ABSTRACT 475(9-1)
TGFβ及びBMPのシグナル伝達の阻害作用におけるSmad7とSmad6との協調作用：林秀敏1,2, Jeffrey L.WRANA2（1名市大・薬, 2The Hospital for Sick Children）
The MAD-Related Protein Smad7 and Smad6 Cooperate in Inhibition of TGFβ and BMP Signalling : Hidetoshi HAYASHI1,2 and Jeffrey L.WRANA2 (1Fac. Pharm. Sci., Nagoya City Univ., 2Program in Develop. Biol., The Hosp. Sick Children, Toronto, CANADA)
Smad proteins are essential components in signalling of the TGFβ superfamily of growth factors. Smad2 or/and Smad3 have been shown to be required for TGFβ /activin signalling, and Smad1 or/and Smad5 (probably Smad8) for BMP signalling. Signalling is initiated by interaction and subsequent phosphorylation of each Smad protein on serine residues in C-terminal SSXS motif by the corresponding type I receptor kinases. These phosphorylated Smad proteins then interact with Smad4 and translocate to the nucleus, where they can regulate transcriptional responses. We have recently identified a novel type of Smad, Smad7 which lacks SSXS motif, associates stably with the TGFβ receptors, and inhibits TGFβ signalling by preventing access and phosphorylation of Smad2 or Smad3 by the type I receptor kinases. Recently Smad6 is also demonstrated as an inhibitor of TGFβ and BMP signalling. In this study, we investigated that the effect of Smad6 on inhibitory action of Smad7 in TGFβ signalling. Smad6 associates with Smad7 in a TGFβ independent manner. Smad6 itself has a little affinity to TβRI, however, in the presence of Smad7, it can bind to activated TβRI through Smad7. Smad6 has a little inhibitory activity in TGFβ signalling, while it modulates the antagonistic effect of Smad7. In mouse embryonic carcinoma, P19 cells, Smad7 shows a dual effect on BMP signalling; at high dose it inhibits a signalling but at low dose it has a little stimulatory effect. Smad6 also modulates the action of Smad7 in BMP signalling. Smad7 can also associate stably to the activated BMP receptors, while Smad6 fails to bind these receptors even in the presence of Smad7. These findings define Smad7 and Smad6 cooperate in the inhibition on the TGFβ and BMP signalling pathway but a mechanism of inhibition in each pathway appear to be different.