Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 111, Issue 5, Pages 1222-1230Publisher
WILEY-BLACKWELL
DOI: 10.1002/jcb.22843
Keywords
THAPSIGARGIN; CaMKII; TGF beta 1; Smad2; CALCIUM
Categories
Funding
- Deutsche Forschungsgemeinschaft [Kr1477/11-2]
- Max-Planck Gesellschaft
- National Nature Science Foundation [30730096, 39070925]
- Shanghai International Project [075407066]
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Transforming growth factor beta (TGF beta) signalling plays important roles in a variety of tissues and cell types. Impaired TGF beta signalling contributes to several pathologies, including cancer, fibrosis as well as neurodegenerative diseases. TGF beta receptor type I-mediated phosphorylation of Smad2, the formation of the Smad2-Smad4 complex and translocation to the nucleus are critical steps of the TGF beta signalling pathway. Here, we demonstrate that thapsigargin-mediated increase of intracellular Ca2+ concentrations inhibited TGF beta 1-induced Smad2 transcriptional activity in the oligodendroglial cell line OLI-neu. We provide evidence that thapsigargin treatment dramatically reduced the nuclear translocation of Smad2 after TGF beta 1 treatment but had no effect on its phosphorylation at Ser465/467. Moreover, using Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitors and a constitutively active CaMKII mutant, we provide evidence that the observed inhibition of TGF beta signalling in OLI-neu cells was strongly dependent on Ca2+-mediated CaMKII activation. In summary, this study clearly shows that the TGF beta 1-induced Smad2 nuclear translocation is negatively regulated by intracellular Ca2+ in OLI-neu cells and that increased intracellular Ca2+ concentrations block Smad2-mediated transcription of TGF beta target genes. These results underline the importance of intracellular Ca2+ for the regulation of TGF beta signalling. J. Cell. Biochem. 111: 1222-1230, 2010. (C) 2010 Wiley-Liss. Inc.
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