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J. Biol. Chem., Vol. 279, Issue 43, 44573-44581, October 22, 2004

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Redox Regulation of the Calcium/Calmodulin-dependent Protein Kinases^*

Christopher J. Howe, Michelle M. LaHair, James A. McCubrey¶||, and Richard A. Franklin¶**

From the Department of Microbiology and Immunology and the Leo Jenkins Cancer Center, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834

Reactive oxygen intermediates (ROI) have been viewed traditionally as damaging to the cell. However, a predominance of evidence has shown that ROI can also function as important activators of key cellular processes, and ROI have been shown to play a vital role in cell signaling networks. The calcium/calmodulin-dependent protein kinases (CaM kinases) are a family of related kinases that are activated in response to increased intracellular calcium concentrations. In this report we demonstrate that hydrogen peroxide treatment results in the activation of both CaM kinase II and IV in Jurkat T lymphocytes. Surprisingly, this activation occurs in the absence of any detectable calcium flux, suggesting a novel means for the activation of these kinases. Treatment of Jurkat cells with phorbol 12-myristate 13-acetate (PMA), which does not cause a calcium flux, also activated the CaM kinases. The addition of catalase to the cultures inhibited PMA-induced activation of the CaM kinases, suggesting that similar to hydrogen peroxide, PMA also activates the CaM kinases via the production of ROI. One mechanism by which this likely occurs is through oxidation and consequential inactivation of cellular phosphatases. In support of this concept, okadaic acid and microcystin-LR, which are inhibitors of protein phosphatase 2A (PP2A), induced CaM kinase II and IV activity in these cells. Overall, these results demonstrate a novel mechanism by which ROI can induce CaM kinase activation in T lymphocytes.

Received for publication, April 14, 2004 , and in revised form, July 28, 2004.

^* This work was supported by Scientist Development Grant 9930099N and Grant-in-aid 0355834U from the American Heart Association (to R. A. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by Grant R01 CA98195 from the National Institutes of Health.

^|| Supported in part by Grant R01 CA51025 from the National Institutes of Health.

^** To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Brody Bldg., Greenville, NC 27834. Tel.: 252-744-2705; Fax: 252-744-3104; E-mail: franklinr{at}mail.ecu.edu.

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