CISH

Cytokine-inducible SH2-containing protein is a protein that in humans is encoded by the CISH gene.[5][6][7] CISH orthologs [8] have been identified in most mammals with sequenced genomes. CISH controls T cell receptor (TCR) signaling, and variations of CISH with certain SNPs are associated with susceptibility to bacteremia, tuberculosis and malaria.[9]

CISH
Identifiers
Aliases	CISH, BACTS2, CIS, CIS-1, G18, SOCS, cytokine inducible SH2 containing protein
External IDs	OMIM: 602441 MGI: 103159 HomoloGene: 7667 GeneCards: CISH
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3p21.2 Start 50,606,490 bp[1] End 50,611,831 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 F1|9 57.99 cM Start 107,296,026 bp[2] End 107,302,784 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • protein kinase inhibitor activity • GO:0001948 protein binding • molecular function • 1-phosphatidylinositol-3-kinase regulator activity Cellular component • cytoplasm • cytosol • cell membrane • cellular component • phosphatidylinositol 3-kinase complex Biological process • regulation of growth • negative regulation of insulin receptor signaling pathway • protein kinase C-activating G-protein coupled receptor signaling pathway • GO:0007243 intracellular signal transduction • negative regulation of signal transduction • regulation of cell growth • protein ubiquitination • negative regulation of protein kinase activity • negative regulation of JAK-STAT cascade • cytokine-mediated signaling pathway • post-translational modification • interleukin-7-mediated signaling pathway • regulation of phosphatidylinositol 3-kinase activity • phosphatidylinositol phosphorylation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1154	12700
Ensembl	ENSG00000114737	ENSMUSG00000032578
UniProt	Q9NSE2	Q62225
RefSeq (mRNA)	NM_013324 NM_145071	NM_009895 NM_001317354
RefSeq (protein)	NP_037456 NP_659508	NP_001304283 NP_034025
Location (UCSC)	Chr 3: 50.61 – 50.61 Mb	Chr 9: 107.3 – 107.3 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

The protein encoded by this gene contains a SH2 domain and a SOCS box domain. The protein thus belongs to the cytokine-induced STAT inhibitor (CIS), also known as suppressor of cytokine signaling (SOCS) or STAT-induced STAT inhibitor (SSI), protein family. CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling.

The expression of this gene can be induced by IL-2, IL-3, GM-CSF and EPO in hematopoietic cells. Proteasome-mediated degradation of this protein has been shown to be involved in the inactivation of the erythropoietin receptor.[7]

CISH is induced by T cell receptor (TCR) ligation and negatively regulates it by targeting the critical signaling intermediate PLC-gamma-1 for degradation.[10] The deletion of Cish in effector T cells has been shown to augment TCR signaling and subsequent effector cytokine release, proliferation and survival. The adoptive transfer of tumor-specific effector T cells knocked out or knocked down for CISH resulted in a significant increase in functional avidity and long-term tumor immunity. There are no changes in activity or phosphorylation of Cish's purported target, STAT5 in either the presence or absence of Cish.

Model organisms

Cish knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Normal
Fertility	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Haematology	Normal
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Normal
Skin Histopathology	Normal
Eye Histopathology	Normal
Salmonella infection	Normal[11]
Citrobacter infection	Normal[12]
All tests and analysis from[13][14]

Model organisms have been used in the study of CISH function. A conditional knockout mouse line, called Cish^{tm1a(KOMP)Wtsi}[15][16] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[17][18][19]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[13][20] Twenty four tests were carried out on mutant mice, however no significant abnormalities were observed.[13]

Interactions

CISH has been shown to interact with IL2RB[21] and Growth hormone receptor.[22] and PLCG1.[10]

