title: Regulation of protein phosphatase 1I by Cdc25C-associated kinase 1 (C-TAK1) and PFTAIRE protein kinase.
abstract: Protein phosphatase 1I (PP-1I) is a major endogenous form of protein phosphatase 1 (PP-1) that consists of the core catalytic subunit PP-1c and the regulatory subunit inhibitor 2 (I-2). Phosphorylation of the Thr-72 residue of I-2 is required for activation of PP-1I. We studied the effects of two protein kinases identified previously in purified brain PP-1I by mass spectrometry, Cdc25C-associated kinase 1 (C-TAK1) and PFTAIRE (PFTK1) kinase, for their ability to regulate PP-1I. Purified C-TAK1 phosphorylated I-2 in reconstituted PP-1I (PP-1c. I-2) on Ser-71, which resulted in partial inhibition of its ATP-dependent phosphatase activity and inhibited subsequent phosphorylation of Thr-72 by the exogenous activating kinase GSK-3. In contrast, purified PFTK1 phosphorylated I-2 at Ser-86, a site known to potentiate Thr-72 phosphorylation and activation of PP-1I phosphatase activity by GSK-3. These findings indicate that brain PP-1I associates with and is regulated by the associated protein kinases C-TAK1 and PFTK1. Multisite phosphorylation of the I-2 regulatory subunit of PP-1I leads to activation or inactivation of PP-1I through bidirectional modulation of Thr-72 phosphorylation, the critical activating residue of I-2.
authors.affiliation: From the Departments of Anesthesiology and Pharmacology, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Jimcy
authors.initials: J
authors.lastname: Platholi
authors.affiliation: From the Departments of Anesthesiology and Pharmacology, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Anna
authors.initials: A
authors.lastname: Federman
authors.affiliation: From the Departments of Anesthesiology and.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Detert
authors.affiliation: From the Departments of Anesthesiology and Pharmacology, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Paul
authors.initials: P
authors.lastname: Heerdt
authors.affiliation: From the Departments of Anesthesiology and Pharmacology, Weill Cornell Medical College, New York, New York 10065 hchemmi@med.cornell.edu.
authors.forename: Hugh C
authors.initials: HC
authors.lastname: Hemmings
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D013552:Swine
chemical_list: C111833:MARK3 protein, human; D017346:Protein Serine-Threonine Kinases; C515076:CDK14 protein, human; D018844:Cyclin-Dependent Kinases; D054645:Protein Phosphatase 1
keywords: Cell Signaling; Enzyme; Enzyme Mechanism; Inhibitor 2; Ischemia; Protein Phosphorylation