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.
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Authors | Shahrzad Abbasi, Jiing-Dwan Lee, Bing Su, Xiang Chen, Joseph L Alcon, JianHua Yang, Rodney E Kellems, Yang Xia |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 281
Issue 12
Pg. 7717-26
(Mar 24 2006)
ISSN: 0021-9258 [Print] United States |
PMID | 16415348
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 14-3-3 Proteins
- DNA-Binding Proteins
- Intracellular Signaling Peptides and Proteins
- Muscle Proteins
- NFATC Transcription Factors
- RCAN1 protein, human
- RNA, Small Interfering
- Angiotensin II
- Serine
- Mitogen-Activated Protein Kinase 7
- MAP Kinase Kinase 5
- Map2k5 protein, rat
- Alkaline Phosphatase
- Calcineurin
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Topics |
- 14-3-3 Proteins
(metabolism)
- Adenoviridae
(genetics)
- Alkaline Phosphatase
(metabolism)
- Angiotensin II
(chemistry)
- Animals
- Blotting, Western
- CHO Cells
- Calcineurin
(chemistry, metabolism)
- Cells, Cultured
- Cricetinae
- DNA-Binding Proteins
- Genes, Reporter
- Immunoprecipitation
- Intracellular Signaling Peptides and Proteins
(chemistry, metabolism)
- MAP Kinase Kinase 5
(metabolism)
- MAP Kinase Signaling System
- Mice
- Mice, Transgenic
- Mitogen-Activated Protein Kinase 7
(metabolism)
- Muscle Proteins
(chemistry, metabolism)
- NFATC Transcription Factors
(metabolism)
- Phosphorylation
- Protein Binding
- RNA, Small Interfering
(metabolism)
- Rats
- Serine
(chemistry)
- Signal Transduction
- Transfection
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