CISH (protein) explained

Cytokine-inducible SH2-containing protein is a protein that in humans is encoded by the CISH gene.^{[1] [2] [3]} CISH orthologs^[4] 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.^[5]

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.

CISH is induced by T cell receptor (TCR) ligation and negatively regulates it by targeting the critical signaling intermediate PLC-gamma-1 for degradation.^[6] 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.

In human tumor-infiltrating lymphocytes (TIL), CISH expression has been reported to be inversely expressed with known T cell activation/exhaustion markers and regulates their expression and neoantigen reactivity. Combination therapy with checkpoint blockade synergistically results in profound tumor regressing in a pre-clinical tumor model ^[7]

Interactions

CISH has been shown to interact with IL2RB^[8] and Growth hormone receptor.^[9] and PLCG1.^[6]

Further reading

• Kile BT, Schulman BA, Alexander WS, Nicola NA, Martin HM, Hilton DJ . The SOCS box: a tale of destruction and degradation . Trends in Biochemical Sciences . 27 . 5 . 235–41 . May 2002 . 12076535 . 10.1016/S0968-0004(02)02085-6 .
• Verdier F, Chrétien S, Muller O, Varlet P, Yoshimura A, Gisselbrecht S, Lacombe C, Mayeux P . 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 . Oct 1998 . 9774439 . 10.1074/jbc.273.43.28185 . free.
• Okabe S, Tauchi T, Morita H, Ohashi H, Yoshimura A, Ohyashiki K . Thrombopoietin induces an SH2-containing protein, CIS1, which binds to Mpl: involvement of the ubiquitin proteosome pathway . Experimental Hematology . 27 . 10 . 1542–7 . Oct 1999 . 10517496 . 10.1016/S0301-472X(99)00094-6 . free .
• Jiang C, Yu L, Zhao Y, Zhang M, Liu Q, Mao N, Geng Z, Zhao S . 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 . 2000 . 10902923 . 10.3109/10425170009033983 . 7986394 .
• Dogusan Z, Hooghe-Peters EL, Berus D, Velkeniers B, Hooghe R . Expression of SOCS genes in normal and leukemic human leukocytes stimulated by prolactin, growth hormone and cytokines . Journal of Neuroimmunology . 109 . 1 . 34–9 . Sep 2000 . 10969179 . 10.1016/S0165-5728(00)00300-3 . 23752435 .
• Yousefi S, Cooper PR, Mueck B, Potter SL, Jarai G . cDNA representational difference analysis of human neutrophils stimulated by GM-CSF . Biochemical and Biophysical Research Communications . 277 . 2 . 401–9 . Oct 2000 . 11032736 . 10.1006/bbrc.2000.3678 .
• Dif F, Saunier E, Demeneix B, Kelly PA, Edery M . Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor . Endocrinology . 142 . 12 . 5286–93 . Dec 2001 . 11713228 . 10.1210/endo.142.12.8549 . free .
• Federici M, Giustizieri ML, Scarponi C, Girolomoni G, Albanesi C . Impaired IFN-gamma-dependent inflammatory responses in human keratinocytes overexpressing the suppressor of cytokine signaling 1 . Journal of Immunology . 169 . 1 . 434–42 . Jul 2002 . 12077274 . 10.4049/jimmunol.169.1.434 . free .
• Du L, Frick GP, Tai LR, Yoshimura A, Goodman HM . Interaction of the growth hormone receptor with cytokine-induced Src homology domain 2 protein in rat adipocytes . Endocrinology . 144 . 3 . 868–76 . Mar 2003 . 12586763 . 10.1210/en.2002-220830 . free .
• Chen S, Anderson PO, Li L, Sjögren HO, Wang P, Li SL . Functional association of cytokine-induced SH2 protein and protein kinase C in activated T cells . . 15 . 3 . 403–9 . Mar 2003 . 12618484 . 10.1093/intimm/dxg039 . free .
• Yamasaki K, Hanakawa Y, Tokumaru S, Shirakata Y, Sayama K, Hanada T, Yoshimura A, Hashimoto K . 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 . Apr 2003 . 12648219 . 10.1046/j.1523-1747.2003.12100.x . free . 11094/44640 . free .
• Cheng J, Zhang D, Zhou C, Marasco WA . 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 . Jan 2004 . 14630083 . 10.1016/S0145-2126(03)00158-9 .
• Bayle J, Letard S, Frank R, Dubreuil P, De Sepulveda P . Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling . The Journal of Biological Chemistry . 279 . 13 . 12249–59 . Mar 2004 . 14707129 . 10.1074/jbc.M313381200 . free .
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM . Functional proteomics mapping of a human signaling pathway . Genome Research . 14 . 7 . 1324–32 . Jul 2004 . 15231748 . 442148 . 10.1101/gr.2334104 .
• Hunter MG, Jacob A, O'donnell LC, Agler A, Druhan LJ, Coggeshall KM, Avalos BR . 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 . Oct 2004 . 15470047 . 10.4049/jimmunol.173.8.5036 . free .

Notes and References

1. Uchida K, Yoshimura A, Inazawa J, Yanagisawa K, Osada H, Masuda A, Saito T, Takahashi T, Miyajima A, Takahashi T . 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 . Mar 1998 . 9465889 . 10.1159/000134658 .
2. Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, Hara T, Miyajima A . 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 . Jun 1995 . 7796808 . 398400 . 10.1002/j.1460-2075.1995.tb07281.x.
3. Web site: Entrez Gene: CISH cytokine inducible SH2-containing protein.
4. Web site: OrthoMaM phylogenetic marker: CISH coding sequence . 2010-02-17 . https://web.archive.org/web/20160304032008/http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000114737_CISH.xml . 2016-03-04 . dead .
5. 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 . CISH and susceptibility to infectious diseases . The New England Journal of Medicine . 362 . 22 . 2092–101 . Jun 2010 . 20484391 . 10.1056/NEJMoa0905606 . 3646238 . [Free Text]
6. 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 . Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance . The Journal of Experimental Medicine . Nov 2015 . 26527801 . 10.1084/jem.20150304 . 4647263 . 212 . 12 . 2095–113.
7. Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade. 10.21203/rs.3.rs-80800/v1. 2020. Palmer. Douglas. Webber. Beau. Patel. Yogin. Johnson. Matthew. Kariya. Christine. Lahr. Walker. Parkhurst. Maria. Gartner. Jared. Prickett. Todd. Lowery. Frank. Kishton. Rigel. Gurusamy. Devikala. Franco. Zulmarie. Vodnala. Suman. Diers. Miechaleen. Wolf. Natalie. Slipek. Nicholas. McKenna. David. Sumstad. Darin. Viney. Lydia. Henley. Tom. Bürckstümmer. Tilmann. Baker. Oliver. Hu. Ying. Yan. Chunhua. Meerzaman. Daoud. Padhan. Kartik. Moriarity. Branden. Lo. Winifred. Malekzadeh. Parisa. 234737847. 1.
8. Aman MJ, Migone TS, Sasaki A, Ascherman DP, Zhu MH, Soldaini E, Imada K, Miyajima A, Yoshimura A, Leonard WJ . CIS associates with the interleukin-2 receptor beta chain and inhibits interleukin-2-dependent signaling . The Journal of Biological Chemistry . 274 . 42 . 30266–72 . Oct 1999 . 10514520 . 10.1074/jbc.274.42.30266 . free .
9. Ram PA, Waxman DJ . SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms . The Journal of Biological Chemistry . 274 . 50 . 35553–61 . Dec 1999 . 10585430 . 10.1074/jbc.274.50.35553 . free.