# CISH (protein)

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Protein-coding gene in the species Homo sapiens

This article is about the CISH gene. For other uses, see [CISH](/source/CISH_(disambiguation)).

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; OMA:CISH - orthologs Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3p21.2 Start 50,606,489 bp[1] End 50,611,774 bp[1] Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 F1|9 57.99 cM Start 107,173,225 bp[2] End 107,179,983 bp[2] RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte left lobe of thyroid gland right lobe of thyroid gland human kidney tibialis anterior muscle right lobe of liver upper lobe of left lung blood placenta apex of heart Top expressed in interventricular septum triceps brachii muscle sternocleidomastoid muscle temporal muscle myocardium of ventricle digastric muscle cardiac muscles choroid plexus of fourth ventricle right ventricle right kidney More reference expression data BioGPS More reference expression data Gene ontology Molecular function protein kinase inhibitor activity protein binding molecular function 1-phosphatidylinositol-3-kinase regulator activity Cellular component cytoplasm cytosol plasma 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 intracellular signal transduction negative regulation of signal transduction regulation of cell growth protein ubiquitination negative regulation of protein kinase activity negative regulation of receptor signaling pathway via JAK-STAT cytokine-mediated signaling pathway post-translational protein modification interleukin-7-mediated signaling pathway regulation of phosphatidylinositol 3-kinase activity phosphatidylinositol phosphate biosynthetic process 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: 107.17 – 107.18 Mb PubMed search [3] [4] Wikidata View/Edit Human View/Edit Mouse

**Cytokine-inducible SH2-containing protein** is a [protein](/source/Protein) that in humans is encoded by the *CISH* [gene](/source/Gene).[5][6][7] *CISH* [orthologs](/source/Orthologs)[8] have been identified in most [mammals](/source/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]

## Function

The protein encoded by this gene contains a [SH2 domain](/source/SH2_domain) and a [SOCS box domain](/source/Suppressor_of_cytokine_signalling). The protein thus belongs to the [cytokine-induced STAT inhibitor](https://en.wikipedia.org/w/index.php?title=Cytokine-induced_STAT_inhibitor&action=edit&redlink=1) (CIS), also known as suppressor of cytokine signaling (SOCS) or STAT-induced STAT inhibitor (SSI), protein family. [CIS family](https://en.wikipedia.org/w/index.php?title=CIS_protein_family&action=edit&redlink=1) 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](/source/Hematopoietic) cells. [Proteasome](/source/Proteasome)-mediated degradation of this protein has been shown to be involved in the inactivation of the [erythropoietin receptor](/source/Erythropoietin_receptor).[7]

CISH is induced by [T cell receptor](/source/T_cell_receptor) (TCR) ligation and negatively regulates it by targeting the critical signaling intermediate [PLC-gamma-1](/source/PLCG1) 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](/source/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]

## Interactions

CISH has been shown to [interact](/source/Protein-protein_interaction) with [IL2RB](/source/IL2RB)[12] and [Growth hormone receptor](/source/Growth_hormone_receptor).[13] and [PLCG1](/source/PLCG1).[10]

## References

1. ^ [***a***](#cite_ref-refGRCh38Ensembl_1-0) [***b***](#cite_ref-refGRCh38Ensembl_1-1) [***c***](#cite_ref-refGRCh38Ensembl_1-2) [GRCh38: Ensembl release 89: ENSG00000114737](http://May2017.archive.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000114737) – [Ensembl](/source/Ensembl_genome_database_project), May 2017

1. ^ [***a***](#cite_ref-refGRCm38Ensembl_2-0) [***b***](#cite_ref-refGRCm38Ensembl_2-1) [***c***](#cite_ref-refGRCm38Ensembl_2-2) [GRCm38: Ensembl release 89: ENSMUSG00000032578](http://May2017.archive.ensembl.org/Mus_musculus/Gene/Summary?db=core;g=ENSMUSG00000032578) – [Ensembl](/source/Ensembl_genome_database_project), May 2017

1. **[^](#cite_ref-3)** ["Human PubMed Reference:"](https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Link&LinkName=gene_pubmed&from_uid=1154). *National Center for Biotechnology Information, U.S. National Library of Medicine*.

1. **[^](#cite_ref-4)** ["Mouse PubMed Reference:"](https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Link&LinkName=gene_pubmed&from_uid=12700). *National Center for Biotechnology Information, U.S. National Library of Medicine*.

