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J. Biol. Chem., Vol. 280, Issue 44, 36737-36746, November 4, 2005

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The Essential Role of MEKK3 Signaling in Angiotensin II-induced Calcineurin/Nuclear Factor of Activated T-cells Activation^*

Shahrzad Abbasi, Bing Su, Rodney E. Kellems, JianHua Yang¶, and Yang Xia1

From the Department of Biochemistry and Molecular Biology, University of Texas at Houston Medical School, Houston, Texas 77030, the ^¶Department of Pediatrics, Texas Children's Hospital Cancer Center, Baylor College of Medicine, Houston, Texas 77030, and the Department of Immunology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77054

Calcineurin is a serine/threonine protein phosphatase that plays a critical role in many physiologic processes, such as T-cell activation, apoptosis, skeletal myocyte differentiation, and cardiac hypertrophy. We determined that active MEKK3 was capable of activating calcineurin/nuclear factor of activated T-cells (NFAT) signaling in cardiac myocytes and reprogramming cardiac gene expression. In contrast, small interference RNA directed against MEKK3 and a dominant negative form of MEKK3 caused the reduction of NFAT activation in response to angiotensin II in cardiac myocytes. Genetic studies showed that MEKK3-deficient mouse embryo fibroblasts failed to activate calcineurin/NFAT in response to angiotensin II, a potent NFAT activator. Conversely, restoring MEKK3 to the MEKK3-deficient cells restored angiotensin II-mediated calcineurin/NFAT activation. We determined that angiotensin II induced MEKK3 phosphorylation. Thus, MEKK3 functions downstream of the AT1 receptor and is essential for calcineurin/NFAT activation. Finally, we determined that MEKK3-mediated activation of calcineurin/NFAT signaling was associated with the phosphorylation of modulatory calcineurin-interacting protein 1 at Ser¹⁰⁸ and Ser¹¹². Taken together, our studies reveal a previously unrecognized novel essential regulatory role of MEKK3 signaling in calcineurin/NFAT activation.

Received for publication, June 14, 2005 , and in revised form, August 24, 2005.

^* This work was supported by American Heart Association, Texas Affiliate, Grant BGIA0365149Y (to Y. X.). 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.

¹ To whom correspondence and reprint requests should be addressed: Dept. of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030. Tel.: 713-500-5039; Fax: 713-500-0652; E-mail: Yang.Xia{at}uth.tmc.edu.

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