ITCH, also called atrophin-1 interacting protein 4 (AIP4), is a HECT-type E3 ubiquitin ligase. It contains an N-terminal Ca<sub)2+-dependent phospholipid-binding C2 domain, four WW domains, and a C-terminal HECT domain. Mice deficient in ITCH protein display many autoimmune-like disease characteristics such as lymphoproliferation in the spleen and lymph nodes. More than a dozen of substrates of ITCH have been identified including p63, p73 and Notch1. The ligase may be responsible for ubiquitinating proteins with K29-, K48-, and/or K63-linked ubiquitin chains.