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A dimerization-dependent mechanism regulates enzymatic activation and nuclear entry of PLK1.

Oncogene (2021-11-12)
Monika Raab, Yves Matthess, Christopher A Raab, Niklas Gutfreund, Volker Dötsch, Sven Becker, Mourad Sanhaji, Klaus Strebhardt
RESUMEN

Polo-like kinase 1 (PLK1) is a crucial regulator of cell cycle progression. It is established that the activation of PLK1 depends on the coordinated action of Aurora-A and Bora. Nevertheless, very little is known about the spatiotemporal regulation of PLK1 during G2, specifically, the mechanisms that keep cytoplasmic PLK1 inactive until shortly before mitosis onset. Here, we describe PLK1 dimerization as a new mechanism that controls PLK1 activation. During the early G2 phase, Bora supports transient PLK1 dimerization, thus fine-tuning the timely regulated activation of PLK1 and modulating its nuclear entry. At late G2, the phosphorylation of T210 by Aurora-A triggers dimer dissociation and generates active PLK1 monomers that support entry into mitosis. Interfering with this critical PLK1 dimer/monomer switch prevents the association of PLK1 with importins, limiting its nuclear shuttling, and causes nuclear PLK1 mislocalization during the G2-M transition. Our results suggest a novel conformational space for the design of a new generation of PLK1 inhibitors.

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Sigma-Aldrich
Anti-β-actina, anticuerpo monoclonal, clone AC-15, purified from hybridoma cell culture
Sigma-Aldrich
Anticuerpo anti-fosfo-histona H3 (Ser10), marcador de mitosis, Upstate®, from rabbit
Sigma-Aldrich
Anti-PLK1 Antibody, clone 35-206, clone 35-206, Upstate®, from mouse
Sigma-Aldrich
Anti-phospho-PLK1 (Ser137) Antibody, from rabbit, purified by affinity chromatography