Polo-Like Kinase 2-Dependent Phosphorylation of NPM/B23 on Serine 4 Triggers Centriole Duplication

Krause, Annekatrin; Hoffmann, Ingrid

doi:10.1371/journal.pone.0009849

Cited by 35 publications

(31 citation statements)

References 42 publications

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“…3). Table 2 shows the selected list of TBK1-PLK1 subnetwork components, which revealed that TBK1 knockdown leads to decreased activating phosphorylation of PLK1 (Thr-210) and its mitotic target proteins (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). These results prompted us to validate our idea that TBK1 is involved in mitotic regulation through activating PLK1.…”

Section: Resultsmentioning

confidence: 70%

Dissection of TBK1 signaling via phosphoproteomics in lung cancer cells

Kim¹,

Welsh²,

Oguz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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TANK-binding kinase 1 (TBK1) has emerged as a novel therapeutic target for unspecified subset of lung cancers. TBK1 reportedly mediates prosurvival signaling by activating NF-κB and AKT. However, we observed that TBK1 knockdown also decreased viability of cells expressing constitutively active NF-κB and interferon regulatory factor 3. Basal phospho-AKT level was not reduced after TBK1 knockdown in TBK1-sensitive lung cancer cells, implicating that TBK1 mediates unknown survival mechanisms. To gain better insight into TBK1 survival signaling, we searched for altered phosphoproteins using mass spectrometry following RNAi-mediated TBK1 knockdown. In total, we identified 2,080 phosphoproteins (4,621 peptides), of which 385 proteins (477 peptides) were affected after TBK1 knockdown. A view of the altered network identified a central role of Polo-like kinase 1 (PLK1) and known PLK1 targets. We found that TBK1 directly phosphorylated PLK1 in vitro. TBK1 phosphorylation was induced at mitosis, and loss of TBK1 impaired mitotic phosphorylation of PLK1 in TBK1-sensitive lung cancer cells. Furthermore, lung cancer cell sensitivity to TBK1 was highly correlated with sensitivity to pharmacological PLK inhibition. We additionally found that TBK1 knockdown decreased metadherin phosphorylation at Ser-568. Metadherin was associated with poor outcome in lung cancer, and loss of metadherin caused growth inhibition and apoptosis in TBK1-sensitive lung cancer cells. These results collectively revealed TBK1 as a mitosis regulator through activation of PLK1 and also suggested metadherin as a putative TBK1 downstream effector involved in lung cancer cell survival.non-canonical IκB kinase | stable isotope labeling by amino acids (SILAC) | astrocyte elevated gene-1 (AEG-1) T ANK-binding kinase 1 (TBK1) was originally identified as an NF-κB-activating kinase (1). TBK1 activates the innate immune response through phosphorylation of two transcription factors, NF-κB and interferon regulatory factor 3 (IRF3), in response to proinflammatory cytokines and Toll-like receptor activation (2, 3). Besides its pivotal role in the innate immune response, increasing evidence indicates that aberrant activation of TBK1 and its closest homolog, IκB kinase e (IKKe), is associated with development of human cancers. IKKe renders cells tumorigenic and is required for breast cancer cell proliferation and survival (4). IKKe has also been found to be amplified or activated in cancers, including lung cancer, ovarian cancer, glioma, and breast cancer (4-7).Mechanisms that activate TBK1 and the downstream proteins and pathways regulated by TBK1 in cancer remain incompletely understood. Some studies have placed TBK1 downstream of RAS signaling, increasing the potential for TBK1-targeting therapeutics in cancer. The RalB GTPase engages TBK1 with oncogenic RAS to support cancer cell survival, suggesting that TBK1 is an unappreciated RAS downstream protein involved in cancer cell survival (8). A systemic RNAi screening study revealed that TBK1 is specifically required ...

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Section: Resultsmentioning

confidence: 70%

Dissection of TBK1 signaling via phosphoproteomics in lung cancer cells

Kim¹,

Welsh²,

Oguz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…During mitosis, NPM is mainly dispersed throughout the cell with a minor fraction located at the spindle poles and its phosphorylation is required for this localization (Yao et al, 2004;Negi and Olson, 2006). Several sites are phosphorylated in mitosis: S4 by polo-like kinase 1 (but also in S-phase by Plk2 (Krause and Hoffmann, 2010)), and S70 and S254 by unknown kinases (Nousiainen et al, 2006). Moreover, NPM is a target of the NimA-like protein kinase (Nek2A), although the phosphorylation sites have not been mapped (Yao et al, 2004).…”

Section: Regulation Of Npm Activities Through Post-translational Modimentioning

confidence: 99%

Nucleophosmin and its complex network: a possible therapeutic target in hematological diseases

2011

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“…Polo-like kinase 2 (Plk2) is also involved in the regulation of centriole reproduction (Warnke et al, 2004). It is known that Plk2 phosphorylates NPM/B23 to trigger centriole duplication and CPAP to control its biological activity for centriole elongation (Chang et al, 2010;Krause and Hoffmann, 2010).…”

Section: Introductionmentioning

confidence: 99%

GCP6 is a substrate of Plk4 and required for centriole duplication

Bahtz

Seidler

Arnold

et al. 2012

Journal of Cell Science

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SummaryCentriole duplication occurs once per cell cycle and requires Plk4, a member of the Polo-like kinase family. A key component of the centrosome is the c-tubulin ring complex (c-TuRC) that nucleates microtubules. GCP6 is a member of the c-TuRC, but its role in human cells and the regulation of its functions remain unclear. Here we report that depletion of human GCP6 prevents assembly of the c-TuRC and induces a high percentage of monopolar spindles. These spindles are characterized by a loss of centrosomal c-tubulin and reduced centriole numbers. We found that GCP6 is localized in the pericentriolar material but also at distal portions of centrioles. In addition, GCP6 is required for centriole duplication and Plk4-induced centriole overduplication. GCP6 interacts with and is phosphorylated by Plk4. Moreover, we find that Plk4-dependent phosphorylation of GCP6 regulates centriole duplication. These data suggest that GCP6 is a target of Plk4 in centriole biogenesis.

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Polo-Like Kinase 2-Dependent Phosphorylation of NPM/B23 on Serine 4 Triggers Centriole Duplication

Cited by 35 publications

References 42 publications

Dissection of TBK1 signaling via phosphoproteomics in lung cancer cells

Dissection of TBK1 signaling via phosphoproteomics in lung cancer cells

Nucleophosmin and its complex network: a possible therapeutic target in hematological diseases

GCP6 is a substrate of Plk4 and required for centriole duplication

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