ITCH
{{Short description|Protein-coding gene in the species Homo sapiens}}
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{{Infobox gene}}
ITCH is a HECT domain–containing E3 ubiquitin ligase that is ablated in non-agouti-lethal 18H (aka Itchy) mice.{{cite journal | vauthors = Perry WL, Hustad CM, Swing DA, O'Sullivan TN, Jenkins NA, Copeland NG | title = The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice | journal = Nature Genetics | volume = 18 | issue = 2 | pages = 143–146 | date = February 1998 | pmid = 9462742 | doi = 10.1038/ng0298-143 | s2cid = 9438916 }}{{Cite web|url=https://swissmodel.expasy.org/repository/uniprot/Q96J02|title = Q96J02 | SWISS-MODEL Repository}} Itchy mice develop a severe immunological phenotype after birth that includes hyperplasia of lymphoid and hematopoietic cells, and stomach and lung inflammation.{{cite journal | vauthors = Melino G, Gallagher E, Aqeilan RI, Knight R, Peschiaroli A, Rossi M, Scialpi F, Malatesta M, Zocchi L, Browne G, Ciechanover A, Bernassola F | title = Itch: a HECT-type E3 ligase regulating immunity, skin and cancer | journal = Cell Death and Differentiation | volume = 15 | issue = 7 | pages = 1103–1112 | date = July 2008 | pmid = 18552861 | doi = 10.1038/cdd.2008.60 | s2cid = 2626150 | doi-access = free }}{{cite journal | vauthors = Aki D, Zhang W, Liu YC | title = The E3 ligase Itch in immune regulation and beyond | journal = Immunological Reviews | volume = 266 | issue = 1 | pages = 6–26 | date = July 2015 | pmid = 26085204 | doi = 10.1111/imr.12301 | s2cid = 42110767 }} In humans ITCH deficiency causes altered physical growth, craniofacial morphology defects, defective muscle development, and aberrant immune system function.{{cite journal | vauthors = Lohr NJ, Molleston JP, Strauss KA, Torres-Martinez W, Sherman EA, Squires RH, Rider NL, Chikwava KR, Cummings OW, Morton DH, Puffenberger EG | title = Human ITCH E3 ubiquitin ligase deficiency causes syndromic multisystem autoimmune disease | journal = American Journal of Human Genetics | volume = 86 | issue = 3 | pages = 447–453 | date = March 2010 | pmid = 20170897 | pmc = 2833372 | doi = 10.1016/j.ajhg.2010.01.028 }} The ITCH gene is located on chromosome 20 in humans.{{cite web|url=https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/13890|title=Symbol report for ITCH|website=HGNC|publisher=HUGO Gene Nomenclature Committee|access-date=12 March 2024}} ITCH contains a C2 domain, proline-rich region, WW domains, HECT domain, and multiple amino acids that are phosphorylated and ubiquitinated.{{Cite web|title=ITCH (human)|url=https://www.phosphosite.org/proteinAction.action?id=6511&showAllSites=true|access-date=2020-10-27|website=www.phosphosite.org}}
Regulation by phosphorylation
ITCH is regulated by MAPK8.{{cite journal | vauthors = Karin M, Gallagher E | title = From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance | journal = IUBMB Life | volume = 57 | issue = 4–5 | pages = 283–295 | date = 2005 | pmid = 16036612 | doi = 10.1080/15216540500097111 | s2cid = 25508987 }} 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.{{cite journal | vauthors = Gao M, Karin M | title = Regulating the regulators: control of protein ubiquitination and ubiquitin-like modifications by extracellular stimuli | journal = Molecular Cell | volume = 19 | issue = 5 | pages = 581–593 | date = September 2005 | pmid = 16137616 | doi = 10.1016/j.molcel.2005.08.017 | doi-access = free }}
Interaction partners
Itch has been shown to interact with a number of proteins,{{Cite web|title=ITCH itchy E3 ubiquitin protein ligase [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene/83737|access-date=2021-12-29|website=www.ncbi.nlm.nih.gov}} including:
