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

2009; Nature Portfolio; Volume: 11; Issue: 5 Linguagem: Inglês

10.1038/ncb1871

1476-4679

Judy Qiju Wu, Jessie Yanxiang Guo, Wanli Tang, Chih‐Sheng Yang, Christopher D. Freel, Chen Chen, Angus C. Nairn, Sally Kornbluth,

Cancer-related Molecular Pathways

Mitotic exit occurs when Cdc2 kinase activity drops and its substrates are dephosphorylated. Protein phosphatase-1 is responsible for this dephosphorylation and its activity is restrained during mitosis by Cdc2 phosphorylation and binding of Inhibitor-1, while auto-dephoshorylation at the Cdc2 site ensures its timely activation. Loss of cell division cycle 2 (Cdc2, also known as Cdk1) activity after cyclin B degradation is necessary, but not sufficient, for mitotic exit. Proteins phosphorylated by Cdc2 and downstream mitotic kinases must be dephosphorylated. We report here that protein phosphatase-1 (PP1) is the main catalyst of mitotic phosphoprotein dephosphorylation. Suppression of PP1 during early mitosis is maintained through dual inhibition by Cdc2 phosphorylation and the binding of inhibitor-1. Protein kinase A (PKA) phosphorylates inhibitor-1, mediating binding to PP1. As Cdc2 levels drop after cyclin B degradation, auto-dephosphorylation of PP1 at its Cdc2 phosphorylation site (Thr 320) allows partial PP1 activation. This promotes PP1-regulated dephosphorylation at the activating site of inhibitor-1 (Thr 35) followed by dissociation of the inhibitor-1–PP1 complex and then full PP1 activation to promote mitotic exit. Thus, Cdc2 both phosphorylates multiple mitotic substrates and inhibits their PP1-mediated dephosphorylation.