PP1-mediated dephosphorylation of phosphoproteins at mitotic exit is controlled by inhibitor-1 and PP1 phosphorylation

Abstract

Loss of Cdc2 activity following Cyclin B degradation is necessary, but not sufficient, for mitotic exit. Proteins phosphorylated by Cdc2 and downstream mitotic kinases must also be dephosphorylated. We report here that protein phosphatase-1 (PP1) is the major catalyst of mitotic phosphoprotein dephosphorylation. Suppression of PP1 during early mitosis is maintained through the dual inhibition of PP1 by Cdc2 phosphorylation and the binding of Inhibitor-1 (I1), which is facilitated by PKA-mediated I1 phosphorylation. As Cdc2 levels drop following Cyclin B degradation, autodephosphorylation of PP1 at the site of Cdc2 phosphorylation (T320) allows partial PP1 activation. This promotes PP1-regulated dephosphorylation of I1 at its activating site (T35), dissociation of the I1-PP1 complex, and full PP1 activation to promote mitotic exit. Thus, Cdc2 both phosphorylates multiple mitotic substrates and inhibits their PP1-mediated dephosphorylation.

Pre-anaphase chromosome oscillations are regulated by the antagonistic activities of Cdk1 and PP1 on Kif18A

“…Thus, our study revealed that PP1 not only stabilizes MT attachment by dephosphorylating Aurora-B substrates at KTs 18,28-30 but also induces plate thinning by dephosphorylating Kif18A. At the same time, this finding establishes Kif18A as the first Cdk1 substrate-apart from PP1 itself [37][38][39] -that is directly dephosphorylated by PP1 demonstrating that PP1 can act as an antagonist of not only Aurora-B but also Cdk1. Dephosphorylation of Kif18A by PP1 depends on a conserved PP1-binding motif located in the Cterminus of Kif18A (Fig.…”

Phosphatase 1 Nuclear Targeting Subunit Is an Essential Regulator of M-phase Entry, Maintenance, and Exit

“…1E). When added to CSF extract, roscovitine inhibits Cdk1, allowing its substrates to be dephosphorylated by counteracting phosphatases and the M-phase extract to be released into interphase (38). Increased expression of Pnuts delayed roscovitine-induced M-phase exit (Fig.…”

Synaptic NMDA receptor stimulation activates PP1 by inhibiting its phosphorylation by Cdk5

“…We then applied MK801, a use-dependent NMDA receptor open channel blocker, to neurons during site, thus blocking access to PP1 substrates (Goldberg et al, 1995). Although this regulatory mechanism has been found to be important for control of the G2/M phase of the cell cycle (Kwon et al, 1997;Wu et al, 2009), little has been done to examine whether it could play a role in the control of synaptic plasticity.…”