CFEOM1-Associated Kinesin KIF21A Is a Cortical Microtubule Growth Inhibitor

Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes....

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Published in:Developmental cell 2013-10, Vol.27 (2), p.145-160
Main Authors: van der Vaart, Babet, van Riel, Wilhelmina E., Doodhi, Harinath, Kevenaar, Josta T., Katrukha, Eugene A., Gumy, Laura, Bouchet, Benjamin P., Grigoriev, Ilya, Spangler, Samantha A., Yu, Ka Lou, Wulf, Phebe S., Wu, Jingchao, Lansbergen, Gideon, van Battum, Eljo Y., Pasterkamp, R. Jeroen, Mimori-Kiyosue, Yuko, Demmers, Jeroen, Olieric, Natacha, Maly, Ivan V., Hoogenraad, Casper C., Akhmanova, Anna
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
Animals
Carrier Proteins - metabolism
Cell Line
Cercopithecus aethiops
COS Cells
Eye Diseases, Hereditary - genetics
Eye Diseases, Hereditary - metabolism
Fibrosis - metabolism
Growth Inhibitors
HEK293 Cells
HeLa Cells
Humans
Kinesin - genetics
Kinesin - metabolism
Microtubules - metabolism
Morphogenesis
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neurons - cytology
Neurons - metabolism
Ocular Motility Disorders - metabolism
Ophthalmoplegia
RNA Interference
RNA, Small Interfering
Tumor Suppressor Proteins - metabolism
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Summary:Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis. [Display omitted] •KIF21A coclusters with KANK1, LL5β, liprin-α1, and liprin-β1 at the cell cortex•KIF21A inhibits microtubule growth in vitro and at the cell cortex•CFEOM1-associated mutations in KIF21A relieve its autoinhibition•Increased KIF21A activity affects axonal morphology and growth cone dynamics KIF21A kinesin is mutated in the neurodevelopmental disorder CFEOM1. Van der Vaart et al. show that KIF21A acts as a microtubule polymerization inhibitor and that CFEOM1-associated mutations relieve KIF21A autoinhibition. Changes in microtubule dynamics caused by the increased activity of KIF21A may contribute to CFEOM1 pathogenesis by altering axonal development.
ISSN:1534-5807
1878-1551
DOI:10.1016/j.devcel.2013.09.010