Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7.
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.
Koinuma
Daizo
D
Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), Toshima-ku, Tokyo, Japan.
Shinozaki
Masahiko
M
Komuro
Akiyoshi
A
Goto
Kouichiro
K
Saitoh
Masao
M
Hanyu
Aki
A
Ebina
Masahito
M
Nukiwa
Toshihiro
T
Miyazawa
Keiji
K
Imamura
Takeshi
T
Miyazono
Kohei
K
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D005810:Multigene Family; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D051906:Smad7 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D017931:DNA Primers; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; C486067:RNF111 protein, human; C427283:Rnf111 protein, mouse; D044767:Ubiquitin-Protein Ligases