Centrosomal and Non-centrosomal Functions Emerged through Eliminating Centrosomes

Takeda, Yutaka; Kuroki, Kanako; Chinen, Takumi; Kitagawa, Daiju

doi:10.1247/csf.20007

Cited by 10 publications

(4 citation statements)

References 79 publications

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“…In higher eukaryotes and plants, the bipolar spindle is formed independent of the centrosome through the pathway referred to as the acentrosomal pathway [112][113][114]. Historically, the acentrosomal pathway is extensively characterised in vitro using extracts prepared from Xenopus oocytes, where the Ran GTPase acts as a master regulator [115,116].…”

Section: Force Generation In the Acentrosomal Cellsmentioning

confidence: 99%

How Essential Kinesin-5 Becomes Non-Essential in Fission Yeast: Force Balance and Microtubule Dynamics Matter

Yukawa

Teratani

Toda

2020

Cells

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The bipolar mitotic spindle drives accurate chromosome segregation by capturing the kinetochore and pulling each set of sister chromatids to the opposite poles. In this review, we describe recent findings on the multiple pathways leading to bipolar spindle formation in fission yeast and discuss these results from a broader perspective. The roles of three mitotic kinesins (Kinesin-5, Kinesin-6 and Kinesin-14) in spindle assembly are depicted, and how a group of microtubule-associated proteins, sister chromatid cohesion and the kinetochore collaborate with these motors is shown. We have paid special attention to the molecular pathways that render otherwise essential Kinesin-5 to become non-essential: how cells build bipolar mitotic spindles without the need for Kinesin-5 and where the alternate forces come from are considered. We highlight the force balance for bipolar spindle assembly and explain how outward and inward forces are generated by various ways, in which the proper fine-tuning of microtubule dynamics plays a crucial role. Overall, these new pathways have illuminated the remarkable plasticity and adaptability of spindle mechanics. Kinesin molecules are regarded as prospective targets for cancer chemotherapy and many specific inhibitors have been developed. However, several hurdles have arisen against their clinical implementation. This review provides insight into possible strategies to overcome these challenges.

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Section: Force Generation In the Acentrosomal Cellsmentioning

confidence: 99%

How Essential Kinesin-5 Becomes Non-Essential in Fission Yeast: Force Balance and Microtubule Dynamics Matter

Yukawa

Teratani

Toda

2020

Cells

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show abstract

“…In higher eukaryotes and plants, the bipolar spindle is formed independent of the centrosome through the pathway referred to as the acentrosomal pathway [99][100][101]. Historically, the acentrosomal pathway is extensively characterised in vitro using extracts prepared from Xenopus oocytes, where the Ran GTPase acts as a master regulator [102,103].…”

Section: Force Generation In the Acentrosomal Cellsmentioning

confidence: 99%

How Essential Kinesin-5 Becomes Non-Essential: Force Balance and Microtubule Dynamics Matter

Yukawa¹,

Teratani²,

Toda³

2020

Preprint

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The bipolar mitotic spindle drives accurate chromosome segregation by capturing the kinetochore and pulling each set of sister chromatids to the opposite poles. In this review, we describe recent findings on the multiple pathways leading to bipolar spindle formation in fission yeast and discuss these results from a broader perspective. Roles of four mitotic kinesins (Kinesin-5, Kinesin-6, Kinesin-12 and Kinesin-14) in spindle assembly are depicted, and how a group of microtubule-associated proteins, sister chromatid cohesion and the kinetochore collaborates with these motors is shown. We have paid special attention to the molecular pathways that render otherwise essential Kinesin-5 to become non-essential: how cells build bipolar mitotic spindles without the need for Kinesin-5 and where the alternate forces come from are considered. We highlight the force balance for bipolar spindle assembly and explain how outward and inward forces are generated by various ways, in which the proper fine-tuning of microtubule dynamics plays a crucial role. Overall, these new pathways have illuminated remarkable plasticity and adaptability of spindle mechanics. Kinesin molecules are regarded as prospective targets for cancer chemotherapy and many specific inhibitors have been developed. However, several hurdles have arisen against their clinical implementation. This review provides insight into possible strategies to overcome these challenges.