1. **[^](#cite_ref-pmid9465889_5-0)** Uchida K, Yoshimura A, Inazawa J, Yanagisawa K, Osada H, Masuda A, et al. (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): 209–212. [doi](/source/Doi_(identifier)):[10.1159/000134658](https://doi.org/10.1159%2F000134658). [PMID](/source/PMID_(identifier)) [9465889](https://pubmed.ncbi.nlm.nih.gov/9465889).

1. **[^](#cite_ref-pmid7796808_6-0)** Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, et al. (June 1995). ["A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC398400). *The EMBO Journal*. **14** (12): 2816–2826. [doi](/source/Doi_(identifier)):[10.1002/j.1460-2075.1995.tb07281.x](https://doi.org/10.1002%2Fj.1460-2075.1995.tb07281.x). [PMC](/source/PMC_(identifier)) [398400](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC398400). [PMID](/source/PMID_(identifier)) [7796808](https://pubmed.ncbi.nlm.nih.gov/7796808).

1. ^ [***a***](#cite_ref-entrez_7-0) [***b***](#cite_ref-entrez_7-1) ["Entrez Gene: CISH cytokine inducible SH2-containing protein"](https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=1154).

1. **[^](#cite_ref-OrthoMaM_8-0)** ["OrthoMaM phylogenetic marker: CISH coding sequence"](https://web.archive.org/web/20160304032008/http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000114737_CISH.xml). Archived from [the original](http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000114737_CISH.xml) on 2016-03-04. Retrieved 2010-02-17.

1. **[^](#cite_ref-Khor_9-0)** Khor CC, Vannberg FO, Chapman SJ, Guo H, Wong SH, Walley AJ, et al. (June 2010). ["CISH and susceptibility to infectious diseases"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646238). *The New England Journal of Medicine*. **362** (22): 2092–2101. [doi](/source/Doi_(identifier)):[10.1056/NEJMoa0905606](https://doi.org/10.1056%2FNEJMoa0905606). [PMC](/source/PMC_(identifier)) [3646238](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646238). [PMID](/source/PMID_(identifier)) [20484391](https://pubmed.ncbi.nlm.nih.gov/20484391).

1. ^ [***a***](#cite_ref-Palmer_2015_10-0) [***b***](#cite_ref-Palmer_2015_10-1) Palmer DC, Guittard GC, Franco Z, Crompton JG, Eil RL, Patel SJ, et al. (November 2015). ["Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647263). *The Journal of Experimental Medicine*. **212** (12): 2095–2113. [doi](/source/Doi_(identifier)):[10.1084/jem.20150304](https://doi.org/10.1084%2Fjem.20150304). [PMC](/source/PMC_(identifier)) [4647263](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647263). [PMID](/source/PMID_(identifier)) [26527801](https://pubmed.ncbi.nlm.nih.gov/26527801).

1. **[^](#cite_ref-11)** Palmer DC, Webber BR, Patel Y, Johnson MJ, Kariya CM, Lahr WS, et al. (2022). ["Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9847506). *Med*. **3** (10): 682–704.e8. [doi](/source/Doi_(identifier)):[10.1016/j.medj.2022.07.008](https://doi.org/10.1016%2Fj.medj.2022.07.008). [PMC](/source/PMC_(identifier)) [9847506](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9847506). [PMID](/source/PMID_(identifier)) [36007524](https://pubmed.ncbi.nlm.nih.gov/36007524).{{[cite journal](https://en.wikipedia.org/wiki/Template:Cite_journal)}}: CS1 maint: overridden setting ([link](https://en.wikipedia.org/wiki/Category:CS1_maint:_overridden_setting))

1. **[^](#cite_ref-pmid10514520_12-0)** Aman MJ, Migone TS, Sasaki A, Ascherman DP, Zhu M, Soldaini E, et al. (October 1999). ["CIS associates with the interleukin-2 receptor beta chain and inhibits interleukin-2-dependent signaling"](https://doi.org/10.1074%2Fjbc.274.42.30266). *The Journal of Biological Chemistry*. **274** (42): 30266–30272. [doi](/source/Doi_(identifier)):[10.1074/jbc.274.42.30266](https://doi.org/10.1074%2Fjbc.274.42.30266). [PMID](/source/PMID_(identifier)) [10514520](https://pubmed.ncbi.nlm.nih.gov/10514520).

1. **[^](#cite_ref-pmid10585430_13-0)** Ram PA, Waxman DJ (December 1999). ["SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms"](https://doi.org/10.1074%2Fjbc.274.50.35553). *The Journal of Biological Chemistry*. **274** (50): 35553–35561. [doi](/source/Doi_(identifier)):[10.1074/jbc.274.50.35553](https://doi.org/10.1074%2Fjbc.274.50.35553). [PMID](/source/PMID_(identifier)) [10585430](https://pubmed.ncbi.nlm.nih.gov/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): 235–241. [doi](/source/Doi_(identifier)):[10.1016/S0968-0004(02)02085-6](https://doi.org/10.1016%2FS0968-0004%2802%2902085-6). [PMID](/source/PMID_(identifier)) [12076535](https://pubmed.ncbi.nlm.nih.gov/12076535).

