ID CISH_HUMAN Reviewed; 258 AA.
AC Q9NSE2; B2R9N1; G5E9R1; Q9NS38; Q9Y5R1;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 24-JAN-2024, entry version 185.
DE RecName: Full=Cytokine-inducible SH2-containing protein;
DE Short=CIS;
DE AltName: Full=CIS-1;
DE AltName: Full=Protein G18;
DE AltName: Full=Suppressor of cytokine signaling;
DE Short=SOCS;
GN Name=CISH; Synonyms=G18;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Fetal lung;
RX PubMed=9465889; DOI=10.1159/000134658;
RA Uchida K., Yoshimura A., Inazawa J., Yanagisawa K., Osada H., Masuda A.,
RA Saito T., Takahashi T., Miyajima A., Takahashi K.;
RT "Molecular cloning of CISH, chromosome assignment to 3p21.3, and analysis
RT of expression in fetal and adult tissues.";
RL Cytogenet. Cell Genet. 78:209-212(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1B).
RC TISSUE=Placenta;
RX PubMed=10902923; DOI=10.3109/10425170009033983;
RA Jiang C., Yu L., Zhao Y., Zhang M., Liu Q., Mao N., Geng Z., Zhao S.;
RT "Cloning and characterization of CIS 1b (cytokine inducible SH2-containing
RT protein 1b), an alternative splicing form of CIS 1 gene.";
RL DNA Seq. 11:149-154(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1C).
RA Wei M.-H., Minna J.D., Lerman M.I.;
RT "The human G18 is an ortholog of the rodent gene CIS-2 and is located in
RT 3p21.3 and homozygously deleted in lung cancer.";
RL Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RX PubMed=11032736; DOI=10.1006/bbrc.2000.3678;
RA Yousefi S., Cooper P.R., Mueck B., Potter S.L., Jarai G.;
RT "cDNA representational difference analysis of human neutrophils stimulated
RT by GM-CSF.";
RL Biochem. Biophys. Res. Commun. 277:401-409(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP INTERACTION WITH EPOR, AND UBIQUITINATION.
RX PubMed=9774439; DOI=10.1074/jbc.273.43.28185;
RA Verdier F., Chretien S., Muller O., Varlet P., Yoshimura A.,
RA Gisselbrecht S., Lacombe C., Mayeux P.;
RT "Proteasomes regulate erythropoietin receptor and signal transducer and
RT activator of transcription 5 (STAT5) activation. Possible involvement of
RT the ubiquitinated CIS protein.";
RL J. Biol. Chem. 273:28185-28190(1998).
RN [10]
RP POLYMORPHISM, AND INVOLVEMENT IN SUSCEPTIBILITY TO TUBERCULOSIS; MALARIA
RP AND BACTS2.
RX PubMed=20484391; DOI=10.1056/nejmoa0905606;
RA Khor C.C., Vannberg F.O., Chapman S.J., Guo H., Wong S.H., Walley A.J.,
RA Vukcevic D., Rautanen A., Mills T.C., Chang K.C., Kam K.M., Crampin A.C.,
RA Ngwira B., Leung C.C., Tam C.M., Chan C.Y., Sung J.J., Yew W.W., Toh K.Y.,
RA Tay S.K., Kwiatkowski D., Lienhardt C., Hien T.T., Day N.P., Peshu N.,
RA Marsh K., Maitland K., Scott J.A., Williams T.N., Berkley J.A., Floyd S.,
RA Tang N.L., Fine P.E., Goh D.L., Hill A.V.;
RT "CISH and susceptibility to infectious diseases.";
RL N. Engl. J. Med. 362:2092-2101(2010).
CC -!- FUNCTION: SOCS family proteins form part of a classical negative
CC feedback system that regulates cytokine signal transduction. CIS is
CC involved in the negative regulation of cytokines that signal through
CC the JAK-STAT5 pathway such as erythropoietin, prolactin and interleukin
CC 3 (IL3) receptor. Inhibits STAT5 trans-activation by suppressing its
CC tyrosine phosphorylation. May be a substrate-recognition component of a
CC SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein
CC ligase complex which mediates the ubiquitination and subsequent
CC proteasomal degradation of target proteins (By similarity).
CC {ECO:0000250}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Stably associated with the tyrosine-phosphorylated IL3
CC receptor beta chain and tyrosine-phosphorylated EPO receptor (EPOR).
