CLNK_HUMAN
ID CLNK_HUMAN Reviewed; 428 AA.
AC Q7Z7G1; Q05C27; Q9P2U9;
DT 15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT 15-JAN-2008, sequence version 2.
DT 03-AUG-2022, entry version 129.
DE RecName: Full=Cytokine-dependent hematopoietic cell linker {ECO:0000250|UniProtKB:Q9QZE2};
DE AltName: Full=Mast cell immunoreceptor signal transducer {ECO:0000303|Ref.1};
GN Name=CLNK; Synonyms=MIST;
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).
RA Goitsuka R.;
RT "Genomic organization of human MIST gene.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
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 [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 19-394 (ISOFORM 1), AND IDENTIFICATION
RP (ISOFORM 3).
RX PubMed=10744659; DOI=10.1093/intimm/12.4.573;
RA Goitsuka R., Kanazashi H., Sasanuma H., Fujimura Y.-C., Hidaka Y.,
RA Tatsuno A., Ra C., Hayashi K., Kitamura D.;
RT "A BASH/SLP-76-related adaptor protein MIST/Clnk involved in IgE receptor-
RT mediated mast cell degranulation.";
RL Int. Immunol. 12:573-580(2000).
RN [5]
RP INTERACTION WITH LBR AND AGO2, AND SUBCELLULAR LOCATION.
RX PubMed=26009488; DOI=10.1016/j.bbrc.2015.05.046;
RA Xu M., Cai C., Sun X., Chen W., Li Q., Zhou H.;
RT "Clnk plays a role in TNF-alpha-induced cell death in murine fibrosarcoma
RT cell line L929.";
RL Biochem. Biophys. Res. Commun. 463:275-279(2015).
CC -!- FUNCTION: An adapter protein which plays a role in the regulation of
CC immunoreceptor signaling, including PLC-gamma-mediated B-cell antigen
CC receptor (BCR) signaling and FC-epsilon R1-mediated mast cell
CC degranulation (By similarity). Together with FGR, it acts as a negative
CC regulator of natural killer cell-activating receptors and inhibits
CC interferon-gamma production (By similarity). Acts as a positive
CC regulator of both T-cell receptor and natural killer T (NKT) cell
CC receptor signaling in CD4-positive NKT cells (By similarity). Together
CC with MAP4K1, it enhances CD3-triggered activation of T-cells and
CC subsequent IL2 production (By similarity). May be involved in tumor
CC necrosis factor induced cell death by promoting reactive oxidative
CC species generation, and MLKL oligomerization, ultimately leading to
CC necrosis (By similarity). Involved in phosphorylation of LAT (By
CC similarity). May be involved in high affinity immunoglobulin epsilon
CC receptor signaling in mast cells (By similarity).
CC {ECO:0000250|UniProtKB:Q9QZE2}.
CC -!- SUBUNIT: When phosphorylated, interacts with PLCG1, PLCG2, GRB2, VAV
CC and LAT (By similarity). Interacts with LBR and AGO2 (PubMed:26009488).
CC Interacts with FGR (By similarity). Part of a complex consisting of
CC CLNK, SKAP1 and FYB1 (By similarity). Interacts (via SH2 domain) with
CC FYB1; this interaction allows SKAP1 and FYB1 to promote tyrosine
CC phosphorylation of CLNK by LYN (By similarity). Interacts (via SH2
CC domain) with MAP4K1 (By similarity). {ECO:0000250|UniProtKB:Q9QZE2,
CC ECO:0000269|PubMed:26009488}.
CC -!- INTERACTION:
CC Q7Z7G1; P00533: EGFR; NbExp=2; IntAct=EBI-7878194, EBI-297353;
CC Q7Z7G1; P04626: ERBB2; NbExp=2; IntAct=EBI-7878194, EBI-641062;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:26009488}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q7Z7G1-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q7Z7G1-2; Sequence=VSP_030330, VSP_030332, VSP_030333;
CC Name=3;
CC IsoId=Q7Z7G1-3; Sequence=VSP_030331;
CC -!- DOMAIN: The N-terminal proline-rich region interacts with the SH3
CC domain of PLCG1. {ECO:0000250|UniProtKB:Q9QZE2}.
