Inactivation of smad-transforming growth factor beta signaling by Ca(2+)-calmodulin-dependent protein kinase II.
Members of the transforming growth factor beta (TGF-beta) family transduce signals through Smad proteins. Smad signaling can be regulated by the Ras/Erk/mitogen-activated protein pathway in response to receptor tyrosine kinase activation and the gamma interferon pathway and also by the functional interaction of Smad2 with Ca(2+)-calmodulin. Here we report that ... Smad-TGF-beta-dependent transcriptional responses are prevented by expression of a constitutively activated Ca(2+)-calmodulin-dependent protein kinase II (Cam kinase II). Smad2 is a target substrate for Cam kinase II in vitro at serine-110, -240, and -260. Cam kinase II induces in vivo phosphorylation of Smad2 and Smad4 and, to a lesser extent, Smad3. A phosphopeptide antiserum raised against Smad2 phosphoserine-240 reacted with Smad2 in vivo when coexpressed with Cam kinase II and by activation of the platelet-derived growth factor receptor, the epidermal growth factor receptor, HER2 (c-erbB2), and the TGF-beta receptor. Furthermore, Cam kinase II blocked nuclear accumulation of a Smad2 and induced Smad2-Smad4 hetero-oligomerization independently of TGF-beta receptor activation, while preventing TGF-beta-dependent Smad2-Smad3 interactions. These findings provide a novel cross-talk mechanism by which Ca(2+)-dependent kinases activated downstream of multiple growth factor receptors antagonize cell responses to TGF-beta.
Mesh Terms:
Animals, COS Cells, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Cell Nucleus, Chromatography, Thin Layer, Cytoplasm, DNA-Binding Proteins, Glutathione Transferase, Humans, Immunoblotting, Luciferases, Microscopy, Fluorescence, Models, Genetic, Phosphorylation, Precipitin Tests, RNA, Receptor, erbB-2, Receptors, Transforming Growth Factor beta, Recombinant Proteins, Reverse Transcriptase Polymerase Chain Reaction, Serine, Signal Transduction, Smad2 Protein, Smad3 Protein, Smad4 Protein, Thapsigargin, Trans-Activators, Transcription, Genetic, Transfection, Transforming Growth Factor beta
Animals, COS Cells, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, Cell Nucleus, Chromatography, Thin Layer, Cytoplasm, DNA-Binding Proteins, Glutathione Transferase, Humans, Immunoblotting, Luciferases, Microscopy, Fluorescence, Models, Genetic, Phosphorylation, Precipitin Tests, RNA, Receptor, erbB-2, Receptors, Transforming Growth Factor beta, Recombinant Proteins, Reverse Transcriptase Polymerase Chain Reaction, Serine, Signal Transduction, Smad2 Protein, Smad3 Protein, Smad4 Protein, Thapsigargin, Trans-Activators, Transcription, Genetic, Transfection, Transforming Growth Factor beta
Mol. Cell. Biol.
Date: Nov. 01, 2000
PubMed ID: 11027280
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