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“…Although additional physiological PLK4 substrates have been identified [6,14,[35][36][37][38], a detailed characterisation of cellular PLK4 substrates phosphorylated during G1/S phase, or indeed across the phases of the cell cycle, is still lacking. Consequently, the contribution of PLK4 to centrosomal and non-centrosomal biology, ciliopathies and congenital abnormalities associated with gene dosage affects, alongside PLK4 kinase-independent functions that stabilise the kinase, remain to be established [6,[39][40][41].…”

Section: Introductionmentioning

confidence: 99%

“…This results in a reported two orders-of-magnitude increase in inhibition of PLK4 relative to Aurora A. Moreover, incubation of human cells with centrinone provides a useful approach for studying a variety of phenotypic effects [ 41 , 52 ], with the explicit caveat that, as with essentially all kinase inhibitors, off-target effects are inevitable. Most notably, prolonged centrinone exposure leads to the depletion of centrosomes, causing cell cycle arrest in G1 via a p53-dependent mechanism, potentially by loss of the interaction between p53 and the ubiquitin E3 ligase MDM2 [ 48 ].…”

Section: Introductionmentioning

confidence: 99%

Use of the Polo-like kinase 4 (PLK4) inhibitor centrinone to investigate intracellular signalling networks using SILAC-based phosphoproteomics

Byrne

Clarke

Brownridge

et al. 2020

Biochemical Journal

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Polo-like kinase 4 (PLK4) is the master regulator of centriole duplication in metazoan organisms. Catalytic activity and protein turnover of PLK4 are tightly coupled in human cells, since changes in PLK4 concentration and catalysis have profound effects on centriole duplication and supernumerary centrosomes, which are associated with aneuploidy and cancer. Recently, PLK4 has been targeted with a variety of small molecule kinase inhibitors exemplified by centrinone, which rapidly induces inhibitory effects on PLK4 and leads to on-target centrosome depletion. Despite this, relatively few PLK4 substrates have been identified unequivocally in human cells, and PLK4 signalling outside centriolar networks remains poorly characterised. We report an unbiased mass spectrometry (MS)-based quantitative analysis of cellular protein phosphorylation in stable PLK4-expressing U2OS human cells exposed to centrinone. PLK4 phosphorylation was itself sensitive to brief exposure to the compound, resulting in PLK4 stabilisation. Analysing asynchronous cell populations, we report hundreds of centrinone-regulated cellular phosphoproteins, including centrosomal and cell cycle proteins and a variety of likely ‘non-canonical’ substrates. Surprisingly, sequence interrogation of ∼300 significantly down-regulated phosphoproteins reveals an extensive network of centrinone-sensitive [Ser/Thr]Pro phosphorylation sequence motifs, which based on our analysis might be either direct or indirect targets of PLK4. In addition, we confirm that NMYC and PTPN12 are PLK4 substrates, both in vitro and in human cells. Our findings suggest that PLK4 catalytic output directly controls the phosphorylation of a diverse set of cellular proteins, including Pro-directed targets that are likely to be important in PLK4-mediated cell signalling.

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Centrosomal and Non-centrosomal Functions Emerged through Eliminating Centrosomes

Cited by 10 publications

References 79 publications

How Essential Kinesin-5 Becomes Non-Essential in Fission Yeast: Force Balance and Microtubule Dynamics Matter

How Essential Kinesin-5 Becomes Non-Essential in Fission Yeast: Force Balance and Microtubule Dynamics Matter

How Essential Kinesin-5 Becomes Non-Essential: Force Balance and Microtubule Dynamics Matter

Use of the Polo-like kinase 4 (PLK4) inhibitor centrinone to investigate intracellular signalling networks using SILAC-based phosphoproteomics

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