CC -!- DOMAIN: The SH2 domain is important for restoration of BCR-induced
CC calcium response and JNK2 activation in BLNK-deficient DT40 cells
CC expressing LAT. {ECO:0000250|UniProtKB:Q9QZE2}.
CC -!- PTM: Tyrosine-phosphorylated upon BCR cross-linking. Tyrosine
CC phosphorylation at both Tyr-69 and Tyr-96 are required for BCR-induced
CC calcium response and are essential to restore PLCG2-mediated signaling
CC in BLNK-deficient DT40 cells, but this phosphorylation is dispensable
CC in cells expressing LAT. Interacts with the SH2 domain of PLCG1 via
CC phosphorylated Tyr-96 (By similarity). Tyrosine phosphorylation is
CC increased when complexed with SKAP1 and FYB1 (By similarity).
CC {ECO:0000250|UniProtKB:Q9QZE2}.
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DR EMBL; AB110420; BAC76765.1; -; mRNA.
DR EMBL; AC005599; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC029887; AAH29887.1; -; mRNA.
DR EMBL; AB032369; BAA96241.1; -; mRNA.
DR CCDS; CCDS47024.1; -. [Q7Z7G1-1]
DR RefSeq; NP_443196.2; NM_052964.3. [Q7Z7G1-1]
DR AlphaFoldDB; Q7Z7G1; -.
DR SMR; Q7Z7G1; -.
DR BioGRID; 125512; 29.
DR IntAct; Q7Z7G1; 27.
DR MINT; Q7Z7G1; -.
DR STRING; 9606.ENSP00000226951; -.
DR iPTMnet; Q7Z7G1; -.
DR PhosphoSitePlus; Q7Z7G1; -.
DR BioMuta; CLNK; -.
DR DMDM; 166217263; -.
DR MassIVE; Q7Z7G1; -.
DR PaxDb; Q7Z7G1; -.
DR PeptideAtlas; Q7Z7G1; -.
DR PRIDE; Q7Z7G1; -.
DR ProteomicsDB; 69537; -. [Q7Z7G1-1]
DR ProteomicsDB; 69538; -. [Q7Z7G1-2]
DR ProteomicsDB; 69539; -. [Q7Z7G1-3]
DR Antibodypedia; 50006; 72 antibodies from 12 providers.
DR DNASU; 116449; -.
DR Ensembl; ENST00000226951.11; ENSP00000226951.6; ENSG00000109684.16. [Q7Z7G1-1]
DR Ensembl; ENST00000507719.1; ENSP00000427208.1; ENSG00000109684.16. [Q7Z7G1-2]
DR GeneID; 116449; -.
DR KEGG; hsa:116449; -.
DR MANE-Select; ENST00000226951.11; ENSP00000226951.6; NM_052964.4; NP_443196.2.
DR UCSC; uc003gmo.5; human. [Q7Z7G1-1]
DR CTD; 116449; -.
DR DisGeNET; 116449; -.
DR GeneCards; CLNK; -.
DR HGNC; HGNC:17438; CLNK.
DR HPA; ENSG00000109684; Tissue enhanced (kidney).
DR MIM; 611434; gene.
DR neXtProt; NX_Q7Z7G1; -.
DR OpenTargets; ENSG00000109684; -.
DR PharmGKB; PA164718067; -.
DR VEuPathDB; HostDB:ENSG00000109684; -.
DR eggNOG; ENOG502S0EU; Eukaryota.
DR GeneTree; ENSGT00940000161846; -.
DR HOGENOM; CLU_052668_0_0_1; -.
DR InParanoid; Q7Z7G1; -.
DR OMA; SRCFSPW; -.
DR PhylomeDB; Q7Z7G1; -.
DR TreeFam; TF326567; -.
DR PathwayCommons; Q7Z7G1; -.
DR SignaLink; Q7Z7G1; -.
DR BioGRID-ORCS; 116449; 7 hits in 1062 CRISPR screens.
DR ChiTaRS; CLNK; human.
DR GenomeRNAi; 116449; -.
DR Pharos; Q7Z7G1; Tbio.
DR PRO; PR:Q7Z7G1; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q7Z7G1; protein.
DR Bgee; ENSG00000109684; Expressed in buccal mucosa cell and 79 other tissues.
