Endofin, a FYVE domain protein, interacts with Smad4 and facilitates transforming growth factor-beta signaling

J Biol Chem. 2007 Mar 30;282(13):9688-9695. doi: 10.1074/jbc.M611704200. Epub 2007 Feb 1.

Abstract

Transforming growth factor-beta (TGF-beta) signaling is facilitated by scaffold proteins such as SARA (Smad anchor for receptor activation). Endofin, a member of the FYVE domain protein family, has been suggested to regulate membrane trafficking. In this study, we report that endofin functions as a scaffold protein to facilitate TGF-beta signaling. Overexpression of endofin FYVE domain-deletion mutants inhibited TGF-beta-induced expression of CAGA-luciferase. Knockdown of endogenous endofin expression by RNA interference specifically led to reduction of the transcriptional responses of TGF-beta, but had no effect on BMP- or Wnt1-induced reporter expression. Furthermore, in endofin small interfering RNA-expressing stable cells, TGF-beta-mediated expression of plasminogen activator inhibitor-1 and p21(Cip1) was significantly reduced, and TGF-beta-promoted apoptosis was also impaired. We further showed that endofin could interact with Smad4 and TGF-beta type I receptors. Reduction of endogenous endofin expression resulted in a decrease of TGF-beta-induced Smad2 phosphorylation and Smad2-Smad4 complex formation. Together, our findings suggest that endofin facilitates TGF-beta signaling as a scaffold protein to promote the R-Smad-Smad4 complex formation by bringing Smad4 to the proximity of the receptor complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / physiology
  • Protein Structure, Tertiary
  • Serine Endopeptidases / metabolism*
  • Serine Endopeptidases / physiology
  • Signal Transduction / physiology*
  • Smad4 Protein / metabolism*
  • Smad4 Protein / physiology
  • Transforming Growth Factor beta / physiology*

Substances

  • Intracellular Signaling Peptides and Proteins
  • SMAD4 protein, human
  • Smad4 Protein
  • Transforming Growth Factor beta
  • ZFYVE16 protein, human
  • Serine Endopeptidases