Phosphorylation signaling in cell division

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ABSTRACT Protein phosphorylation is an essential post-translational modification that plays pivotal roles in the regulation of protein function, localization, and stability and governs most cellular processes, including cell division. Phosphorylation by protein kinases, including the master regulators Cdk1, Plk1, Aurora kinase A and Aurora kinase B, are required to coordinate the functions of a wide array of substrates to promote faithful transit of cells through mitosis. Indeed, dysregulation of mitotic kinase functions underlies many human diseases such as birth defects and cancer. In particular, the kinase Plk1 promotes mitotic entry by regulating Cdk1/cyclin B activity, centrosome separation and maturation, as well as spindle assembly. Plk1 is required for the removal of sister chromatid cohesion and spindle assembly checkpoint (SAC) signaling, and fine-tunes microtubule-kinetochore attachment dynamics. Plk1 also contributes to mitotic exit and cytokinesis by regulating the anaphase promoting complex/cyclosome (APC/C) and recruiting proteins to the central spindle and the midbody. Example Plk1 substrates that facilitate these functions include docking/scaffolding proteins, motor proteins including kinesins, structural proteins, proteases, E3 ubiquitin ligases, and other kinases. While entry into mitosis is driven by the activation of kinases and a net increase in phosphorylation, dynamic regulation of phosphorylation levels is needed for mitotic progression and exit. We found that Plk1 inhibits PP6 to promote its own activation. However, PP1 and PP2A-B56 restrain Plk1 activity to silence the SAC. Thus, complex regulatory interactions between kinases and phosphatases control mitosis. Our overarching goals are to identify and uncover the principles that govern phosphorylation signaling in mitosis as a means to better understand cell division. Specifically, we will focus on the role of Plk1 as an apical mediator in mitosis and it is regulatory interactions with other kinases and phosphatases. To accomplish this, we will develop and apply a combination of proteomic, bioinformatic, cell biological and biochemical strategies to connect kinases to their substrates, investigate substrate function, and uncover new regulatory interactions of kinases and phosphatases Our past studies have enabled us and other researchers to functionally interrogate specific mechanisms that underlie many biological processes of interest. We are dedicated to sharing our findings with the research community and will continue to do so as publically available resources.