ITCH (D8Q6D) Rabbit mAb #12117

ITCH is a HECT domain-containing E3 ubiquitin ligase, first identified in genetic studies of the mouse agouti locus, in which mutations result in characteristic coat color changes. One particular agouti mutation (non-agouti-lethal 18H) is notable for the development of immunological defects not observed in other agouti mutant mice; these include lymphoid hyperplasia and chronic stomach, lung and skin inflammation (manifest as constant itching). The 18H agouti mutation was traced to a chromosomal inversion that disrupted expression of an adjacent gene in the agouti locus, subsequently termed Itch to reflect the chronic itching phenotype (1-3).
Further characterizations revealed that Itch encoded a NEDD4-like E3-ubiquitin ligase capable of catalyzing Lys29, Lys48, and/or Lys63-linked ubiquitination of target proteins, leading to their degradation by the proteosome pathway (4-6). The distinct phenotypes of Itch mutant mice led to the identification of an important regulatory role for ITCH-mediated ubiquitination in inflammatory signaling pathways. For example, ITCH-mediated ubiquitination of the transcription factor JunB was shown to play a direct inhibitory role in regulating expression of the proinflammatory cytokine IL-4. ITCH-null T lymphocytes consequently exhibit increased production of IL-4, leading to biased differentiation of naive CD4⁺ cells towards the proinflammatory Th2 lineage (7). In accordance with the findings from mutant Itch mouse models, a genetic linkage study in humans identified loss-of-function mutations in ITCH as a direct cause of syndromic multisystem autoimmune disease (SMAD) (8).
Notably, targets of ITCH-mediated ubiquitination are not restricted to immune signaling pathways. For example, key mediators of the Hedgehog (9,10), Wnt/β-catenin (11), Hippo (12), and Notch signaling pathways (13,14) have been identified as important targets of ITCH-mediated ubiquitination (2).