- Verdier F, Chrétien S, Muller O, Varlet P, Yoshimura A, Gisselbrecht S, et al. (October 1998). ["Proteasomes regulate erythropoietin receptor and signal transducer and activator of transcription 5 (STAT5) activation. Possible involvement of the ubiquitinated Cis protein"](https://doi.org/10.1074%2Fjbc.273.43.28185). *The Journal of Biological Chemistry*. **273** (43): 28185–28190. [doi](/source/Doi_(identifier)):[10.1074/jbc.273.43.28185](https://doi.org/10.1074%2Fjbc.273.43.28185). [PMID](/source/PMID_(identifier)) [9774439](https://pubmed.ncbi.nlm.nih.gov/9774439).

- Okabe S, Tauchi T, Morita H, Ohashi H, Yoshimura A, Ohyashiki K (October 1999). ["Thrombopoietin induces an SH2-containing protein, CIS1, which binds to Mpl: involvement of the ubiquitin proteosome pathway"](https://doi.org/10.1016%2FS0301-472X%2899%2900094-6). *Experimental Hematology*. **27** (10): 1542–1547. [doi](/source/Doi_(identifier)):[10.1016/S0301-472X(99)00094-6](https://doi.org/10.1016%2FS0301-472X%2899%2900094-6). [PMID](/source/PMID_(identifier)) [10517496](https://pubmed.ncbi.nlm.nih.gov/10517496).

- Jiang C, Yu L, Zhao Y, Zhang M, Liu Q, Mao N, et al. (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): 149–154. [doi](/source/Doi_(identifier)):[10.3109/10425170009033983](https://doi.org/10.3109%2F10425170009033983). [PMID](/source/PMID_(identifier)) [10902923](https://pubmed.ncbi.nlm.nih.gov/10902923). [S2CID](/source/S2CID_(identifier)) [7986394](https://api.semanticscholar.org/CorpusID:7986394).

- Dogusan Z, Hooghe-Peters EL, Berus D, Velkeniers B, Hooghe R (September 2000). "Expression of SOCS genes in normal and leukemic human leukocytes stimulated by prolactin, growth hormone and cytokines". *Journal of Neuroimmunology*. **109** (1): 34–39. [doi](/source/Doi_(identifier)):[10.1016/S0165-5728(00)00300-3](https://doi.org/10.1016%2FS0165-5728%2800%2900300-3). [PMID](/source/PMID_(identifier)) [10969179](https://pubmed.ncbi.nlm.nih.gov/10969179). [S2CID](/source/S2CID_(identifier)) [23752435](https://api.semanticscholar.org/CorpusID:23752435).

- Yousefi S, Cooper PR, Mueck B, Potter SL, Jarai G (October 2000). "cDNA representational difference analysis of human neutrophils stimulated by GM-CSF". *Biochemical and Biophysical Research Communications*. **277** (2): 401–409. [Bibcode](/source/Bibcode_(identifier)):[2000BBRC..277..401Y](https://ui.adsabs.harvard.edu/abs/2000BBRC..277..401Y). [doi](/source/Doi_(identifier)):[10.1006/bbrc.2000.3678](https://doi.org/10.1006%2Fbbrc.2000.3678). [PMID](/source/PMID_(identifier)) [11032736](https://pubmed.ncbi.nlm.nih.gov/11032736).

- Dif F, Saunier E, Demeneix B, Kelly PA, Edery M (December 2001). ["Cytokine-inducible SH2-containing protein suppresses PRL signaling by binding the PRL receptor"](https://doi.org/10.1210%2Fendo.142.12.8549). *Endocrinology*. **142** (12): 5286–5293. [doi](/source/Doi_(identifier)):[10.1210/endo.142.12.8549](https://doi.org/10.1210%2Fendo.142.12.8549). [PMID](/source/PMID_(identifier)) [11713228](https://pubmed.ncbi.nlm.nih.gov/11713228).

- Federici M, Giustizieri ML, Scarponi C, Girolomoni G, Albanesi C (July 2002). ["Impaired IFN-gamma-dependent inflammatory responses in human keratinocytes overexpressing the suppressor of cytokine signaling 1"](https://doi.org/10.4049%2Fjimmunol.169.1.434). *Journal of Immunology*. **169** (1): 434–442. [doi](/source/Doi_(identifier)):[10.4049/jimmunol.169.1.434](https://doi.org/10.4049%2Fjimmunol.169.1.434). [PMID](/source/PMID_(identifier)) [12077274](https://pubmed.ncbi.nlm.nih.gov/12077274).

