KIF5C S176 phosphorylation regulates microtubule binding and transport efficiency in mammalian neurons

Research output: Contribution to journalArticle

Abstract

Increased phosphorylation of the KIF5 anterograde motor is associated with impaired axonal transport and neurodegeneration, but paradoxically also with normal transport, though the details are not fully defined. JNK phosphorylates KIF5C on S176 in the motor domain; a site that we show is phosphorylated in brain. Microtubule pelleting assays demonstrate that phosphomimetic KIF5C (1-560)S176D associates weakly with microtubules compared to KIF5C (1-560)WT. Consistent with this, 50% of KIF5C (1-560)S176D shows diffuse movement in neurons. However, the remaining 50% remains microtubule bound and displays decreased pausing and increased bidirectional movement. The same directionality switching is observed with KIF5C(1-560)WT in the presence of an active JNK chimera, MKK7-JNK. Yet, in cargo trafficking assays where peroxisome cargo is bound, KIF5C(1-560)S176D-GFP-FRB transports normally to microtubule plus ends. We also find that JNK increases the ATP hydrolysis of KIF5C in vitro. These data suggest that phosphorylation of KIF5C-S176 primes the motor to either disengage entirely from microtubule tracks as previously observed in response to stress, or to display improved efficiency. The final outcome may depend on cargo load and motor ensembles.

Details

Authors
  • Artur Padzik
  • Prasannakumar Deshpande
  • Patrik Hollos
  • Mariella Franker
  • Emmy H. Rannikko
  • Dawen Cai
  • Piotr Prus
  • Mats Mågård
  • Nina Westerlund
  • Kristen J. Verhey
  • Peter James
  • Casper C. Hoogenraad
  • Eleanor T. Coffey
Organisations
External organisations
  • University of Turku
  • Utrecht University
  • University of Oulu
  • University of Michigan
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell Biology

Keywords

  • Axonal transport, BDNF, JNK, Kinesin, Molecular motors, Neurons, Phosphorylation, SCG10
Original languageEnglish
Article number57
JournalFrontiers in Cellular Neuroscience
Volume10
Issue numberMAR2016
Publication statusPublished - 2016 Mar 15
Publication categoryResearch
Peer-reviewedYes