- CXCR4,{{cite journal | vauthors = Bhandari D, Robia SL, Marchese A | title = The E3 ubiquitin ligase atrophin interacting protein 4 binds directly to the chemokine receptor CXCR4 via a novel WW domain-mediated interaction | journal = Molecular Biology of the Cell | volume = 20 | issue = 5 | pages = 1324–1339 | date = March 2009 | pmid = 19116316 | pmc = 2649280 | doi = 10.1091/mbc.e08-03-0308 }}
- c-Jun,{{cite journal | vauthors = Fang D, Kerppola TK | title = Ubiquitin-mediated fluorescence complementation reveals that Jun ubiquitinated by Itch/AIP4 is localized to lysosomes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 41 | pages = 14782–14787 | date = October 2004 | pmid = 15469925 | pmc = 522008 | doi = 10.1073/pnas.0404445101 | doi-access = free | bibcode = 2004PNAS..10114782F }}
- MAP2K4,{{cite journal | vauthors = Ahn YH, Kurie JM | title = MKK4/SEK1 is negatively regulated through a feedback loop involving the E3 ubiquitin ligase itch | journal = The Journal of Biological Chemistry | volume = 284 | issue = 43 | pages = 29399–29404 | date = October 2009 | pmid = 19737936 | pmc = 2785572 | doi = 10.1074/jbc.M109.044958 | doi-access = free }}
- MAP3K1,{{cite journal | vauthors = Enzler T, Chang X, Facchinetti V, Melino G, Karin M, Su B, Gallagher E | title = MEKK1 binds HECT E3 ligase Itch by its amino-terminal RING motif to regulate Th2 cytokine gene expression | journal = Journal of Immunology | volume = 183 | issue = 6 | pages = 3831–3838 | date = September 2009 | pmid = 19710465 | doi = 10.4049/jimmunol.0803412 | s2cid = 12554570 | doi-access = free }}
- MAP3K7,{{cite journal | vauthors = Kathania M, Zeng M, Yadav VN, Moghaddam SJ, Yang B, Venuprasad K | title = Ndfip1 regulates itch ligase activity and airway inflammation via UbcH7 | journal = Journal of Immunology | volume = 194 | issue = 5 | pages = 2160–2167 | date = March 2015 | pmid = 25632008 | doi = 10.4049/jimmunol.1402742 | s2cid = 22850215 | doi-access = free }}
- MAPK8,{{cite journal | vauthors = Gallagher E, Gao M, Liu YC, Karin M | title = Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 6 | pages = 1717–1722 | date = February 2006 | pmid = 16446428 | pmc = 1413664 | doi = 10.1073/pnas.0510664103 | doi-access = free | bibcode = 2006PNAS..103.1717G }}
- N4BP1,{{cite journal | vauthors = Oberst A, Malatesta M, Aqeilan RI, Rossi M, Salomoni P, Murillas R, Sharma P, Kuehn MR, Oren M, Croce CM, Bernassola F, Melino G | title = The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 27 | pages = 11280–11285 | date = July 2007 | pmid = 17592138 | pmc = 2040890 | doi = 10.1073/pnas.0701773104 | doi-access = free | bibcode = 2007PNAS..10411280O }}
- NOTCH1,{{cite journal | vauthors = Puca L, Chastagner P, Meas-Yedid V, Israël A, Brou C | title = Α-arrestin 1 (ARRDC1) and β-arrestins cooperate to mediate Notch degradation in mammals | journal = Journal of Cell Science | volume = 126 | issue = Pt 19 | pages = 4457–4468 | date = October 2013 | pmid = 23886940 | doi = 10.1242/jcs.130500 | s2cid = 9783441 | doi-access = free }}
- TP63,{{cite journal | vauthors = Rossi M, Aqeilan RI, Neale M, Candi E, Salomoni P, Knight RA, Croce CM, Melino G | title = The E3 ubiquitin ligase Itch controls the protein stability of p63 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 34 | pages = 12753–12758 | date = August 2006 | pmid = 16908849 | pmc = 1550770 | doi = 10.1073/pnas.0603449103 | doi-access = free | bibcode = 2006PNAS..10312753R }} and
- TP73.{{cite journal | vauthors = Rossi M, De Laurenzi V, Munarriz E, Green DR, Liu YC, Vousden KH, Cesareni G, Melino G | title = The ubiquitin-protein ligase Itch regulates p73 stability | journal = The EMBO Journal | volume = 24 | issue = 4 | pages = 836–848 | date = February 2005 | pmid = 15678106 | pmc = 549609 | doi = 10.1038/sj.emboj.7600444 }}
References
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External links
- {{MeshName|ITCH+protein,+human}}