CC -!- INTERACTION:
CC Q9NSE2; P54253: ATXN1; NbExp=6; IntAct=EBI-617866, EBI-930964;
CC Q9NSE2; Q8N187: CARF; NbExp=3; IntAct=EBI-617866, EBI-745541;
CC Q9NSE2; P50570-2: DNM2; NbExp=3; IntAct=EBI-617866, EBI-10968534;
CC Q9NSE2; P00533: EGFR; NbExp=4; IntAct=EBI-617866, EBI-297353;
CC Q9NSE2; P04626: ERBB2; NbExp=4; IntAct=EBI-617866, EBI-641062;
CC Q9NSE2; O14773: TPP1; NbExp=3; IntAct=EBI-617866, EBI-2800203;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9NSE2-1; Sequence=Displayed;
CC Name=1B;
CC IsoId=Q9NSE2-2; Sequence=VSP_006194;
CC Name=1C;
CC IsoId=Q9NSE2-3; Sequence=VSP_006195;
CC -!- TISSUE SPECIFICITY: Expressed in various epithelial tissues. Abundantly
CC expressed in liver and kidney, and to a lesser extent in lung. The
CC tissue distribution of isoforms 1 and 1B is distinct.
CC {ECO:0000269|PubMed:11032736}.
CC -!- INDUCTION: By a subset of cytokines including EPO/erythropoietin.
CC -!- PTM: Association with EPOR may target the protein for proteolysis by
CC the ubiquitin-dependent proteasome pathway. CIS is mainly
CC monubiquitinated (37 kDa form) but may also exist in a
CC polyubiquitinated form (45 kDa). {ECO:0000269|PubMed:9774439}.
CC -!- POLYMORPHISM: CISH polymorphisms are involved in susceptibility to
CC malaria [MIM:611162]. {ECO:0000269|PubMed:20484391}.
CC -!- POLYMORPHISM: Genetic variations in CISH are involved in susceptibility
CC to tuberculosis [MIM:607948]. {ECO:0000269|PubMed:20484391}.
CC -!- POLYMORPHISM: Genetic variations in CISH are associated with
CC susceptibility to bacterial invasion of the blood and define the
CC bacteremia susceptibility locus 2 (BACTS2) [MIM:614383].
CC {ECO:0000269|PubMed:20484391}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD28471.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; D83532; BAA92328.1; -; mRNA.
DR EMBL; AF035947; AAF97410.1; -; mRNA.
DR EMBL; AF132297; AAD28471.2; ALT_INIT; mRNA.
DR EMBL; AK313850; BAG36578.1; -; mRNA.
DR EMBL; AC096920; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471055; EAW65128.1; -; Genomic_DNA.
DR EMBL; CH471055; EAW65129.1; -; Genomic_DNA.
DR EMBL; BC031590; AAH31590.1; -; mRNA.
DR EMBL; BC064354; AAH64354.1; -; mRNA.
DR CCDS; CCDS2831.1; -. [Q9NSE2-1]
DR CCDS; CCDS46834.1; -. [Q9NSE2-3]
DR PIR; JC7512; JC7512.
DR RefSeq; NP_037456.5; NM_013324.5. [Q9NSE2-3]
DR RefSeq; NP_659508.1; NM_145071.2. [Q9NSE2-1]
DR RefSeq; XP_011531631.1; XM_011533329.2.
DR AlphaFoldDB; Q9NSE2; -.
DR SMR; Q9NSE2; -.
DR BioGRID; 107574; 33.
DR IntAct; Q9NSE2; 15.
DR MINT; Q9NSE2; -.
DR STRING; 9606.ENSP00000409346; -.
DR iPTMnet; Q9NSE2; -.
DR PhosphoSitePlus; Q9NSE2; -.
DR BioMuta; CISH; -.
DR DMDM; 13124022; -.
DR MassIVE; Q9NSE2; -.
DR MaxQB; Q9NSE2; -.
DR PaxDb; 9606-ENSP00000409346; -.
DR PeptideAtlas; Q9NSE2; -.
DR ProteomicsDB; 34017; -.
DR ProteomicsDB; 82539; -. [Q9NSE2-1]
DR ProteomicsDB; 82540; -. [Q9NSE2-2]
DR ProteomicsDB; 82541; -. [Q9NSE2-3]
DR Antibodypedia; 14135; 212 antibodies from 31 providers.
DR DNASU; 1154; -.
DR Ensembl; ENST00000348721.4; ENSP00000294173.3; ENSG00000114737.16. [Q9NSE2-1]
DR Ensembl; ENST00000443053.6; ENSP00000409346.2; ENSG00000114737.16. [Q9NSE2-3]
DR GeneID; 1154; -.
DR KEGG; hsa:1154; -.
DR MANE-Select; ENST00000348721.4; ENSP00000294173.3; NM_145071.4; NP_659508.1.
DR UCSC; uc003dax.4; human. [Q9NSE2-1]
DR AGR; HGNC:1984; -.
DR CTD; 1154; -.
DR DisGeNET; 1154; -.
DR GeneCards; CISH; -.
DR HGNC; HGNC:1984; CISH.
DR HPA; ENSG00000114737; Tissue enhanced (liver).
DR MalaCards; CISH; -.
DR MIM; 602441; gene.
DR MIM; 607948; phenotype.
