The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation

The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation

The Eyes Absent proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour-promoting across a range of cancer types. To date, the targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as an interactor and p...

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Bibliographic Details
Published in:Nature communications Vol. 15; no. 1; p. 1385
Main Authors: Nelson, Christopher B., Rogers, Samuel, Roychoudhury, Kaushik, Tan, Yaw Sing, Atkinson, Caroline J., Sobinoff, Alexander P., Tomlinson, Christopher G., Hsu, Anton, Lu, Robert, Dray, Eloise, Haber, Michelle, Fletcher, Jamie I., Cesare, Anthony J., Hegde, Rashmi S., Pickett, Hilda A.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 15-02-2024
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Subjects:
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Cell cycle
Cell death
Centrosomes
Dephosphorylation
G2 phase
Humanities and Social Sciences
Kinases
Localization
Mitosis
Molecular dynamics
multidisciplinary
Phosphatase
Phosphotyrosine
Polo-like kinase
Polo-like kinase 1
Proteins
Science
Science (multidisciplinary)
Signal transduction
Substrates
Tyrosine
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Summary:The Eyes Absent proteins (EYA1-4) are a biochemically unique group of tyrosine phosphatases known to be tumour-promoting across a range of cancer types. To date, the targets of EYA phosphatase activity remain largely uncharacterised. Here, we identify Polo-like kinase 1 (PLK1) as an interactor and phosphatase substrate of EYA4 and EYA1, with pY445 on PLK1 being the primary target site. Dephosphorylation of pY445 in the G2 phase of the cell cycle is required for centrosome maturation, PLK1 localization to centrosomes, and polo-box domain (PBD) dependent interactions between PLK1 and PLK1-activation complexes. Molecular dynamics simulations support the rationale that pY445 confers a structural impairment to PBD-substrate interactions that is relieved by EYA-mediated dephosphorylation. Depletion of EYA4 or EYA1, or chemical inhibition of EYA phosphatase activity, dramatically reduces PLK1 activation, causing mitotic defects and cell death. Overall, we have characterized a phosphotyrosine signalling network governing PLK1 and mitosis. The Eyes Absent proteins (EYA1-4) are a group of tyrosine phosphatases. Here, the authors report a signalling pathway in which EYA4 and EYA1 dephosphorylate Polo-like kinase 1 (PLK1) at pY445 to support PLK1 activation and mitosis.
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content type line 23
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-45683-4