Abstract
The peptidyl-prolyl isomerase Pin1 interacts in a phosphorylation-dependent manner with several proteins involved in cell cycle events. In this study, we demonstrate that Pin1 interacts with protein kinase CK2, an enzyme that generally exists in tetrameric complexes composed of two catalytic CK2 alpha and/or CK2 alpha' subunits together with two regulatory CK2 beta subunits. Our results indicate that Pin1 can interact with CK2 complexes that contain CK2 alpha. Furthermore, Pin1 can interact directly with the C-terminal domain of CK2 alpha that contains residues that are phosphorylated in vitro by p34(Cdc2) and in mitotic cells. Substitution of the phosphorylation sites of CK2 alpha with alanines resulted in decreased interactions between Pin1 and CK2. The other catalytic isoform of CK2, designated CK2 alpha', is not phosphorylated in mitotic cells and does not interact with Pin1, but a chimeric protein consisting of CK2 alpha' with the C terminus of CK2 alpha was phosphorylated in mitotic cells and interacts with Pin1, further implicating the phosphorylation sites in the interaction. In vitro, Pin1 inhibits the phosphorylation of Thr-1342 on human topoisomerase II alpha by CK2. Topoisomerase II alpha also interacts with Pin1 suggesting that the effect of Pin1 on the phosphorylation of Thr-1342 could result from its interactions with CK2 and/or topoisomerase II alpha. As compared with wild-type Pin1, isomerase-deficient and WW domain-deficient mutants of Pin1 are impaired in their ability to interact with CK2 and to inhibit the CK2-catalyzed phosphorylation of topoisomerase II alpha. Collectively, these results indicate that Pin1 and CK2 alpha interact and suggest a possible role for Pin1 in the regulation of topoisomerase II alpha. Furthermore, these results provide new insights into the functional role of the mitotic phosphorylation of CK2 and provide a new mechanism for selectively regulating the ability of CK2 to phosphorylate one of its mitotic targets.
Highlights
The peptidyl-prolyl isomerase Pin1 interacts in a phosphorylation-dependent manner with several proteins involved in cell cycle events
We demonstrate that Pin1 interacts with protein kinase CK2, an enzyme that generally exists in tetrameric complexes composed of two catalytic CK2␣ and/or CK2␣ subunits together with two regulatory CK2 subunits
Pin1 Interacts with Protein Kinase CK2—As a first step toward testing whether Pin1 could interact with CK2, recombinant Pin1 proteins were generated
Summary
The peptidyl-prolyl isomerase Pin interacts in a phosphorylation-dependent manner with several proteins involved in cell cycle events. These results link Pin to the G2/M transition and events regulating mitosis Another important protein implicated in cell cycle events and in cell viability is the highly conserved Ser/Thr protein kinase CK2,1 a tetrameric enzyme that is composed of two catalytic (CK2␣ and/or CK2␣Ј) subunits and two regulatory (CK2) subunits Topoisomerase II is hypo-phosphorylated and inactive, suggesting that it is a bona fide physiological target for CK2 It was recently demonstrated in mammalian cells that CK2 phosphorylates residues on topoisomerase II␣, including Thr-1342, which are residues that are maximally phosphorylated in mitotic cells [32,33,34]. Maximal inhibition of phosphorylation of Thr-1342 by CK2 requires full-length Pin with intact WW and isomerase domains
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