References

1. GRCh38: Ensembl release 89: ENSG00000114737 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000032578 - 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. Uchida K, Yoshimura A, Inazawa J, Yanagisawa K, Osada H, Masuda A, Saito T, Takahashi T, Miyajima A, Takahashi T (Mar 1998). "Molecular cloning of CISH, chromosome assignment to 3p21.3, and analysis of expression in fetal and adult tissues". Cytogenetics and Cell Genetics. 78 (3–4): 209–12. doi:10.1159/000134658. PMID 9465889.
6. Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, Hara T, Miyajima A (Jun 1995). "A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors". The EMBO Journal. 14 (12): 2816–26. doi:10.1002/j.1460-2075.1995.tb07281.x. PMC 398400. PMID 7796808.
7. "Entrez Gene: CISH cytokine inducible SH2-containing protein".
8. "OrthoMaM phylogenetic marker: CISH coding sequence". Archived from the original on 2016-03-04. Retrieved 2010-02-17.
9. Khor CC, Vannberg FO, Chapman SJ, Guo H, Wong SH, Walley AJ, Vukcevic D, Rautanen A, Mills TC, Chang KC, Kam KM, Crampin AC, Ngwira B, Leung CC, Tam CM, Chan CY, Sung JJ, Yew WW, Toh KY, Tay SK, Kwiatkowski D, Lienhardt C, Hien TT, Day NP, Peshu N, Marsh K, Maitland K, Scott JA, Williams TN, Berkley JA, Floyd S, Tang NL, Fine PE, Goh DL, Hill AV (Jun 2010). "CISH and susceptibility to infectious diseases". The New England Journal of Medicine. 362 (22): 2092–101. doi:10.1056/NEJMoa0905606. PMC 3646238. PMID 20484391. [Free Text]
10. Palmer DC, Guittard GC, Franco Z, Crompton JG, Eil RL, Patel SJ, Ji Y, Van Panhuys N, Klebanoff CA, Sukumar M, Clever D, Chichura A, Roychoudhuri R, Varma R, Wang E, Gattinoni L, Marincola FM, Balagopalan L, Samelson LE, Restifo NP (Nov 2015). "Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance". The Journal of Experimental Medicine. 212 (12): 2095–113. doi:10.1084/jem.20150304. PMC 4647263. PMID 26527801.
11. "Salmonella infection data for Cish". Wellcome Trust Sanger Institute.
12. "Citrobacter infection data for Cish". Wellcome Trust Sanger Institute.
13. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88 (S248). doi:10.1111/j.1755-3768.2010.4142.x.
14. Mouse Resources Portal, Wellcome Trust Sanger Institute.
15. "International Knockout Mouse Consortium". Archived from the original on 2012-04-03. Retrieved 2012-01-05.
16. "Mouse Genome Informatics".
17. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
18. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
19. Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
20. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
21. Aman MJ, Migone TS, Sasaki A, Ascherman DP, Zhu MH, Soldaini E, Imada K, Miyajima A, Yoshimura A, Leonard WJ (Oct 1999). "CIS associates with the interleukin-2 receptor beta chain and inhibits interleukin-2-dependent signaling". The Journal of Biological Chemistry. 274 (42): 30266–72. doi:10.1074/jbc.274.42.30266. PMID 10514520.
22. Ram PA, Waxman DJ (Dec 1999). "SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms". The Journal of Biological Chemistry. 274 (50): 35553–61. doi:10.1074/jbc.274.50.35553. PMID 10585430.

