Balanced ubiquitylation and deubiquitylation of Frizzled regulate cellular responsiveness to Wg/Wnt

EMBO J. 2010 Jul 7;29(13):2114-25. doi: 10.1038/emboj.2010.100. Epub 2010 May 21.


Wingless (Wg)/Wnt has been proposed to exert various functions as a morphogen depending on the levels of its signalling. Therefore, not just the concentration of Wg/Wnt, but also the responsiveness of Wg/Wnt-target cells to the ligand, must have a crucial function in controlling cellular outputs. Here, we show that a balance of ubiquitylation and deubiquitylation of the Wg/Wnt receptor Frizzled determines the cellular responsiveness to Wg/Wnt both in mammalian cells and in Drosophila, and that the cell surface level of Frizzled is regulated by deubiquitylating enzyme UBPY/ubiquitin-specific protease 8 (USP8). Although ubiquitylated Frizzled underwent lysosomal trafficking and degradation, UBPY/USP8-dependent deubiquitylation led to recycling of Frizzled to the plasma membrane, thereby elevating its surface level. Importantly, a gain and loss of UBPY/USP8 function led to up- and down-regulation, respectively, of canonical Wg/Wnt signalling. These results unveil a novel mechanism that regulates the cellular responsiveness to Wg/Wnt by controlling the cell surface level of Frizzled.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Drosophila / embryology*
  • Drosophila / metabolism*
  • Drosophila Proteins / metabolism*
  • Endocytosis
  • Frizzled Receptors / metabolism*
  • Gene Expression Regulation
  • Humans
  • Larva / metabolism
  • Protein Transport
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism
  • Ubiquitin-Specific Proteases / metabolism*
  • Ubiquitination*
  • Wings, Animal / embryology
  • Wings, Animal / metabolism
  • Wnt Proteins / metabolism
  • Wnt1 Protein / metabolism*


  • Drosophila Proteins
  • Frizzled Receptors
  • Wnt Proteins
  • Wnt1 Protein
  • wg protein, Drosophila
  • USP8 protein, Drosophila
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases