Misplaced Pages

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) Band 20q11.22 Start 34,363,241 bp End 34,540,748 bp
Gene location (Mouse) Chr. Chromosome 2 (mouse) Band 2 H1|2 76.94 cM Start 154,975,429 bp End 155,068,775 bp
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
Wikidata
View/Edit Human View/Edit Mouse

ITCH is a HECT domain–containing 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. The ITCH gene is located on chromosome 20 in humans. 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:

• CXCR4,
• c-Jun,
• MAP2K4,
• MAP3K1,
• MAP3K7,
• MAPK8,
• N4BP1,
• NOTCH1,
• TP63, and
• TP73.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000078747 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000027598 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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. PMID 9462742. S2CID 9438916.
6. "Q96J02 | SWISS-MODEL Repository".
7. Melino G, Gallagher E, Aqeilan RI, Knight R, Peschiaroli A, Rossi M, et al. (July 2008). "Itch: a HECT-type E3 ligase regulating immunity, skin and cancer". Cell Death and Differentiation. 15 (7): 1103–1112. doi:10.1038/cdd.2008.60. PMID 18552861. S2CID 2626150.
8. Aki D, Zhang W, Liu YC (July 2015). "The E3 ligase Itch in immune regulation and beyond". Immunological Reviews. 266 (1): 6–26. doi:10.1111/imr.12301. PMID 26085204. S2CID 42110767.
9. Lohr NJ, Molleston JP, Strauss KA, Torres-Martinez W, Sherman EA, Squires RH, et al. (March 2010). "Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease". American Journal of Human Genetics. 86 (3): 447–453. doi:10.1016/j.ajhg.2010.01.028. PMC 2833372. PMID 20170897.
10. "Symbol report for ITCH". HGNC. HUGO Gene Nomenclature Committee. Retrieved 12 March 2024.
11. "ITCH (human)". www.phosphosite.org. Retrieved 2020-10-27.
12. Karin M, Gallagher E (2005). "From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance". IUBMB Life. 57 (4–5): 283–295. doi:10.1080/15216540500097111. PMID 16036612. S2CID 25508987.
13. Gao M, Karin M (September 2005). "Regulating the regulators: control of protein ubiquitination and ubiquitin-like modifications by extracellular stimuli". Molecular Cell. 19 (5): 581–593. doi:10.1016/j.molcel.2005.08.017. PMID 16137616.
14. "ITCH itchy E3 ubiquitin protein ligase [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-12-29.
15. Bhandari D, Robia SL, Marchese A (March 2009). "The E3 ubiquitin ligase atrophin interacting protein 4 binds directly to the chemokine receptor CXCR4 via a novel WW domain-mediated interaction". Molecular Biology of the Cell. 20 (5): 1324–1339. doi:10.1091/mbc.e08-03-0308. PMC 2649280. PMID 19116316.
16. Fang D, Kerppola TK (October 2004). "Ubiquitin-mediated fluorescence complementation reveals that Jun ubiquitinated by Itch/AIP4 is localized to lysosomes". Proceedings of the National Academy of Sciences of the United States of America. 101 (41): 14782–14787. Bibcode:2004PNAS..10114782F. doi:10.1073/pnas.0404445101. PMC 522008. PMID 15469925.
17. Ahn YH, Kurie JM (October 2009). "MKK4/SEK1 is negatively regulated through a feedback loop involving the E3 ubiquitin ligase itch". The Journal of Biological Chemistry. 284 (43): 29399–29404. doi:10.1074/jbc.M109.044958. PMC 2785572. PMID 19737936.
18. Enzler T, Chang X, Facchinetti V, Melino G, Karin M, Su B, et al. (September 2009). "MEKK1 binds HECT E3 ligase Itch by its amino-terminal RING motif to regulate Th2 cytokine gene expression". Journal of Immunology. 183 (6): 3831–3838. doi:10.4049/jimmunol.0803412. PMID 19710465. S2CID 12554570.
19. Kathania M, Zeng M, Yadav VN, Moghaddam SJ, Yang B, Venuprasad K (March 2015). "Ndfip1 regulates itch ligase activity and airway inflammation via UbcH7". Journal of Immunology. 194 (5): 2160–2167. doi:10.4049/jimmunol.1402742. PMID 25632008. S2CID 22850215.
20. Gallagher E, Gao M, Liu YC, Karin M (February 2006). "Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change". Proceedings of the National Academy of Sciences of the United States of America. 103 (6): 1717–1722. Bibcode:2006PNAS..103.1717G. doi:10.1073/pnas.0510664103. PMC 1413664. PMID 16446428.
21. Oberst A, Malatesta M, Aqeilan RI, Rossi M, Salomoni P, Murillas R, et al. (July 2007). "The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch". Proceedings of the National Academy of Sciences of the United States of America. 104 (27): 11280–11285. Bibcode:2007PNAS..10411280O. doi:10.1073/pnas.0701773104. PMC 2040890. PMID 17592138.
22. Puca L, Chastagner P, Meas-Yedid V, Israël A, Brou C (October 2013). "Α-arrestin 1 (ARRDC1) and β-arrestins cooperate to mediate Notch degradation in mammals". Journal of Cell Science. 126 (Pt 19): 4457–4468. doi:10.1242/jcs.130500. PMID 23886940. S2CID 9783441.
23. Rossi M, Aqeilan RI, Neale M, Candi E, Salomoni P, Knight RA, et al. (August 2006). "The E3 ubiquitin ligase Itch controls the protein stability of p63". Proceedings of the National Academy of Sciences of the United States of America. 103 (34): 12753–12758. Bibcode:2006PNAS..10312753R. doi:10.1073/pnas.0603449103. PMC 1550770. PMID 16908849.
24. Rossi M, De Laurenzi V, Munarriz E, Green DR, Liu YC, Vousden KH, et al. (February 2005). "The ubiquitin-protein ligase Itch regulates p73 stability". The EMBO Journal. 24 (4): 836–848. doi:10.1038/sj.emboj.7600444. PMC 549609. PMID 15678106.

External links

• ITCH+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

• Genes on human chromosome 20