Protein Kinase-mediated Regulation of Calcineurin Through the Phosphorylation of Modulatory Calcineurin-interacting Protein 1.
From: Department of Biochemistry and Molecular Biology, The University of Texas-Houston Medical School, Houston, Texas 77030, USA.
The Journal of biological chemistry
- Publish Date: Mar 2006
- ISSN: 0021-9258
- Volume: 281
- Issue: 12
- Pages: 7717-26
- Medium: Print
- Language: English
- Citation (JAMA): Abbasi Shahrzad, Lee Jiing-Dwan, Su Bing, et al. Protein Kinase-mediated Regulation of Calcineurin Through the Phosphorylation of Modulatory Calcineurin-interacting Protein 1.. J. Biol. Chem. Mar 2006;281:7717-26
Abstract
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.
Mesh Headings (Keywords): 14-3-3 Proteins, Adenoviridae, Alkaline Phosphatase, Angiotensin II, Animals, Blotting, Western, CHO Cells, Calcineurin, Cells, Cultured, Cricetinae, Genes, Reporter, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, MAP Kinase Kinase 5, MAP Kinase Signaling System, Mice, Mice, Transgenic, Mitogen-Activated Protein Kinase 7, Muscle Proteins, NFATC Transcription Factors, Phosphorylation, Protein Binding, RNA, Small Interfering, Rats, Serine, Signal Transduction, Transfection
Check for Full Text / PubMed Unique Identifier (PMID): 16415348
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