HCST_HUMAN
ID HCST_HUMAN Reviewed; 93 AA.
AC Q9UBK5; Q9UBS1; Q9Y3Y0;
DT 29-APR-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 144.
DE RecName: Full=Hematopoietic cell signal transducer;
DE AltName: Full=DNAX-activation protein 10;
DE AltName: Full=Membrane protein DAP10;
DE AltName: Full=Transmembrane adapter protein KAP10;
DE Flags: Precursor;
GN Name=HCST; Synonyms=DAP10, KAP10, PIK3AP; ORFNames=UNQ587/PRO1157;
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), FUNCTION, TISSUE SPECIFICITY,
RP INTERACTION WITH PIK3R1 AND GRB2, AND PHOSPHORYLATION.
RX PubMed=10528161;
RA Chang C., Dietrich J., Harpur A.G., Lindquist J.A., Haude A., Loke Y.W.,
RA King A., Colonna M., Trowsdale J., Wilson M.J.;
RT "KAP10, a novel transmembrane adapter protein genetically linked to DAP12
RT but with unique signaling properties.";
RL J. Immunol. 163:4651-4654(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, INTERACTION WITH
RP KLRK1 AND PIK3R1, GLYCOSYLATION, SUBCELLULAR LOCATION, PHOSPHORYLATION, AND
RP MUTAGENESIS OF ASP-57.
RX PubMed=10426994; DOI=10.1126/science.285.5428.730;
RA Wu J., Song Y., Bakker A.B.H., Bauer S., Spies T., Lanier L.L.,
RA Phillips J.H.;
RT "An activating immunoreceptor complex formed by NKG2D and DAP10.";
RL Science 285:730-732(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
RX PubMed=11398969; DOI=10.1007/s002510100321;
RA Yim D., Jie H.-B., Sotiriadis J., Kim Y.-S., Kim K.-S., Rothschild M.F.,
RA Lanier L.L., Kim Y.B.;
RT "Molecular cloning and characterization of pig immunoreceptor DAP10 and
RT NKG2D.";
RL Immunogenetics 53:243-249(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Uterus;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung, and Pancreas;
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 [7]
RP FUNCTION, AND INTERACTION WITH KLRK1.
RX PubMed=11015446; DOI=10.1084/jem.192.7.1059;
RA Wu J., Cherwinski H., Spies T., Phillips J.H., Lanier L.L.;
RT "DAP10 and DAP12 form distinct, but functionally cooperative, receptor
RT complexes in natural killer cells.";
RL J. Exp. Med. 192:1059-1068(2000).
RN [8]
RP FUNCTION.
RX PubMed=11777960; DOI=10.4049/jimmunol.168.2.671;
RA Sutherland C.L., Chalupny N.J., Schooley K., VandenBos T., Kubin M.,
RA Cosman D.;
RT "UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D
RT and activate multiple signaling pathways in primary NK cells.";
RL J. Immunol. 168:671-679(2002).
RN [9]
RP FUNCTION.
RX PubMed=12740575; DOI=10.1038/ni929;
RA Billadeau D.D., Upshaw J.L., Schoon R.A., Dick C.J., Leibson P.J.;
RT "NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent
RT regulatory pathway.";
RL Nat. Immunol. 4:557-564(2003).
RN [10]
RP FUNCTION.
RX PubMed=12740576; DOI=10.1038/ni930;
RA Zompi S., Hamerman J.A., Ogasawara K., Schweighoffer E., Tybulewicz V.L.J.,
RA Di Santo J.P., Lanier L.L., Colucci F.;
RT "NKG2D triggers cytotoxicity in mouse NK cells lacking DAP12 or Syk family
RT kinases.";
RL Nat. Immunol. 4:565-572(2003).
RN [11]
RP INTERACTION WITH KLRK1.
RX PubMed=15294961; DOI=10.4049/jimmunol.173.4.2470;
RA Rosen D.B., Araki M., Hamerman J.A., Chen T., Yamamura T., Lanier L.L.;
RT "A Structural basis for the association of DAP12 with mouse, but not human,
RT NKG2D.";
RL J. Immunol. 173:2470-2478(2004).
RN [12]
RP FUNCTION.
RX PubMed=16002667; DOI=10.4049/jimmunol.175.2.720;
RA Wiemann K., Mittruecker H.-W., Feger U., Welte S.A., Yokoyama W.M.,
RA Spies T., Rammensee H.-G., Steinle A.;
RT "Systemic NKG2D down-regulation impairs NK and CD8 T cell responses in
RT vivo.";
RL J. Immunol. 175:720-729(2005).
