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TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation.

The Journal of cell biology (2015-09-02)
Takashi Watanabe, Mai Kakeno, Toshinori Matsui, Ikuko Sugiyama, Nariko Arimura, Kenji Matsuzawa, Aya Shirahige, Fumiyoshi Ishidate, Tomoki Nishioka, Shinichiro Taya, Mikio Hoshino, Kozo Kaibuchi
ABSTRACT

Microtubules (MTs) play critical roles in various cellular events, including cell migration. End-binding proteins (EBs) accumulate at the ends of growing MTs and regulate MT end dynamics by recruiting other plus end-tracking proteins (+TIPs). However, how EBs contribute to MT dynamics through +TIPs remains elusive. We focused on tau-tubulin kinase 2 (TTBK2) as an EB1/3-binding kinase and confirmed that TTBK2 acted as a +TIP. We identified MT-depolymerizing kinesin KIF2A as a novel substrate of TTBK2. TTBK2 phosphorylated KIF2A at S135 in intact cells in an EB1/3-dependent fashion and inactivated its MT-depolymerizing activity in vitro. TTBK2 depletion reduced MT lifetime (facilitated shrinkage and suppressed rescue) and impaired HeLa cell migration, and these phenotypes were partially restored by KIF2A co-depletion. Expression of nonphosphorylatable KIF2A, but not wild-type KIF2A, reduced MT lifetime and slowed down the cell migration. These findings indicate that TTBK2 with EB1/3 phosphorylates KIF2A and antagonizes KIF2A-induced depolymerization at MT plus ends for cell migration.

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