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Thapsigargin‐induced Ca 2+ increase inhibits TGFβ1‐mediated Smad2 transcriptional responses via Ca 2+ /calmodulin‐dependent protein kinase II
Author(s) -
Ming Ming,
Manzini Ivan,
Le Weidong,
Krieglstein Kerstin,
Spittau Björn
Publication year - 2010
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.22843
Subject(s) - thapsigargin , calmodulin , chemistry , protein kinase a , kinase , microbiology and biotechnology , biophysics , biology , biochemistry , enzyme , extracellular
Transforming growth factor β (TGFβ) signalling plays important roles in a variety of tissues and cell types. Impaired TGFβ signalling contributes to several pathologies, including cancer, fibrosis as well as neurodegenerative diseases. TGFβ receptor type I‐mediated phosphorylation of Smad2, the formation of the Smad2–Smad4 complex and translocation to the nucleus are critical steps of the TGFβ signalling pathway. Here, we demonstrate that thapsigargin‐mediated increase of intracellular Ca 2+ concentrations inhibited TGFβ1‐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 TGFβ1 treatment but had no effect on its phosphorylation at Ser465/467. Moreover, using Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII) inhibitors and a constitutively active CaMKII mutant, we provide evidence that the observed inhibition of TGFβ signalling in OLI‐neu cells was strongly dependent on Ca 2+ ‐mediated CaMKII activation. In summary, this study clearly shows that the TGFβ1‐induced Smad2 nuclear translocation is negatively regulated by intracellular Ca 2+ in OLI‐neu cells and that increased intracellular Ca 2+ concentrations block Smad2‐mediated transcription of TGFβ target genes. These results underline the importance of intracellular Ca 2+ for the regulation of TGFβ signalling. J. Cell. Biochem. 111: 1222–1230, 2010. © 2010 Wiley‐Liss, Inc.