LNX functions as a RING type E3 ubiquitin ligase that targets the cell fate determinant Numb for ubiquitin‐dependent degradation

LNX functions as a RING type E3 ubiquitin ligase that targets the cell fate determinant Numb for... LNX is a RING finger and PDZ domain containing protein that interacts with the cell fate determinant Numb. To investigate the function of LNX, we tested its RING finger domain for ubiquitin ligase activity. The isolated RING finger domain was able to function as an E2‐dependent, E3 ubiquitin ligase in vitro and mutation of a conserved cysteine residue within the RING domain abolished its activity, indicating that LNX is the first described PDZ domain‐containing member of the E3 ubiquitin ligase family. We have identified Numb as a substrate of LNX E3 activity in vitro and in vivo. In addition to the RING finger, a region of LNX, including the Numb PTB domain‐binding site and the first PDZ domain, is required for Numb ubiquitylation. Expression of wild‐type but not mutant LNX causes proteasome‐dependent degradation of Numb and can enhance Notch signalling. These results suggest that the levels of mammalian Numb protein and therefore, by extension, the processes of asymmetric cell division and cell fate determination may be regulated by ubiquitin‐dependent proteolysis. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The EMBO Journal Wiley

LNX functions as a RING type E3 ubiquitin ligase that targets the cell fate determinant Numb for ubiquitin‐dependent degradation

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Publisher
Wiley
Copyright
Copyright © 2013 Wiley Periodicals, Inc
ISSN
0261-4189
eISSN
1460-2075
D.O.I.
10.1093/emboj/21.1.93
Publisher site
See Article on Publisher Site

Abstract

LNX is a RING finger and PDZ domain containing protein that interacts with the cell fate determinant Numb. To investigate the function of LNX, we tested its RING finger domain for ubiquitin ligase activity. The isolated RING finger domain was able to function as an E2‐dependent, E3 ubiquitin ligase in vitro and mutation of a conserved cysteine residue within the RING domain abolished its activity, indicating that LNX is the first described PDZ domain‐containing member of the E3 ubiquitin ligase family. We have identified Numb as a substrate of LNX E3 activity in vitro and in vivo. In addition to the RING finger, a region of LNX, including the Numb PTB domain‐binding site and the first PDZ domain, is required for Numb ubiquitylation. Expression of wild‐type but not mutant LNX causes proteasome‐dependent degradation of Numb and can enhance Notch signalling. These results suggest that the levels of mammalian Numb protein and therefore, by extension, the processes of asymmetric cell division and cell fate determination may be regulated by ubiquitin‐dependent proteolysis.

Journal

The EMBO JournalWiley

Published: Jan 15, 2002

References

  • Cell polarity: squaring the circle
    Bilder, Bilder
  • The RING finger domain: a recent example of a sequence‐structure family
    Borden, Borden; Freemont, Freemont
  • Recognition specificity of individual EH domains of mammals and yeast
    Paoluzi, Paoluzi
  • Numb is an endocytic protein
    Santolini, Santolini; Puri, Puri; Salcini, Salcini; Gagliani, Gagliani; Pelicci, Pelicci; Tacchetti, Tacchetti; Di Fiore, Di Fiore
  • Mammalian Numb is an evolutionarily conserved signaling adapter protein that specifies cell fate
    Verdi, Verdi; Schmandt, Schmandt; Bashirullah, Bashirullah; Jacob, Jacob; Salvino, Salvino; Craig, Craig; Lipshitz, Lipshitz; McGlade, McGlade
  • Cell fate determination in Drosophila
    Vervoort, Vervoort; Dambly‐Chaudiere, Dambly‐Chaudiere; Ghysen, Ghysen
  • Multiple roles of mouse Numb in tuning developmental cell fates
    Zilian, Zilian; Saner, Saner; Hagedorn, Hagedorn; Lee, Lee; Sauberli, Sauberli; Suter, Suter; Sommer, Sommer; Aguet, Aguet

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