Recognition and ubiquitination of notch by Itch, a hect-type E3 ubiquitin ligase

Genetic studies identified Itch, which is a homologous to the EG-associated protein carboxyl terminus (Hect) domain-containing E3 ubiquitin-protein li gase that is disrupted in non-agouti lethal mice or Itchy mice. Itch-defici ency results in abnormal immune responses and constant itching in the skin. Here, Itch was shown to associate with Notch, a protein involved in cell f ate decision in many mammalian cell types, including cells in the immune Sy stem. Itch binds to the N-terminal portion of the Notch intracellular domai n via its WW domains and promotes ubiquitination of Notch through its Hect ubiquitin ligase domain. Thus, Itch may participate in the-regulation of im mune responses by modifying Notch-mediated signaling.