Abstract
TANK Binding Kinase 1 (TBK1) is a non-canonical IκB kinase that contributes to KRAS-driven lung cancer. Here we report that TBK1 plays essential roles in mammalian cell division. Specifically, levels of active phospho-TBK1 increase during mitosis and localize to centrosomes, mitotic spindles and midbody, and selective inhibition or silencing of TBK1 triggers defects in spindle assembly and prevents mitotic progression. TBK1 binds to the centrosomal protein CEP170 and to the mitotic apparatus protein NuMA, and both CEP170 and NuMA are TBK1 substrates. Further, TBK1 is necessary for CEP170 centrosomal localization and binding to the microtubule depolymerase Kif2b, and for NuMA binding to dynein. Finally, selective disruption of the TBK1–CEP170 complex augments microtubule stability and triggers defects in mitosis, suggesting that TBK1 functions as a mitotic kinase necessary for microtubule dynamics and mitosis.
Highlights
TANK Binding Kinase 1 (TBK1) is a non-canonical IkB kinase that contributes to KRAS-driven lung cancer
TBK1 is essential for the survival of non-small cell lung cancers driven by oncogenic KRAS9–11; this synthetic lethal interaction of TBK1 with mutant K-Ras was governed by its ability to activate NFkB anti-apoptotic signalling through c-Rel and BCL-XL
Immunofluorescence experiments using a phospho-TBK1 specific antibody on A549, H1650, Calu-6 and PC9 non-small cell lung cancer (NSCLC) cell lines as well as the immortalized human tracheobronchial epithelial cell line AALE established that phospho-TBK1 localized to centrosomal regions during prophase and prometaphase, where it co-localized with alpha tubulin (Fig. 1a, Supplementary Fig. 1a–d)
Summary
TANK Binding Kinase 1 (TBK1) is a non-canonical IkB kinase that contributes to KRAS-driven lung cancer. Selective disruption of the TBK1–CEP170 complex augments microtubule stability and triggers defects in mitosis, suggesting that TBK1 functions as a mitotic kinase necessary for microtubule dynamics and mitosis. TBK1 is essential for the survival of non-small cell lung cancers driven by oncogenic KRAS9–11; this synthetic lethal interaction of TBK1 with mutant K-Ras was governed by its ability to activate NFkB anti-apoptotic signalling through c-Rel and BCL-XL. We demonstrate direct roles for TBK1 in regulating mitosis, where it binds to and phosphorylates CEP170, a forkhead domain and centrosome- and spindle microtubuleassociated protein[14], as well as NuMA, which associates with the pericentrosomal domains of the spindle apparatus and is necessary for cytokinesis[15]. We demonstrate that TBK1 regulates microtubule dynamics and mitotic progression by modulating CEP170 and NuMA functions
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