Protein kinase-mediated regulation of calcineurin through the phosphorylation of modulatory calcineurin-interacting protein 1.

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.

• 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)

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

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