The essential role of MEKK3 signaling in angiotensin-II-induced calcineurin/NFAT activation

doi:10.1074/jbc.M506493200

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Papers In Press, published online ahead of print August 26, 2005
J. Biol. Chem, 10.1074/jbc.M506493200
Submitted on June 14, 2005
Revised on August 24, 2005
Accepted on August 26, 2005

The essential role of MEKK3 signaling in angiotensin-II-induced calcineurin/NFAT activation

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

Dept. of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, TX 77030

Corresponding Author: yang.xia{at}uth.tmc.edu

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/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 the 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 MCIP1 (modulatory calcineurin interacting protein 1) at S108 and S112. Taken together, our studies reveal a previously unrecognized novel essential regulatory role of MEKK3 signaling in calcineurin/NFAT activation.

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