ITCH is a HECT domainE3 ubiquitin ligase that is ablated in non-agouti-lethal 18H (aka Itchy) mice.[5][6]Itchy mice develop a severe immunological phenotype after birth that includes hyperplasia of lymphoid and hematopoietic cells, and stomach and lung inflammation.[7][8] In humans ITCH deficiency causes altered physical growth, craniofacial morphology defects, defective muscle development, and aberrant immune system function.[9] ITCH contains a C2 domain, proline-rich region, WW domains, HECT domain, and multiple amino acids that are phosphorylated and ubiquitinated.[10]
Regulation by phosphorylation
ITCH is regulated by MAPK8.[11] 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.[12]
MAPK8 regulates JUNB protein turnover by the phosphorylation of ITCH and a conformational change. Importantly, this regulatory process controls the balance of T helper 2 cytokine production by negatively regulating JUNB turnover and Interleukin 4 transcription.
Interaction partners
Itch has been shown to interact with a number of proteins,[13] including:
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Perry WL, Hustad CM, Swing DA, O'Sullivan TN, Jenkins NA, Copeland NG (February 1998). "The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice". Nature Genetics. 18 (2): 143–146. doi:10.1038/ng0298-143. PMID9462742. S2CID9438916.
