Mol Biol Cell. 2015 May 15;26(10):1845-56. doi: 10.1091/mbc.E14-11-1560. Epub 2015 Mar 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / metabolism*
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosome Segregation / drug effects
  • Dynactin Complex
  • Dyneins / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Farnesyltranstransferase / antagonists & inhibitors*
  • Farnesyltranstransferase / metabolism
  • Humans
  • Kinetochores / drug effects*
  • Kinetochores / metabolism
  • Microtubule-Associated Proteins / drug effects
  • Mitosis / drug effects*
  • Protein Prenylation
  • Xenopus

Substances

  • Carrier Proteins
  • Chromosomal Proteins, Non-Histone
  • Dynactin Complex
  • Enzyme Inhibitors
  • Microtubule-Associated Proteins
  • SPDL1 protein, human
  • centromere protein E
  • Farnesyltranstransferase
  • Dyneins