Further reading

• Kile BT, Schulman BA, Alexander WS, Nicola NA, Martin HM, Hilton DJ (May 2002). "The SOCS box: a tale of destruction and degradation". Trends in Biochemical Sciences. 27 (5): 235–41. doi:10.1016/S0968-0004(02)02085-6. PMID 12076535.
• Verdier F, Chrétien S, Muller O, Varlet P, Yoshimura A, Gisselbrecht S, Lacombe C, Mayeux P (Oct 1998). "Proteasomes regulate erythropoietin receptor and signal transducer and activator of transcription 5 (STAT5) activation. Possible involvement of the ubiquitinated Cis protein". The Journal of Biological Chemistry. 273 (43): 28185–90. doi:10.1074/jbc.273.43.28185. PMID 9774439.
• Okabe S, Tauchi T, Morita H, Ohashi H, Yoshimura A, Ohyashiki K (Oct 1999). "Thrombopoietin induces an SH2-containing protein, CIS1, which binds to Mpl: involvement of the ubiquitin proteosome pathway". Experimental Hematology. 27 (10): 1542–7. doi:10.1016/S0301-472X(99)00094-6. PMID 10517496.
• Jiang C, Yu L, Zhao Y, Zhang M, Liu Q, Mao N, Geng Z, Zhao S (2000). "Cloning and characterization of CIS 1b (cytokine inducible SH2-containing protein 1b), an alternative splicing form of CIS 1 gene". DNA Sequence. 11 (1–2): 149–54. doi:10.3109/10425170009033983. PMID 10902923.
• Dogusan Z, Hooghe-Peters EL, Berus D, Velkeniers B, Hooghe R (Sep 2000). "Expression of SOCS genes in normal and leukemic human leukocytes stimulated by prolactin, growth hormone and cytokines". Journal of Neuroimmunology. 109 (1): 34–9. doi:10.1016/S0165-5728(00)00300-3. PMID 10969179.
• Yousefi S, Cooper PR, Mueck B, Potter SL, Jarai G (Oct 2000). "cDNA representational difference analysis of human neutrophils stimulated by GM-CSF". Biochemical and Biophysical Research Communications. 277 (2): 401–9. doi:10.1006/bbrc.2000.3678. PMID 11032736.
• Dif F, Saunier E, Demeneix B, Kelly PA, Edery M (Dec 2001). "Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor". Endocrinology. 142 (12): 5286–93. doi:10.1210/endo.142.12.8549. PMID 11713228.
• Federici M, Giustizieri ML, Scarponi C, Girolomoni G, Albanesi C (Jul 2002). "Impaired IFN-gamma-dependent inflammatory responses in human keratinocytes overexpressing the suppressor of cytokine signaling 1". Journal of Immunology. 169 (1): 434–42. doi:10.4049/jimmunol.169.1.434. PMID 12077274.
• Du L, Frick GP, Tai LR, Yoshimura A, Goodman HM (Mar 2003). "Interaction of the growth hormone receptor with cytokine-induced Src homology domain 2 protein in rat adipocytes". Endocrinology. 144 (3): 868–76. doi:10.1210/en.2002-220830. PMID 12586763.
• Chen S, Anderson PO, Li L, Sjögren HO, Wang P, Li SL (Mar 2003). "Functional association of cytokine-induced SH2 protein and protein kinase C in activated T cells". International Immunology. 15 (3): 403–9. doi:10.1093/intimm/dxg039. PMID 12618484.
• Yamasaki K, Hanakawa Y, Tokumaru S, Shirakata Y, Sayama K, Hanada T, Yoshimura A, Hashimoto K (Apr 2003). "Suppressor of cytokine signaling 1/JAB and suppressor of cytokine signaling 3/cytokine-inducible SH2 containing protein 3 negatively regulate the signal transducers and activators of transcription signaling pathway in normal human epidermal keratinocytes". The Journal of Investigative Dermatology. 120 (4): 571–80. doi:10.1046/j.1523-1747.2003.12100.x. PMID 12648219.
• Cheng J, Zhang D, Zhou C, Marasco WA (Jan 2004). "Down-regulation of SHP1 and up-regulation of negative regulators of JAK/STAT signaling in HTLV-1 transformed cell lines and freshly transformed human peripheral blood CD4+ T-cells". Leukemia Research. 28 (1): 71–82. doi:10.1016/S0145-2126(03)00158-9. PMID 14630083.
• Bayle J, Letard S, Frank R, Dubreuil P, De Sepulveda P (Mar 2004). "Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling". The Journal of Biological Chemistry. 279 (13): 12249–59. doi:10.1074/jbc.M313381200. PMID 14707129.
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM (Jul 2004). "Functional proteomics mapping of a human signaling pathway". Genome Research. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.
• Hunter MG, Jacob A, O'donnell LC, Agler A, Druhan LJ, Coggeshall KM, Avalos BR (Oct 2004). "Loss of SHIP and CIS recruitment to the granulocyte colony-stimulating factor receptor contribute to hyperproliferative responses in severe congenital neutropenia/acute myelogenous leukemia". Journal of Immunology. 173 (8): 5036–45. doi:10.4049/jimmunol.173.8.5036. PMID 15470047.

External links

• Human CISH genome location and CISH gene details page in the UCSC Genome Browser.