- Du L, Frick GP, Tai LR, Yoshimura A, Goodman HM (March 2003). ["Interaction of the growth hormone receptor with cytokine-induced Src homology domain 2 protein in rat adipocytes"](https://doi.org/10.1210%2Fen.2002-220830). *Endocrinology*. **144** (3): 868–876. [doi](/source/Doi_(identifier)):[10.1210/en.2002-220830](https://doi.org/10.1210%2Fen.2002-220830). [PMID](/source/PMID_(identifier)) [12586763](https://pubmed.ncbi.nlm.nih.gov/12586763).

- Chen S, Anderson PO, Li L, Sjögren HO, Wang P, Li SL (March 2003). ["Functional association of cytokine-induced SH2 protein and protein kinase C in activated T cells"](https://doi.org/10.1093%2Fintimm%2Fdxg039). *International Immunology*. **15** (3): 403–409. [doi](/source/Doi_(identifier)):[10.1093/intimm/dxg039](https://doi.org/10.1093%2Fintimm%2Fdxg039). [hdl](/source/Hdl_(identifier)):[10481/94886](https://hdl.handle.net/10481%2F94886). [PMID](/source/PMID_(identifier)) [12618484](https://pubmed.ncbi.nlm.nih.gov/12618484).

- Yamasaki K, Hanakawa Y, Tokumaru S, Shirakata Y, Sayama K, Hanada T, et al. (April 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"](https://doi.org/10.1046%2Fj.1523-1747.2003.12100.x). *The Journal of Investigative Dermatology*. **120** (4): 571–580. [doi](/source/Doi_(identifier)):[10.1046/j.1523-1747.2003.12100.x](https://doi.org/10.1046%2Fj.1523-1747.2003.12100.x). [hdl](/source/Hdl_(identifier)):[11094/44640](https://hdl.handle.net/11094%2F44640). [PMID](/source/PMID_(identifier)) [12648219](https://pubmed.ncbi.nlm.nih.gov/12648219).

- Cheng J, Zhang D, Zhou C, Marasco WA (January 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](/source/Doi_(identifier)):[10.1016/S0145-2126(03)00158-9](https://doi.org/10.1016%2FS0145-2126%2803%2900158-9). [PMID](/source/PMID_(identifier)) [14630083](https://pubmed.ncbi.nlm.nih.gov/14630083).

- Bayle J, Letard S, Frank R, Dubreuil P, De Sepulveda P (March 2004). ["Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling"](https://doi.org/10.1074%2Fjbc.M313381200). *The Journal of Biological Chemistry*. **279** (13): 12249–12259. [doi](/source/Doi_(identifier)):[10.1074/jbc.M313381200](https://doi.org/10.1074%2Fjbc.M313381200). [PMID](/source/PMID_(identifier)) [14707129](https://pubmed.ncbi.nlm.nih.gov/14707129).

- Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, et al. (July 2004). ["Functional proteomics mapping of a human signaling pathway"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC442148). *Genome Research*. **14** (7): 1324–1332. [doi](/source/Doi_(identifier)):[10.1101/gr.2334104](https://doi.org/10.1101%2Fgr.2334104). [PMC](/source/PMC_(identifier)) [442148](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC442148). [PMID](/source/PMID_(identifier)) [15231748](https://pubmed.ncbi.nlm.nih.gov/15231748).

- Hunter MG, Jacob A, O'donnell LC, Agler A, Druhan LJ, Coggeshall KM, et al. (October 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"](https://doi.org/10.4049%2Fjimmunol.173.8.5036). *Journal of Immunology*. **173** (8): 5036–5045. [doi](/source/Doi_(identifier)):[10.4049/jimmunol.173.8.5036](https://doi.org/10.4049%2Fjimmunol.173.8.5036). [PMID](/source/PMID_(identifier)) [15470047](https://pubmed.ncbi.nlm.nih.gov/15470047).

## External links

- Human [*CISH*](https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&singleSearch=knownCanonical&position=CISH) genome location and [*CISH*](https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_type=knownGene&hgg_gene=CISH) gene details page in the [UCSC Genome Browser](/source/UCSC_Genome_Browser).

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Adapted from the Wikipedia article [CISH (protein)](https://en.wikipedia.org/wiki/CISH_(protein)) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/CISH_(protein)?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.