Thapsigargin-induced Ca2+ increase inhibits TGFβ1-mediated Smad2 transcriptional responses via Ca2+/calmodulin-dependent protein kinase II

Ming Ming, Ivan Manzini, Weidong Le, Kerstin Krieglstein, Björn Spittau

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

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 Ca2+ 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 Ca2+/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 Ca2+-mediated CaMKII activation. In summary, this study clearly shows that the TGFβ1-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 TGFβ target genes. These results underline the importance of intracellular Ca2+ for the regulation of TGFβ signalling.

Original languageEnglish (US)
Pages (from-to)1222-1230
Number of pages9
JournalJournal of Cellular Biochemistry
Volume111
Issue number5
DOIs
StatePublished - Dec 1 2010

Keywords

  • calcium
  • CaMKII
  • Smad2
  • TGFβ1
  • thapsigargin

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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