RN [13]
RP FUNCTION.
RX PubMed=16339517; DOI=10.4049/jimmunol.175.12.7819;
RA Karimi M., Cao T.M., Baker J.A., Verneris M.R., Soares L., Negrin R.S.;
RT "Silencing human NKG2D, DAP10, and DAP12 reduces cytotoxicity of activated
RT CD8+ T cells and NK cells.";
RL J. Immunol. 175:7819-7828(2005).
RN [14]
RP SUBUNIT.
RX PubMed=15894612; DOI=10.1073/pnas.0502439102;
RA Garrity D., Call M.E., Feng J., Wucherpfennig K.W.;
RT "The activating NKG2D receptor assembles in the membrane with two signaling
RT dimers into a hexameric structure.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:7641-7646(2005).
RN [15]
RP INDUCTION.
RX PubMed=16424177; DOI=10.4049/jimmunol.176.3.1490;
RA Burgess S.J., Marusina A.I., Pathmanathan I., Borrego F., Coligan J.E.;
RT "IL-21 down-regulates NKG2D/DAP10 expression on human NK and CD8+ T
RT cells.";
RL J. Immunol. 176:1490-1497(2006).
RN [16]
RP FUNCTION, INTERACTION WITH GRB2-VAV1 AND PIK3R1, PHOSPHORYLATION AT TYR-86,
RP AND MUTAGENESIS OF ASN-88 AND MET-89.
RX PubMed=16582911; DOI=10.1038/ni1325;
RA Upshaw J.L., Arneson L.N., Schoon R.A., Dick C.J., Billadeau D.D.,
RA Leibson P.J.;
RT "NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and
RT phosphatidylinositol-3-kinase in human natural killer cells.";
RL Nat. Immunol. 7:524-532(2006).
RN [17]
RP FUNCTION, AND INDUCTION.
RX PubMed=18097042; DOI=10.4049/jimmunol.180.1.409;
RA Marusina A.I., Burgess S.J., Pathmanathan I., Borrego F., Coligan J.E.;
RT "Regulation of human DAP10 gene expression in NK and T cells by Ap-1
RT transcription factors.";
RL J. Immunol. 180:409-417(2008).
RN [18]
RP INTERACTION WITH CD300H.
RX PubMed=26221034; DOI=10.1074/jbc.m115.643361;
RA Niizuma K., Tahara-Hanaoka S., Noguchi E., Shibuya A.;
RT "Identification and Characterization of CD300H, a New Member of the Human
RT CD300 Immunoreceptor Family.";
RL J. Biol. Chem. 290:22298-22308(2015).
CC -!- FUNCTION: Transmembrane adapter protein which associates with KLRK1 to
CC form an activation receptor KLRK1-HCST in lymphoid and myeloid cells;
CC this receptor plays a major role in triggering cytotoxicity against
CC target cells expressing cell surface ligands such as MHC class I chain-
CC related MICA and MICB, and UL16-binding proteins (ULBPs); these ligands
CC are up-regulated by stress conditions and pathological state such as
CC viral infection and tumor transformation. Functions as docking site for
CC PI3-kinase PIK3R1 and GRB2. Interaction of ULBPs with KLRK1-HCST
CC triggers calcium mobilization and activation of the PIK3R1, MAP2K/ERK,
CC and JAK2/STAT5 signaling pathways. Both PIK3R1 and GRB2 are required
CC for full KLRK1-HCST-mediated activation and ultimate killing of target
CC cells. In NK cells, KLRK1-HCST signaling directly induces cytotoxicity
CC and enhances cytokine production initiated via DAP12/TYROBP-associated
CC receptors. In T-cells, it provides primarily costimulation for TCR-
CC induced signals. KLRK1-HCST receptor plays a role in immune
CC surveillance against tumors and is required for cytolysis of tumors
CC cells; indeed, melanoma cells that do not express KLRK1 ligands escape
CC from immune surveillance mediated by NK cells.
CC {ECO:0000269|PubMed:10426994, ECO:0000269|PubMed:10528161,
CC ECO:0000269|PubMed:11015446, ECO:0000269|PubMed:11777960,
CC ECO:0000269|PubMed:12740575, ECO:0000269|PubMed:12740576,
CC ECO:0000269|PubMed:16002667, ECO:0000269|PubMed:16339517,
CC ECO:0000269|PubMed:16582911, ECO:0000269|PubMed:18097042}.