DR MIM; 611162; phenotype.
DR MIM; 614383; phenotype.
DR neXtProt; NX_Q9NSE2; -.
DR OpenTargets; ENSG00000114737; -.
DR PharmGKB; PA26521; -.
DR VEuPathDB; HostDB:ENSG00000114737; -.
DR eggNOG; KOG4566; Eukaryota.
DR GeneTree; ENSGT00940000157392; -.
DR HOGENOM; CLU_079452_4_1_1; -.
DR InParanoid; Q9NSE2; -.
DR OMA; LSEPIMQ; -.
DR OrthoDB; 5362214at2759; -.
DR PhylomeDB; Q9NSE2; -.
DR TreeFam; TF321368; -.
DR PathwayCommons; Q9NSE2; -.
DR Reactome; R-HSA-1266695; Interleukin-7 signaling.
DR Reactome; R-HSA-8951664; Neddylation.
DR Reactome; R-HSA-982772; Growth hormone receptor signaling.
DR SignaLink; Q9NSE2; -.
DR SIGNOR; Q9NSE2; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 1154; 9 hits in 1193 CRISPR screens.
DR ChiTaRS; CISH; human.
DR GeneWiki; CISH; -.
DR GenomeRNAi; 1154; -.
DR Pharos; Q9NSE2; Tbio.
DR PRO; PR:Q9NSE2; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q9NSE2; Protein.
DR Bgee; ENSG00000114737; Expressed in granulocyte and 166 other cell types or tissues.
DR Genevisible; Q9NSE2; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005942; C:phosphatidylinositol 3-kinase complex; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR GO; GO:0046935; F:1-phosphatidylinositol-3-kinase regulator activity; IBA:GO_Central.
DR GO; GO:0035556; P:intracellular signal transduction; NAS:UniProtKB.
DR GO; GO:0009968; P:negative regulation of signal transduction; IEA:UniProtKB-KW.
DR GO; GO:0046854; P:phosphatidylinositol phosphate biosynthetic process; IBA:GO_Central.
DR GO; GO:0007205; P:protein kinase C-activating G protein-coupled receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway.
DR GO; GO:0001558; P:regulation of cell growth; NAS:UniProtKB.
DR CDD; cd10718; SH2_CIS; 1.
DR CDD; cd03734; SOCS_CIS1; 1.
DR Gene3D; 3.30.505.10; SH2 domain; 1.
DR Gene3D; 1.10.750.20; SOCS box; 1.
DR InterPro; IPR035887; CIS_SH2.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR001496; SOCS_box.
DR InterPro; IPR036036; SOCS_box-like_dom_sf.
DR PANTHER; PTHR10155:SF9; CYTOKINE-INDUCIBLE SH2-CONTAINING PROTEIN; 1.
DR PANTHER; PTHR10155; PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT; 1.
DR Pfam; PF00017; SH2; 1.
DR Pfam; PF07525; SOCS_box; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR SMART; SM00252; SH2; 1.
DR SMART; SM00253; SOCS; 1.
DR SMART; SM00969; SOCS_box; 1.
DR SUPFAM; SSF55550; SH2 domain; 1.
DR SUPFAM; SSF158235; SOCS box-like; 1.
DR PROSITE; PS50001; SH2; 1.
DR PROSITE; PS50225; SOCS; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Growth regulation; Reference proteome; SH2 domain;
KW Signal transduction inhibitor; Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1..258
FT /note="Cytokine-inducible SH2-containing protein"
FT /id="PRO_0000181231"
FT DOMAIN 82..163
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT DOMAIN 209..257
FT /note="SOCS box"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00194"
FT REGION 169..201
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 178..201
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VAR_SEQ 1..7
FT /note="MVLCVQG -> MGPPLTAHPLPSR (in isoform 1B)"
FT /evidence="ECO:0000303|PubMed:10902923"
FT /id="VSP_006194"
FT VAR_SEQ 1..7
FT /note="MVLCVQG -> MYLEHTSHCPHHDDDTAMDTPLPR (in isoform 1C)"
FT /evidence="ECO:0000303|Ref.3"
FT /id="VSP_006195"
SQ SEQUENCE 258 AA; 28663 MW; 0BA97804E3B0F608 CRC64;
MVLCVQGPRP LLAVERTGQR PLWAPSLELP KPVMQPLPAG AFLEEVAEGT PAQTESEPKV
LDPEEDLLCI AKTFSYLRES GWYWGSITAS EARQHLQKMP EGTFLVRDST HPSYLFTLSV
KTTRGPTNVR IEYADSSFRL DSNCLSRPRI LAFPDVVSLV QHYVASCTAD TRSDSPDPAP
TPALPMPKED APSDPALPAP PPATAVHLKL VQPFVRRSSA RSLQHLCRLV INRLVADVDC
LPLPRRMADY LRQYPFQL
//
