The RNA-binding protein IGF2BP1 is an important protumorigenic factor in liver carcinogenesis. Hence, therapeutic targeting of IGF2BP1 may offer options for intervention in human HCC.
Entry into mitosis is mediated by the phosphorylation of key cell cycle regulators by cyclin-dependent kinase 1 (Cdk1). In Xenopus embryos, the M-phase-promoting activity of Cdk1 is antagonized by protein phosphatase PP2A-B55. Hence, to ensure robust cell cycle transitions, Cdk1 and PP2A-B55 must be regulated so that their activities are mutually exclusive. The mechanism underlying PP2A-B55 inactivation at mitotic entry is well understood: Cdk1-activated Greatwall (Gwl) kinase phosphorylates Ensa/Arpp19, thereby enabling them to bind to and inhibit PP2A-B55. However, the re-activation of PP2A-B55 during mitotic exit, which is essential for cell cycle progression, is less well understood. Here, we identify protein phosphatase PP1 as an essential component of the PP2A-B55 re-activation pathway in Xenopus embryo extracts. PP1 initiates the re-activation of PP2A-B55 by dephosphorylating Gwl. We provide evidence that PP1 targets the auto-phosphorylation site of Gwl, resulting in efficient Gwl inactivation. This step is necessary to facilitate subsequent complete dephosphorylation of Gwl by PP2A-B55. Thus, by identifying PP1 as the phosphatase initiating Gwl inactivation, our study provides the molecular explanation for how Cdk1 inactivation is coupled to PP2A-B55 re-activation at mitotic exit.
The challenging task of mitotic cell divisions is to generate two genetically identical daughter cells from a single precursor cell. To accomplish this task, a complex regulatory network evolved, which ensures that all events critical for the duplication of cellular contents and their subsequent segregation occur in the correct order, at specific intervals and with the highest possible fidelity. Transitions between cell cycle stages are triggered by changes in the phosphorylation state and levels of components of the cell cycle machinery. Entry into S-phase and M-phase are mediated by cyclin-dependent kinases (Cdks), serine-threonine kinases that require a regulatory cyclin subunit for their activity. Resetting the system to the interphase state is mediated by protein phosphatases (PPs) that counteract Cdks by dephosphorylating their substrates. To avoid futile cycles of phosphorylation and dephosphorylation, Cdks and PPs must be regulated in a manner such that their activities are mutually exclusive.
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