DR ExpressionAtlas; Q7Z7G1; baseline and differential.
DR Genevisible; Q7Z7G1; HS.
DR GO; GO:0005737; C:cytoplasm; IMP:UniProtKB.
DR GO; GO:0042629; C:mast cell granule; IEA:Ensembl.
DR GO; GO:0032991; C:protein-containing complex; IEA:Ensembl.
DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0043303; P:mast cell degranulation; IEA:Ensembl.
DR GO; GO:0032815; P:negative regulation of natural killer cell activation; IEA:Ensembl.
DR GO; GO:0002729; P:positive regulation of natural killer cell cytokine production; IEA:Ensembl.
DR GO; GO:0010941; P:regulation of cell death; IEA:Ensembl.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR036860; SH2_dom_sf.
DR Pfam; PF00017; SH2; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR SMART; SM00252; SH2; 1.
DR SUPFAM; SSF55550; SSF55550; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cytoplasm; Phosphoprotein; Reference proteome;
KW SH2 domain.
FT CHAIN 1..428
FT /note="Cytokine-dependent hematopoietic cell linker"
FT /id="PRO_0000314597"
FT DOMAIN 309..419
FT /note="SH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00191"
FT REGION 1..22
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 135..198
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 159..164
FT /note="Mediates interaction with PLCG1; essential for BCR
FT signaling; involved in restoration of BCR-induced calcium
FT response and ERK2 and JNK2 activation in BLNK-deficient
FT cells expressing LAT"
FT /evidence="ECO:0000250|UniProtKB:Q9QZE2"
FT REGION 178..180
FT /note="Mediates interaction with LAT, GRB2, and FGR;
FT involved in translocation to the glycolipid-enriched
FT microdomain and restoration of BCR-induced calcium response
FT in BLNK-deficient DT40 cells expressing LAT"
FT /evidence="ECO:0000250|UniProtKB:Q9QZE2"
FT REGION 244..271
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 135..150
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 158..184
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 244..262
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 335
FT /note="Interaction with FYB1"
FT /evidence="ECO:0000250|UniProtKB:Q9QZE2"
FT MOD_RES 69
FT /note="Phosphotyrosine; by LYN"
FT /evidence="ECO:0000250|UniProtKB:Q9QZE2"
FT MOD_RES 96
FT /note="Phosphotyrosine; by LYN"
FT /evidence="ECO:0000250|UniProtKB:Q9QZE2"
FT VAR_SEQ 1..42
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_030330"
FT VAR_SEQ 147..183
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_030331"
FT VAR_SEQ 211
FT /note="V -> P (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_030332"
FT VAR_SEQ 212..428
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_030333"
FT VARIANT 65
FT /note="S -> G (in dbSNP:rs16869924)"
FT /id="VAR_037984"
FT CONFLICT 140
FT /note="K -> R (in Ref. 1; BAC76765 and 3; BAA96241)"
FT /evidence="ECO:0000305"
FT CONFLICT 198
FT /note="R -> G (in Ref. 1; BAC76765 and 3; BAA96241)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 428 AA; 49554 MW; 98DEDD4378D395A7 CRC64;
MNRQGNRKTT KEGSNDLKFQ NFSLPKNRSW PRINSATGQY QRMNKPLLDW ERNFAAVLDG
AKGHSDDDYD DPELRMEETW QSIKILPARP IKESEYADTH YFKVAMDTPL PLDTRTSISI
GQPTWNTQTR LERVDKPISK DVRSQNIKGD ASVRKNKIPL PPPRPLITLP KKYQPLPPEP
ESSRPPLSQR HTFPEVQRMP SQISLRDLSE VLEAEKVPHN QRKPESTHLL ENQNTQEIPL
AISSSSFTTS NHSVQNRDHR GGMQPCSPQR CQPPASCSPH ENILPYKYTS WRPPFPKRSD
RKDVQHNEWY IGEYSRQAVE EAFMKENKDG SFLVRDCSTK SKEEPYVLAV FYENKVYNVK
IRFLERNQQF ALGTGLRGDE KFDSVEDIIE HYKNFPIILI DGKDKTGVHR KQCHLTQPLP
LTRHLLPL