CC -!- SUBUNIT: Interacts with CLEC5A (By similarity). Forms an
CC CLEC5A/TYROBP/HCST trimolecular complex depending almost solely on
CC TYROBP (By similarity). Homodimer; Disulfide-linked. Heterohexamer
CC composed of four subunits of HCST/DAP10 and two subunits of KLRK1.
CC Interacts (via transmembrane domain) with KLRK1 (via transmembrane
CC domain); the interaction is required for KLRK1 NK cell surface and
CC induces NK cell-mediated cytotoxicity. Interacts with PIK3R1 and GRB2.
CC Interacts with CD300H (PubMed:26221034). {ECO:0000250,
CC ECO:0000269|PubMed:10426994, ECO:0000269|PubMed:10528161,
CC ECO:0000269|PubMed:11015446, ECO:0000269|PubMed:15294961,
CC ECO:0000269|PubMed:15894612, ECO:0000269|PubMed:16582911,
CC ECO:0000269|PubMed:26221034}.
CC -!- INTERACTION:
CC Q9UBK5; P23560-2: BDNF; NbExp=3; IntAct=EBI-2801937, EBI-12275524;
CC Q9UBK5; Q96IW7: SEC22A; NbExp=3; IntAct=EBI-2801937, EBI-8652744;
CC Q9UBK5; O95772: STARD3NL; NbExp=3; IntAct=EBI-2801937, EBI-3916943;
CC Q9UBK5; Q6UX27-3: VSTM1; NbExp=3; IntAct=EBI-2801937, EBI-12190699;
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000269|PubMed:10426994}; Single-
CC pass type I membrane protein {ECO:0000269|PubMed:10426994}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9UBK5-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9UBK5-2; Sequence=VSP_033022;
CC -!- TISSUE SPECIFICITY: Predominantly expressed in hemopoietic cells such
CC as NK cells, subset of T-cells and monocytes. Detected in leukocytes,
CC spleen, and thymus. {ECO:0000269|PubMed:10528161}.
CC -!- INDUCTION: By T-cell receptor (TCR) ligation, which leads to enhanced
CC KLRK1-HCST cell surface expression. Down-regulated by IL21/interleukin-
CC 21 in T-cells and NK cells. {ECO:0000269|PubMed:16424177,
CC ECO:0000269|PubMed:18097042}.
CC -!- PTM: Phosphorylated; PIK3R1 and GRB2 associate specifically with
CC tyrosine-phosphorylated HCST. {ECO:0000269|PubMed:10426994,
CC ECO:0000269|PubMed:10528161, ECO:0000269|PubMed:16582911}.
CC -!- PTM: O-glycosylated. {ECO:0000269|PubMed:10426994}.
CC -!- MISCELLANEOUS: Silencing of HCST suppresses cytolytic activity of T-
CC cells and NK cells.
CC -!- SIMILARITY: Belongs to the DAP10 family. {ECO:0000305}.
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DR EMBL; AF172929; AAD50293.1; -; mRNA.
DR EMBL; AF072844; AAD46986.1; -; mRNA.
DR EMBL; AF072845; AAD46987.1; -; Genomic_DNA.
DR EMBL; AF122904; AAD47911.1; -; mRNA.
DR EMBL; AF285447; AAG29425.1; -; mRNA.
DR EMBL; AY359058; AAQ89417.1; -; mRNA.
DR EMBL; AL050163; CAB43303.2; -; mRNA.
DR EMBL; BC035931; AAH35931.1; -; mRNA.
DR EMBL; BC046348; AAH46348.1; -; mRNA.
DR EMBL; BC065224; AAH65224.1; -; mRNA.
DR CCDS; CCDS32998.1; -. [Q9UBK5-1]
DR CCDS; CCDS46057.1; -. [Q9UBK5-2]
DR PIR; T08788; T08788.
DR RefSeq; NP_001007470.1; NM_001007469.1. [Q9UBK5-2]
DR RefSeq; NP_055081.1; NM_014266.3. [Q9UBK5-1]
DR AlphaFoldDB; Q9UBK5; -.
DR SMR; Q9UBK5; -.
DR BioGRID; 116079; 231.
DR CORUM; Q9UBK5; -.
DR IntAct; Q9UBK5; 8.
DR STRING; 9606.ENSP00000246551; -.
DR iPTMnet; Q9UBK5; -.
DR PhosphoSitePlus; Q9UBK5; -.
DR BioMuta; HCST; -.
