Constitutive and UV-induced fibronectin degradation is a ubiquitination-dependent process controlled by beta-TrCP

J Biol Chem. 2006 Aug 11;281(32):23060-5. doi: 10.1074/jbc.M604311200. Epub 2006 Jun 6.


Loss of fibronectin (FN) assembly in the extracellular matrix has long been recognized as a feature of cellular transformation. However, such assembly is regulated not only by FN synthesis but also by its post-translational modifications. The mechanism controlling FN protein stability has remained unclear so far. Recently it was demonstrated that FN matrix turnover occurs intracellularly at the lysosome following caveolin-1-dependent endocytosis. Although FN was reported to undergo ubiquitindependent degradation, the ubiquitin ligase responsible for FN ubiquitination is unknown. In this study, we have identified beta-TrCP as the ubiquitin ligase for lysosomal degradation of FN. We found two conserved beta-TrCP recognition motif (DSGVVYS and DSGSIVVS) in the primary amino acid sequence of human, mouse, and rat FN. Down-regulation of either beta-TrCP1 or beta-TrCP2 by small interference (siRNA) caused significant accumulation of FN. Immunolocalization studies showed intracellular accumulation of FN in beta-TrCP siRNA-treated cells without showing much alteration in its matrix association. We also observed that exposure of cells to UV irradiation effectively down-regulated FN following increased ubiquitination, which was significantly inhibited either by lysosomal inhibitor or by siRNA-mediated down-regulation of beta-TrCP. Taken together, constitutive FN degradation, as well as UV-induced degradation, is ubiquitination dependent and controlled by beta-TrCP.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Caveolin 1 / chemistry
  • Cell Line, Tumor
  • Fibronectins / chemistry
  • Fibronectins / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lysosomes / chemistry
  • Lysosomes / metabolism
  • Mice
  • Protein Processing, Post-Translational
  • Rats
  • Ubiquitin / chemistry*
  • Ultraviolet Rays
  • beta-Transducin Repeat-Containing Proteins / chemistry*


  • Caveolin 1
  • Fibronectins
  • Ubiquitin
  • beta-Transducin Repeat-Containing Proteins