Crystal structure of the catalytic subunit of Cdc25B required for G 2 /M phase transition of the cell cycle 1 1Edited by I. A. Wilson

Reynolds, R.A.; Yem, Anthony W.; Wolfe, Cindy L.; Deibel, Martin R.; Chidester, C. G.; Watenpaugh, Keith David

doi:10.1006/jmbi.1999.3168

Cited by 173 publications

(214 citation statements)

References 16 publications

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“…Thus, the deletion of the B domain reconstitutes one phosphorylation site (S 151 MPD) and probably induces a conformational change in the structure of the N-terminal part of CDC25B that unmasks an alternative phosphorylation site for the CK2 kinase (S 189 APD). To date, only the 3D structure of CDC25B catalytic domain is known (Reynolds et al, 1999); thus, the clarification of this issue will have to await the resolution of the complete structure of the enzyme. Furthermore, the N-terminal regulating domain of CDC25B alone (including interaction and phosphorylation sites) is not phoshorylated by CK2, which confirms once again that the overall conformation of the protein is important for the regulation of its phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase CK2 regulates CDC25B phosphatase activity

et al. 2003

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Human dual-specificity phosphatases CDC25 (A, B and C) play an important role in the control of cell cycle progression by activating the cyclin-dependent kinases (CDKs). Regulation of these phosphatases during the cell cycle involves post-translational modifications such as phosphorylation and protein-protein interactions. Given the suspected involvement of the protein kinase CK2 at the G2/M transition, we have investigated its effects on the CDC25B phosphatase. We show that in vitro CK2 phosphorylates CDC25B, but not CDC25C. Mass spectrometry analysis demonstrates that at least two serine residues, Ser-186 and Ser-187, are phosphorylated in vivo. We also report that CDC25B interacts with CK2, and this interaction, mediated by the CK2b regulatory subunit, involves domains that are located within the first 55 amino acids of CK2b and between amino acids 122 and 200 on CDC25B. This association was confirmed in vivo, in Sf9 insect cells and in U 2 OS human cells expressing an HA epitope-tagged CDC25B. Finally, we demonstrate that phosphorylation of CDC25B by protein kinase CK2 increases the catalytic activity of the phosphatase in vitro as well as in vivo. We discuss the possibility that CDC25B phosphorylation by CK2 could play a role in the regulation of the activity of CDC25B as a starter of mitosis.

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Section: Discussionmentioning

confidence: 99%

Protein kinase CK2 regulates CDC25B phosphatase activity

et al. 2003

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“…This includes a Cys-(X)5-Arg motif that is conserved in all dualspecificity phosphatases, and the CH2A and CH2B homology motifs that are also found in MAP kinase phosphatases (Keyse and Ginsburg, 1993). Crystallographic data, however, show conformational differences in the carboxy-terminal regions of the three CDC25 proteins, suggesting that their catalytic properties may not be identical (Fauman et al, 1998;Reynolds et al, 1999;Wilborn et al, 2001). The Cdc25 phosphatases are essential regulators of cell-cycle transitions.…”

Section: The Cdc25 Phosphatasesmentioning

confidence: 99%

The Plk3-Cdc25 circuit

2005

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“…Inhibitors of PTPases represent a new approach to interference with the cell cycle and also a novel set of tools for dissecting the role of phosphatases in specific cellular signaling pathways. Although two crystal structures have been published for the Cdc25A and B-catalytic domains (Fauman et al, 1998;Reynolds et al, 1999), neither have suggested the nature of the interactions with small molecule inhibitors. In addition, the protein substrate itself has been shown to be capable of inducing conformational changes in the PTPs that are important for their activity (Andersen et al, 2001).…”

Section: Future Directionsmentioning

confidence: 99%

K vitamins, PTP antagonism, and cell growth arrest

Carr

Wang

Kar

2002

Journal Cellular Physiology

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The main function of K vitamins is to act as co-factors for g-glutamyl carboxylase. However, they have also recently been shown to inhibit cell growth. We have chemically synthesized a series of K vitamin analogs with various side chains at the 2 or 3 position of the core naphthoquinone structure. The analogs with short thio-ethanol side chains are found to be more potent growth inhibitors in vitro of various tumor cell lines. Cpd 5 or [2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone] is one of the most potent. The anti-proliferation activity of these compounds is antagonized by exogenous thiols but not by non-thiol antioxidants. This suggests that the growth inhibition is mediated by sulfhydryl arylation of cellular glutathione and cysteine-containing proteins and not by oxidative stress. The protein tyrosine phosphatases (PTP) are an important group of proteins that contain cysteine at their catalytic site. PTPs regulate mitogenic signal transduction and cell cycle progression. PTP inhibition by Cpd 5 results in prolonged tyrosine phosphorylation and activation of several kinases and transcription factors including EGFR, ERK1/2, and Elk1. Cpd 5 could activate ERK1/2 either by signaling from an activated EGFR, which is upstream in the signaling cascade, or by direct inhibition of ERK1/2 phosphatase(s). Prolonged ERK1/2 phosphorylation strongly correlates with Cpd 5-mediated growth inhibition. Cpd 5 can also bind to and inhibit the Cdc25 family of dual specific phosphatases. As a result, several Cdc25 substrates (Cdk1, Cdk2, Cdk4) involved in cell cycle progression are tyrosine phosphorylated and thereby inhibited by its action. Cpd 5 could also inhibit both normal liver regeneration and hepatoma growth in vivo. DNA synthesis during rat liver regeneration following partial hepatectomy, transplantable rat hepatoma cell growth, and glutathione-S-transferase-pi expressing hepatocytes after administration of the chemical carcinogen diethylnitrosamine, are all inhibited by Cpd 5 administration. The growth inhibitory effect during liver regeneration and transplantable tumor growth is also correlated with ERK1/2 phosphorylation induced by Cpd 5. Thus, Cpd 5-mediated inhibition of PTPs, such as Cdc25 leads to cell growth arrest due to altered activity of key cellular kinases involved in signal transduction and cell cycle progression. This prototype K vitamin analog represents a novel class of growth inhibitor based upon its action as a selective PTP antagonist. It is clearly associated with prolonged ERK1/2 phosphorylation, which is in contrast with the transient ERK1/2 phosphorylation induced by growth stimulatory mitogens.

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Crystal structure of the catalytic subunit of Cdc25B required for G 2 /M phase transition of the cell cycle 1 1Edited by I. A. Wilson

Cited by 173 publications

References 16 publications

Protein kinase CK2 regulates CDC25B phosphatase activity

Protein kinase CK2 regulates CDC25B phosphatase activity

The Plk3-Cdc25 circuit

K vitamins, PTP antagonism, and cell growth arrest

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