E3 ubiquitin-protein ligase Itchy homolog (ITCH)

E3 ubiquitin-protein ligase Itchy homolog (ITCH) is an enzyme encoded by the *ITCH* gene on chromosome 20. As a member of the HECT domain-containing family of E3 ubiquitin ligases, it catalyzes the transfer of ubiquitin from an E2 conjugating enzyme to specific substrate proteins—marking them for proteasomal degradation. This process regulates numerous cellular functions including immune responses and signal transduction. In both mouse models ("Itchy" mice) and humans, loss-of-function mutations lead to profound immune system abnormalities—such as lymphoid hyperplasia and multi-organ inflammation—as well as developmental defects like altered growth patterns and craniofacial anomalies. The activity and specificity of ITCH are regulated by phosphorylation events mediated by kinases such as MAPK8/JNK; this controls downstream effects on transcription factors like JUNB. Through interactions with various signaling molecules—including CXCR4, c-Jun family members, NOTCH receptors—it plays a central role at multiple nodes within cell signaling networks relevant to immunity and development.

Other names

Itchy E3 ubiquitin protein ligaseItchITCH (gene/protein symbol)

Drugs or molecules that would target ITCH would likely act by: Modulating its E3 ubiquitin ligase activity to alter substrate degradation. Affecting its regulation by upstream kinases such as MAPK8/JNK pathway components. No approved drugs or clinical candidates specifically modulating ITCH are referenced.