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¹ Laboratory of Molecular Biology, Azabu University School of Veterinary Medicine, Sagamihara 229-8501, Japan
² Laboratory of Nutritional Science, Kyoto University Graduate School of Agriculture, Kyoto 606-8502, Japan
³ Laboratory of Cellular Biochemistry, RIKEN, Wako, Saitama 351-0198, Japan
⁴ Laboratory of Veterinary Immunology, Azabu University School of Veterinary Medicine, Sagamihara 229-8501, Japan
⁵ Laboratory of Nutrition, Azabu University School of Veterinary Medicine, Sagamihara 229-8501, Japan

In current models of transforming growth factor-β (TGF-β) family signaling, type II receptors activate specific activin receptor-like kinase (ALK) type I receptors. These serine/threonine kinases activate ligand-dependent receptor regulated (R)-Smad by phosphorylating carboxy-terminal serines. We found that the receptor expression levels affected the phosphorylation and activation of the two R-Smad subclasses, activin/TGF-β-specific (AR-Smad) and bone morphogenetic protein (BMP)-specific (BR-Smad). Co-expressing constitutively active type I and type II receptors in COS7 cells resulted in the phosphorylation of both R-Smad subclasses in a ligand-independent manner. This was verified using in vitro kinase assays. In untransfected B16 melanoma cells, TGF-β1 and BMP-2 induced phosphorylation of both R-Smad subclasses, and TGF-β1 up-regulated the inhibitor of differentiation (Id) gene, which is usually regulated by BMP. By contrast, BMP-2 up-regulated plasminogen activator inhibitor-1 (PAI-1), which is an AR-Smad-regulated gene. Except for ALK4 and ALK6, levels of type I and type II receptor mRNAs were higher in B16 cells than in HeLa and HepG2 cells, in which TGF-β1 and BMP-2 induced phosphorylation of only the expected R-Smad. These results help to explain the diverse effects of this ligand family.

^* Correspondence: mfunaba{at}kais.kyoto-u.ac.jp

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