ITCH is an E3 ubiquitin-protein ligase that accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. ITCH regulates the transcriptional activity of several transcription factors including the hematopoietic transcription factor NF-E2, and may play an important role in the regulation of immune response. ITCH down-regulates Epstein-Barr virus LMP2A activity in B cell signaling, and also interacts with NOTCH1, OCLN, JUN, and JUNB. ITCH has a wide tissue distribution and is localized within the nucleus and cytoplasm. Two ITCH splice variants have been described; an approximately 103 kDa form as well as a truncated form (~98 kDa) lacking 42 amino acids in the N-terminal half of the protein. ITCH contains a MAP Kinase binding site and its activity is modulated by phosphorylation at multiple threonine residues by JNK1.