Koinuma Daizo, Shinozaki Masahiko, Komuro Akiyoshi, Goto Kouichiro, Saitoh Masao, Hanyu Aki, Ebina Masahito, Nukiwa Toshihiro, Miyazawa Keiji, Imamura Takeshi, Miyazono Kohei
Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), Toshima-ku, Tokyo, Japan.
EMBO J. 2003 Dec 15;22(24):6458-70. doi: 10.1093/emboj/cdg632.
Arkadia was originally identified as a protein that enhances signalling activity of Nodal and induces mammalian nodes during early embryogenesis; however, the mechanisms by which Arkadia affects transforming growth factor-beta (TGF-beta) superfamily signalling have not been determined. Here we show that Arkadia is widely expressed in mammalian tissues, and that it enhances both TGF-beta and bone morphogenetic protein (BMP) signalling. Arkadia physically interacts with inhibitory Smad, Smad7, and induces its poly-ubiquitination and degradation. In contrast to Smurf1, which interacts with TGF-beta receptor complexes through Smad7 and degrades them, Arkadia fails to associate with TGF-beta receptors. In contrast to Smad7, expression of Arkadia is down-regulated by TGF-beta. Silencing of the Arkadia gene resulted in repression of transcriptional activities induced by TGF-beta and BMP, and accumulation of the Smad7 protein. Arkadia may thus play an important role as an amplifier of TGF-beta superfamily signalling under both physiological and pathological conditions.
Arkadia最初被鉴定为一种在早期胚胎发育过程中增强Nodal信号活性并诱导哺乳动物节点形成的蛋白质；然而，Arkadia影响转化生长因子-β（TGF-β）超家族信号传导的机制尚未确定。在这里，我们表明Arkadia在哺乳动物组织中广泛表达，并且它增强了TGF-β和骨形态发生蛋白（BMP）信号传导。Arkadia与抑制性Smad即Smad7发生物理相互作用，并诱导其多聚泛素化和降解。与通过Smad7与TGF-β受体复合物相互作用并使其降解的Smurf1不同，Arkadia不能与TGF-β受体结合。与Smad7相反，Arkadia的表达受TGF-β下调。Arkadia基因的沉默导致TGF-β和BMP诱导的转录活性受到抑制，以及Smad7蛋白的积累。因此，Arkadia可能在生理和病理条件下作为TGF-β超家族信号传导的放大器发挥重要作用。
