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

Christopher B. Nelson, Samuel Rogers, Kaushik Roychoudhury, Yaw Sing Tan, Caroline J. Atkinson, Alexander P. Sobinoff, Christopher G. Tomlinson, Anton Hsu, Robert Lu, Eloise Dray, Michelle Haber, Jamie I. Fletcher, Anthony J. Cesare, Rashmi S. Hegde and Hilda A. Pickett ()
Additional contact information
Christopher B. Nelson: University of Sydney
Samuel Rogers: University of Sydney
Kaushik Roychoudhury: Cincinnati Children’s Hospital Medical Center
Yaw Sing Tan: Agency for Science, Technology and Research (A*STAR)
Caroline J. Atkinson: UNSW Medicine & Health, UNSW Sydney
Alexander P. Sobinoff: University of Sydney
Christopher G. Tomlinson: University of Sydney
Anton Hsu: University of Sydney
Robert Lu: University of Sydney
Eloise Dray: University of Texas Health Science Center at San Antonio
Michelle Haber: UNSW Medicine & Health, UNSW Sydney
Jamie I. Fletcher: UNSW Medicine & Health, UNSW Sydney
Anthony J. Cesare: University of Sydney
Rashmi S. Hegde: Cincinnati Children’s Hospital Medical Center
Hilda A. Pickett: University of Sydney

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45683-4

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