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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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8-Bromo Cyclic Adenosine Monophosphate / pharmacology
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Animals
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CDC2 Protein Kinase
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Cell Cycle / physiology
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / metabolism*
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Cyclin B / metabolism
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Cyclin B / pharmacology
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Cyclin-Dependent Kinases
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HeLa Cells
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Humans
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Mitosis / physiology*
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Models, Biological
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Okadaic Acid / pharmacology
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Oocytes / drug effects
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Oocytes / metabolism
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Phosphoproteins / metabolism*
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Phosphorylation
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Protein Binding / physiology
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Protein Kinase Inhibitors / pharmacology
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Protein Kinases / metabolism
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Protein Phosphatase 1 / antagonists & inhibitors
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Protein Phosphatase 1 / metabolism*
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Protein Phosphatase 1 / pharmacology
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Proteins / metabolism*
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Proteins / pharmacology
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Purines / pharmacology
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Roscovitine
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Threonine / metabolism
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Xenopus Proteins / antagonists & inhibitors
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Xenopus Proteins / metabolism
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Xenopus laevis
Substances
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Cell Cycle Proteins
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Cyclin B
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Phosphoproteins
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Protein Kinase Inhibitors
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Proteins
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Purines
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Xenopus Proteins
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phosphoprotein phosphatase inhibitor 1
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protein phosphatase inhibitor-2
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Roscovitine
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Okadaic Acid
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8-Bromo Cyclic Adenosine Monophosphate
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Threonine
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Protein Kinases
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CDK1 protein, Xenopus
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Cyclic AMP-Dependent Protein Kinases
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CDC2 Protein Kinase
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CDK1 protein, human
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Cyclin-Dependent Kinases
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Protein Phosphatase 1