ITCH
ITCH is a HECT domain E3 ubiquitin ligase that is ablated in non-agouti-lethal 18H (aka "Itchy") mice. "Itchy" mice develop a severe immunological phenotype after birth that includes hyperplasia of lymphoid and hematopoietic cells, and stomach and lung inflammation. In humans ITCH deficiency causes altered physical growth, craniofacial morphology defects, defective muscle development, and aberrant immune system function. ITCH contains a C2 domain, proline-rich region, WW domains, HECT domain, and multiple amino acids that are phosphorylated and ubiquitinated. Regulation by phosphorylation. ITCH is regulated by MAPK8. MAPK8 regulates JUNB protein turnover by MAPK8-dependent phosphorylation of  ITCH and a subsequent conformational change in ITCH. This mechanism is discrete from the direct activation of Jun family transcription factors by direct phosphorylation. ITCH serves as a paradigm for our understanding of the regulation of the ubiquitylation machinery by direct protein phosphorylation of its components. Importantly, this regulatory process controls the balance of Th2 cytokine secretion by negatively regulating JUNB levels and Interleukin 4 transcription. Interaction partners. Itch has been shown to interact with a number of proteins, including: