ITCH

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
Gene location (Human)
Chr.	Chromosome 20 (human)[1]
End	34,540,748 bp[1]
Gene location (Mouse)
Chr.	Chromosome 2 (mouse)[2]
End	155,226,855 bp[2]
Gene ontology
Molecular function	• CXCR chemokine receptor binding; • GO:0001948 protein binding; • ribonucleoprotein complex binding; • ubiquitin-like protein transferase activity; • transferase activity; • ligase activity; • GO:1904264, GO:1904822, GO:0090622, GO:0090302 ubiquitin protein ligase activity; • ubiquitin-protein transferase activity; • ubiquitin-like protein ligase binding; • arrestin family protein binding;
Cellular component	• cytosol; • extracellular exosome; • cell membrane; • membrane; • nucleoplasm; • cell nucleus; • cell cortex; • cytoplasmic vesicle; • cytoplasm; • early endosome; • endosome; • endosome membrane; • early endosome membrane; • macromolecular 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; • negative regulation of type I interferon production; • inflammatory response; • GO:0022415 viral process; • nucleotide-binding oligomerization domain containing signaling pathway; • apoptotic process; • innate immune system; • 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
	83737
	16396
	ENSG00000078747
	ENSMUSG00000027598
	Q96J02
	Q8C863
	NM_001257137; NM_001257138; NM_031483; NM_001324197; NM_001324198
	NM_001243712; NM_008395
	NP_001244066; NP_001244067; NP_001311126; NP_001311127; NP_113671
	NP_001230641; NP_032421
	Wikidata
View/Edit Human	View/Edit Mouse

ITCH is a HECT domain 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] ITCH contains multiple amino acids that are phosphorylated and ubiquitinated.[10]

Regulation by post-translational modifications

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.

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.

References

GRCh38: Ensembl release 89: ENSG00000078747 - Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000027598 - Ensembl, May 2017
"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): 143–6. doi:10.1038/ng0298-143. PMID 9462742. S2CID 9438916.
https://swissmodel.expasy.org/repository/uniprot/Q96J02
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): 1103–12. doi:10.1038/cdd.2008.60. PMID 18552861. S2CID 2626150.
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.
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): 447–53. doi:10.1016/j.ajhg.2010.01.028. PMC 2833372. PMID 20170897.
"ITCH (human)". www.phosphosite.org. Retrieved 2020-10-27.
Karin M, Gallagher E (2005). "From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance". IUBMB Life. 57 (4–5): 283–95. doi:10.1080/15216540500097111. PMID 16036612. S2CID 25508987.

External links

ITCH+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)

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[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000078747 - Ensembl, May 2017

[refGRCm38Ensembl-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): 143–6. doi:10.1038/ng0298-143. PMID 9462742. S2CID 9438916.

[6] ttps://swissmodel.expasy.org/repository/uniprot/Q96J02

[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): 1103–12. 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): 447–53. doi:10.1016/j.ajhg.2010.01.028. PMC 2833372. PMID 20170897.

[10] "ITCH (human)". www.phosphosite.org. Retrieved 2020-10-27.

[11] Karin M, Gallagher E (2005). "From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance". IUBMB Life. 57 (4–5): 283–95. doi:10.1080/15216540500097111. PMID 16036612. S2CID 25508987.