Nedd4 is a member of a family of HECT containing E3 ubiquitin ligases. This family of proteins shares a common structure, which includes an N-terminal C2 domain, 2�C4 WW domains, as well as a C-terminal HECT domain. Nedd4 acts at the plasma membrane and the Golgi apparatus to monoubiquitinate substrates for degradation in the lysosome. TSG101, another binding partner of LITAF, operates downstream of Nedd4. TSG101 acts to recognize and sort mono-ubiquitinated substrates into multivesicular bodies for future lysosomal degradation. The interaction between LITAF and Nedd4 or WWOX is mediated by PPXY motifs found in the N-terminus of LITAF. Itch is another member of the Nedd4/Nedd4-like HECT E3 family that binds to PPXY motifs via its WW domains. Itch, a homologue of the human atrophin-1-interacting protein 4, was first identified as a gene disrupted in non-agouti-lethal 18H mice that develop a spectrum of immunological diseases and constant itching of the skin. The Itch gene encodes an 864 amino acid protein that regulates important cellular functions by inducing proteasomal degradation of a variety of substrates. As it is demonstrated by the a18H phenotype, Itch plays a role in the immune response by binding c-jun and JunB via its WW domains. Itch induces ubiquitination and degradation of these transcription factors involved in TH2 differentiation, providing a molecular link between Itch deficiency and the itching phenotype. Itch��s WW Fulvestrant domains also bind to a PPPY motif in the C-terminus of p73, inducing its ubiquitination and degradation. This transcription factor is involved in the response to DNA damage and in cell cycle control, providing another role for the ligase. Furthermore, the implications of Itch also extend to cell death by promoting c- FLIP turnover, an anti-apoptotic protein inhibiting caspase-8. Itch also acts as a key molecule between EGF signaling and cell survival through downregulation of tBid, an important Bortezomib Proteasome inhibitor intermediate in ligand-induced apoptosis via caspase-3 activation. Itch does not only affect receptor signaling, but can also influence EGFR stability at the plasma membrane by controlling the expression of Cbl and Endophilin, two trafficking proteins required for receptor endocytosis. The Itch ligase localizes to the trans-Golgi network and to endosomal compartments, which confers the capacity to interact with internalized proteins and their endocytic accessory proteins and cause their proteasomal degradation, which affects protein trafficking. Similar to Itch, LITAF has also been reported to localize to late endosomes, raising the possibility that these proteins may interact in vivo and influence each other��s activity.