The E3 ubiquitin ligase Itch controls the protein stability of p63

Mario Rossi, Rami I. Aqeilan, Michael Neale, Eleonora Candi, Paolo Salomoni, Richard A. Knight, Carlo M. Croce*, Gerry Melino

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

204 Scopus citations


p63, a member of the p53 family of transcription factors, plays an important role in epithelial development, regulating both cell cycle and apoptosis. Even though p63 activity is regulated mainly at the posttranslational level, the control of p63 protein stability is far from being fully understood. Here, we show that the Hect (homologous to the E6-associated protein C terminus)-containing Nedd4-like ubiquitin protein ligase Itch binds, ubiquitylates, and promotes the degradation of p53. The physical interaction occurs at the border between the PY and the SAM (sterile α motif) domains; a single Y504F mutation significantly affects p63 degradation. Itch and p63 are coexpressed in the epidermis and in primary keratinocytes where Itch controls the p63 protein steady-state level. Accordingly, p63 protein levels are significantly increased in Itch knockout keratinocytes. These data suggest that Itch has a fundamental role in the mechanism that controls endogenous p63 protein levels and therefore contributes to regulation of p63 in physiological conditions.

Original languageAmerican English
Pages (from-to)12753-12758
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number34
StatePublished - 22 Aug 2006
Externally publishedYes


  • AIP4
  • Keratinocytes
  • Ubiquitination
  • p73


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