DR DMDM; 74734930; -.
DR MassIVE; Q9UBK5; -.
DR PaxDb; Q9UBK5; -.
DR PeptideAtlas; Q9UBK5; -.
DR PRIDE; Q9UBK5; -.
DR ProteomicsDB; 83979; -. [Q9UBK5-1]
DR ProteomicsDB; 83980; -. [Q9UBK5-2]
DR Antibodypedia; 29605; 159 antibodies from 22 providers.
DR DNASU; 10870; -.
DR Ensembl; ENST00000246551.9; ENSP00000246551.3; ENSG00000126264.10. [Q9UBK5-1]
DR Ensembl; ENST00000437550.2; ENSP00000400516.1; ENSG00000126264.10. [Q9UBK5-2]
DR GeneID; 10870; -.
DR KEGG; hsa:10870; -.
DR MANE-Select; ENST00000246551.9; ENSP00000246551.3; NM_014266.4; NP_055081.1.
DR UCSC; uc002ock.2; human. [Q9UBK5-1]
DR CTD; 10870; -.
DR DisGeNET; 10870; -.
DR GeneCards; HCST; -.
DR HGNC; HGNC:16977; HCST.
DR HPA; ENSG00000126264; Group enriched (bone marrow, lymphoid tissue).
DR MIM; 604089; gene.
DR neXtProt; NX_Q9UBK5; -.
DR OpenTargets; ENSG00000126264; -.
DR PharmGKB; PA134956649; -.
DR VEuPathDB; HostDB:ENSG00000126264; -.
DR eggNOG; ENOG502TKP3; Eukaryota.
DR GeneTree; ENSGT00390000012777; -.
DR HOGENOM; CLU_196934_0_0_1; -.
DR InParanoid; Q9UBK5; -.
DR OMA; YINMPAR; -.
DR OrthoDB; 1650742at2759; -.
DR PhylomeDB; Q9UBK5; -.
DR TreeFam; TF338335; -.
DR PathwayCommons; Q9UBK5; -.
DR Reactome; R-HSA-198933; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell.
DR SignaLink; Q9UBK5; -.
DR BioGRID-ORCS; 10870; 11 hits in 1063 CRISPR screens.
DR ChiTaRS; HCST; human.
DR GeneWiki; HCST_(gene); -.
DR GenomeRNAi; 10870; -.
DR Pharos; Q9UBK5; Tbio.
DR PRO; PR:Q9UBK5; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q9UBK5; protein.
DR Bgee; ENSG00000126264; Expressed in granulocyte and 153 other tissues.
DR Genevisible; Q9UBK5; HS.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; IDA:UniProtKB.
DR GO; GO:0005102; F:signaling receptor binding; IPI:UniProtKB.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IGI:CACAO.
DR GO; GO:0050776; P:regulation of immune response; IEA:InterPro.
DR InterPro; IPR009861; HCST.
DR PANTHER; PTHR21409; PTHR21409; 1.
DR Pfam; PF07213; DAP10; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; Disulfide bond; Glycoprotein; Membrane;
KW Phosphoprotein; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..93
FT /note="Hematopoietic cell signal transducer"
FT /id="PRO_0000330287"
FT TOPO_DOM 19..48
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 49..69
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 70..93
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 86..89
FT /note="PIK3R1 binding site"
FT REGION 86..88
FT /note="GRB2 binding site"
FT MOD_RES 86
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:16582911"
FT VAR_SEQ 81
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10426994,
FT ECO:0000303|PubMed:12975309"
FT /id="VSP_033022"
FT MUTAGEN 57
FT /note="D->A: Abolishes stable interaction with KLRK1."
FT /evidence="ECO:0000269|PubMed:10426994"
FT MUTAGEN 88
FT /note="N->Q: Abrogates cell killing and interaction with
FT GRB2. No effect on interaction with PIK3R1."
FT /evidence="ECO:0000269|PubMed:16582911"
FT MUTAGEN 89
FT /note="M->Q: Abrogates cell killing and interaction with
FT PIK3R1. No effect on interaction with GRB2."
FT /evidence="ECO:0000269|PubMed:16582911"
SQ SEQUENCE 93 AA; 9489 MW; 97786F24F8A2EE44 CRC64;
MIHLGHILFL LLLPVAAAQT TPGERSSLPA FYPGTSGSCS GCGSLSLPLL AGLVAADAVA
SLLIVGAVFL CARPRRSPAQ EDGKVYINMP GRG
