Thu, 21 Aug 2008 09:33:27 BST CiteULike: swennemanns Yang http://www.citeulike.org/user/swennemann/author/Yang CiteULike.org en-gb Copyright © 2004-2008 citeulike.org http://www.citeulike.org/user/swennemann/article/599317 <i>J Biol Chem, Vol. 281, No. 12. (24 March 2006), pp. 7717-7726.</i><br /><br />Calcineurin is a serine/threonine protein phosphatase that plays a critical role in many physiologic processes such as T-cell activation, skeletal myocyte differentiation, and cardiac hypertrophy. We previously showed that active MEKK3 is capable of stimulating calcineurin/nuclear factor of activated T-cells (NFAT) signaling in cardiac myocytes through phosphorylation of modulatory calcineurin-interacting protein 1 (MCIP1). However, the protein kinases that function downstream of MEKK3 to mediate MCIP1 phosphorylation and the mechanism of MCIP1-mediated calcineurin regulation have not been defined. Here, we show that MEK5 and big MAP kinase 1 (BMK1) function downstream of MEKK3 in a signaling cascade that induces calcineurin activity through phosphorylation of MCIP1. Genetic studies showed that BMK1-deficient mouse lung fibroblasts failed to mediate MCIP1 phosphorylation and activate calcineurin/NFAT in response to angiotensin II, a potent NFAT activator. Conversely, restoring BMK1 to the deficient cells restored angiotensin II-mediated calcineurin/NFAT activation. Thus, using BMK1-deficient mouse lung fibroblast cells, we provided the genetic evidence that BMK1 is required for angiotensin II-mediated calcineurin/NFAT activation through MICP1 phosphorylation. Finally, we discovered that phosphorylated MCIP1 dissociates from calcineurin and binds with 14-3-3, thereby relieving its inhibitory effect on calcineurin activity. In summary, our findings reveal a previously unrecognized essential regulatory role of mitogen-activated protein kinase signaling in calcineurin activation through the reversible phosphorylation of a calcineurin-interacting protein, MCIP1. Protein kinase-mediated regulation of calcineurin through the phosphorylation of modulatory calcineurin-interacting protein 1. S Abbasi JD Lee B Su X Chen JL Alcon J Yang RE Kellems Y Xia doi:10.1074/jbc.M510775200 J Biol Chem, Vol. 281, No. 12. (24 March 2006), pp. 7717-7726. 2006-04-25T07:53:19-00:00 2006 J Biol Chem 0021-9258 281 12 7717 7726 calcineurin calcium flux http://www.citeulike.org/user/swennemann/article/599316 <i>Trends Biochem Sci, Vol. 29, No. 5. (May 2004), pp. 233-242.</i> Advances in protein kinase B signalling: AKTion on multiple fronts. DP Brazil ZZ Yang BA Hemmings doi:10.1016/j.tibs.2004.03.006 Trends Biochem Sci, Vol. 29, No. 5. (May 2004), pp. 233-242. 2006-04-25T07:45:51-00:00 2004 Trends Biochem Sci 0968-0004 29 5 233 242 akt pkb signalling