CDK1 and PLK1 cooperate to regulate BICD2, dynein activation and recruitment to the nucleus during centrosome separation in G2/M.

Trabajo presentado en el EMBO Workshop Centrosomes in development, disease and evolution, celebrado en Estambul (Turquía) del 26 al 29 de septiembre de 2023.Centrosome separation in G2/early M is key for the proper attachment of chromosomes to the mitotic spindle and their subsequent segregation in late mitosis. Our group has been studying how this process is regulated by the signaling module formed by the protein kinase PLK1 and its downstream effectors NEK9, NEK6 and NEK7 through the control of different cellular motors, including Eg5 and dynein. We now have found that PLK1 directly regulates one of the best-known dynein activating adaptors, BICD2, through phosphorylation. In G2/M, PLK1 is able to efficiently interact with CDK-phosphorylated BICD2 and in turn modify the adaptor in its N-terminus. Using different techniques, our work shows that this modification results in a structural change that facilitates the binding of BICD2 to dynein and dynactin and the formation of an active motor complex. Moreover, BICD2 phosphorylation allows the interaction of the adaptor with the nucleoporin RanBP2, provided that this nucleoporin has been previously modified by CDK1. Altogether, PLK1 phosphorylation of BICD2 results in dynein recruitment to the nuclear envelope and centrosome tethering to the nucleus in G2, and is instrumental for correct centrosome separation in prophase. Our results describe a novel mode of regulation for dynein that we propose could be extended to different adaptors and be key to the spatiotemporal control of the motor in different physiological contexts. In addition we unveil an important step of the complex regulatory network that controls the movements of the centrosome in G2 and mitosis