CISH (protein)

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]

This article is about the CISH gene. For other uses, see CISH.
CISH
Identifiers
AliasesCISH, BACTS2, CIS, CIS-1, G18, SOCS, cytokine inducible SH2 containing protein
External IDsOMIM: 602441 MGI: 103159 HomoloGene: 7667 GeneCards: CISH
Orthologs
SpeciesHumanMouse
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 MbChr 9: 107.17 – 107.18 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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.

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 [11]

Model organisms

Model organisms have been used in the study of CISH function. A conditional knockout mouse line, called Cishtm1a(KOMP)Wtsi[16][17] 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.[18][19][20]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[14][21] Twenty four tests were carried out on mutant mice, however no significant abnormalities were observed.[14]

Interactions

CISH has been shown to interact with IL2RB[22] and Growth hormone receptor.[23] 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. Palmer, Douglas; et al. (2020). "Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade". doi:10.21203/rs.3.rs-80800/v1. S2CID 234737847. {{cite journal}}: Cite journal requires |journal= (help)
  12. "Salmonella infection data for Cish". Wellcome Trust Sanger Institute.
  13. "Citrobacter infection data for Cish". Wellcome Trust Sanger Institute.
  14. 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. S2CID 85911512.
  15. Mouse Resources Portal, Wellcome Trust Sanger Institute.
  16. "International Knockout Mouse Consortium". Archived from the original on 2012-04-03. Retrieved 2012-01-05.
  17. "Mouse Genome Informatics".
  18. 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.
  19. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  20. 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. S2CID 18872015.
  21. 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.
  22. 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.
  23. 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
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