title: PP1-mediated dephosphorylation of phosphoproteins at mitotic exit is controlled by inhibitor-1 and PP1 phosphorylation.
abstract: 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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Judy Qiju
authors.initials: JQ
authors.lastname: Wu
authors.forename: Jessie Yanxiang
authors.initials: JY
authors.lastname: Guo
authors.forename: Wanli
authors.initials: W
authors.lastname: Tang
authors.forename: Chih-Sheng
authors.initials: CS
authors.lastname: Yang
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Freel
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.forename: Sally
authors.initials: S
authors.lastname: Kornbluth
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D016203:CDC2 Protein Kinase; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism / Q000494:pharmacology; D018844:Cyclin-Dependent Kinases; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000502:physiology*; D008954:Models, Biological; D019319:Okadaic Acid / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism* / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D013912:Threonine / Q000378:metabolism; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014982:Xenopus laevis; D000097847:Protein Phosphatase Inhibitory Proteins
chemical_list: D015124:8-Bromo Cyclic Adenosine Monophosphate; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D019926:Cyclin B; D018844:Cyclin-Dependent Kinases; D019319:Okadaic Acid; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D054645:Protein Phosphatase 1; D011506:Proteins; D011687:Purines; D000077546:Roscovitine; D013912:Threonine; D029867:Xenopus Proteins; C073882:phosphoprotein phosphatase inhibitor 1; C024833:protein phosphatase inhibitor-2; D000097847:Protein Phosphatase Inhibitory Proteins; C070577:CDK1 protein, Xenopus; C528899:CDK1 protein, human