Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • DNA Primers
  • DNA, Complementary / genetics
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Mice
  • Multigene Family
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Polymerase Chain Reaction
  • RNA, Small Interfering / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology
  • Smad7 Protein
  • Trans-Activators / metabolism*
  • Transfection
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / physiology*
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases


  • DNA Primers
  • DNA, Complementary
  • DNA-Binding Proteins
  • Nuclear Proteins
  • RNA, Small Interfering
  • SMAD7 protein, human
  • Smad7 Protein
  • Smad7 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Ubiquitin
  • RNF111 protein, human
  • Rnf111 protein, mouse
  • Ubiquitin-Protein Ligases