ITCH

ITCH is a HECT domain–containing E3 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] The ITCH gene is located on chromosome 20 in humans.^[10] ITCH contains a C2 domain, proline-rich region, WW domains, HECT domain, and multiple amino acids that are phosphorylated and ubiquitinated.^[11]

ITCH
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2DMV, 2KYK, 2NQ3, 2P4R, 2YSF, 3TUG, 4ROF, 5CQ2, 5DWS, 5DZD, 5C7M
Identifiers
Aliases	ITCH, AIF4, AIP4, NAPP1, dJ468O1.1, ADMFD, itchy E3 ubiquitin protein ligase
External IDs	OMIM: 606409; MGI: 1202301; HomoloGene: 88442; GeneCards: ITCH; OMA:ITCH - orthologs
Gene location (Human) Chr. Chromosome 20 (human)[1] Band 20q11.22 Start 34,363,241 bp[1] End 34,540,748 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2 H1|2 76.94 cM Start 154,975,429 bp[2] End 155,068,775 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sperm Achilles tendon sural nerve epithelium of colon islet of Langerhans monocyte internal globus pallidus rectum stromal cell of endometrium corpus callosum Top expressed in Rostral migratory stream genital tubercle mesenteric lymph nodes calvaria hand jejunum tail of embryo lacrimal gland epithelium of small intestine right kidney More reference expression data BioGPS n/a
Gene ontology Molecular function CXCR chemokine receptor binding protein binding ribonucleoprotein complex binding ubiquitin-like protein transferase activity transferase activity ligase activity ubiquitin protein ligase activity ubiquitin-protein transferase activity ubiquitin-like protein ligase binding arrestin family protein binding Cellular component cytosol extracellular exosome plasma membrane membrane nucleoplasm nucleus cell cortex cytoplasmic vesicle cytoplasm early endosome endosome endosome membrane early endosome membrane protein-containing complex intracellular membrane-bounded organelle Biological process Notch signaling pathway protein K29-linked ubiquitination immune system process protein K63-linked ubiquitination negative regulation of apoptotic process defense response to virus regulation of cell growth viral entry into host cell negative regulation of type I interferon production inflammatory response viral process nucleotide-binding oligomerization domain containing signaling pathway apoptotic process innate immune response protein polyubiquitination positive regulation of T cell anergy ubiquitin-dependent protein catabolic process negative regulation of NF-kappaB transcription factor activity positive regulation of protein catabolic process negative regulation of JNK cascade negative regulation of alpha-beta T cell proliferation negative regulation of defense response to virus protein K48-linked ubiquitination regulation of protein deubiquitination proteasome-mediated ubiquitin-dependent protein catabolic process regulation of hematopoietic stem cell differentiation protein ubiquitination protein autoubiquitination positive regulation of receptor catabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 83737 16396 Ensembl ENSG00000078747 ENSMUSG00000027598 UniProt Q96J02 Q8C863 RefSeq (mRNA) NM_001257137 NM_001257138 NM_031483 NM_001324197 NM_001324198 NM_001243712 NM_008395 RefSeq (protein) NP_001244066 NP_001244067 NP_001311126 NP_001311127 NP_113671 NP_001230641 NP_032421 Location (UCSC) Chr 20: 34.36 – 34.54 Mb Chr 2: 154.98 – 155.07 Mb PubMed search [3] [4]
Wikidata
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Regulation by phosphorylation

ITCH is regulated by MAPK8.^[12] 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.^[13]

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,^[14] including:

• CXCR4,^[15]
• c-Jun,^[16]
• MAP2K4,^[17]
• MAP3K1,^[18]
• MAP3K7,^[19]
• MAPK8,^[20]
• N4BP1,^[21]
• NOTCH1,^[22]
• TP63,^[23] and
• TP73.^[24]