HCST_MOUSE
ID HCST_MOUSE Reviewed; 79 AA.
AC Q9QUJ0; Q9R1E7;
DT 29-APR-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 131.
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;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, PHOSPHORYLATION, AND
RP INTERACTION WITH PIK3R1 AND GRB2.
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).
RC STRAIN=C57BL/6J;
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] (ISOFORM 1).
RX PubMed=11491539; DOI=10.1007/s002510100333;
RA Wilson M.J., Haude A., Trowsdale J.;
RT "The mouse Dap10 gene.";
RL Immunogenetics 53:347-350(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=C57BL/6J; TISSUE=Small intestine;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 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 [6]
RP FUNCTION, AND INTERACTION WITH KLRK1.
RX PubMed=12426565; DOI=10.1038/ni858;
RA Diefenbach A., Tomasello E., Lucas M., Jamieson A.M., Hsia J.K., Vivier E.,
RA Raulet D.H.;
RT "Selective associations with signaling proteins determine stimulatory
RT versus costimulatory activity of NKG2D.";
RL Nat. Immunol. 3:1142-1149(2002).
RN [7]
RP DISRUPTION PHENOTYPE.
RX PubMed=12426564; DOI=10.1038/ni857;
RA Gilfillan S., Ho E.L., Cella M., Yokoyama W.M., Colonna M.;
RT "NKG2D recruits two distinct adapters to trigger NK cell activation and
RT costimulation.";
RL Nat. Immunol. 3:1150-1155(2002).
RN [8]
RP FUNCTION.
RX PubMed=15365099; DOI=10.1084/jem.20031847;
RA Cella M., Fujikawa K., Tassi I., Kim S., Latinis K., Nishi S., Yokoyama W.,
RA Colonna M., Swat W.;
RT "Differential requirements for Vav proteins in DAP10- and ITAM-mediated NK
RT cell cytotoxicity.";
RL J. Exp. Med. 200:817-823(2004).
RN [9]
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 [10]
RP FUNCTION.
RX PubMed=16086018; DOI=10.1038/ni1236;
RA Ogasawara K., Benjamin J., Takaki R., Phillips J.H., Lanier L.L.;
RT "Function of NKG2D in natural killer cell-mediated rejection of mouse bone
RT marrow grafts.";
RL Nat. Immunol. 6:938-945(2005).
RN [11]
RP FUNCTION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=17100879; DOI=10.1111/j.1600-065x.2006.00456.x;
RA Hyka-Nouspikel N., Phillips J.H.;
RT "Physiological roles of murine DAP10 adapter protein in tumor immunity and
RT autoimmunity.";
RL Immunol. Rev. 214:106-117(2006).
RN [12]
RP FUNCTION, AND INTERACTION WITH GRB2-VAV1.
RX PubMed=16887996; DOI=10.4049/jimmunol.177.4.2349;
RA Graham D.B., Cella M., Giurisato E., Fujikawa K., Miletic A.V.,
RA Kloeppel T., Brim K., Takai T., Shaw A.S., Colonna M., Swat W.;
RT "Vav1 controls DAP10-mediated natural cytotoxicity by regulating actin and
RT microtubule dynamics.";
RL J. Immunol. 177:2349-2355(2006).
RN [13]
RP DISRUPTION PHENOTYPE.
RX PubMed=17785813; DOI=10.4049/jimmunol.179.6.3763;
RA Hyka-Nouspikel N., Lucian L., Murphy E., McClanahan T., Phillips J.H.;
RT "DAP10 deficiency breaks the immune tolerance against transplantable
RT syngeneic melanoma.";
RL J. Immunol. 179:3763-3771(2007).
RN [14]
RP INTERACTION WITH CLEC5A.
RX PubMed=19251634; DOI=10.1073/pnas.0900463106;
RA Inui M., Kikuchi Y., Aoki N., Endo S., Maeda T., Sugahara-Tobinai A.,
RA Fujimura S., Nakamura A., Kumanogoh A., Colonna M., Takai T.;
RT "Signal adaptor DAP10 associates with MDL-1 and triggers osteoclastogenesis
RT in cooperation with DAP12.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:4816-4821(2009).
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:10528161, ECO:0000269|PubMed:12426565,
CC ECO:0000269|PubMed:15365099, ECO:0000269|PubMed:16086018,
CC ECO:0000269|PubMed:16887996, ECO:0000269|PubMed:17100879}.
CC -!- SUBUNIT: Homodimer; Disulfide-linked. Interacts with KLRK1 to form a
CC stable complex, which results in surface expression of both proteins,
CC whereas alone, it is minimally expressed. Interacts with PIK3R1 and
CC GRB2. Interacts with CLEC5A (By similarity). Forms an
CC CLEC5A/TYROBP/HCST trimolecular complex depending almost solely on
CC TYROBP. Heterohexamer composed of four subunits of HCST/DAP10 and two
CC subunits of KLRK1. Interacts (via transmembrane domain) with KLRK1
CC isoform 1 (via transmembrane domain); the interaction is required for
CC KLRK1 cell surface expression on naive NK cells and activated CD8(+) T-
CC cells, but is dispensable on activated TYROBP-expressing NK cells.
CC Interacts (via transmembrane domain) with KLRK1 isoform 2 (via
CC transmembrane domain); the interaction is required for KLRK1 NK cell
CC surface expression and induces NK cell-mediated cytotoxicity. Interacts
CC with CD300H (By similarity). {ECO:0000250,
CC ECO:0000250|UniProtKB:Q9UBK5, ECO:0000269|PubMed:10528161,
CC ECO:0000269|PubMed:12426565, ECO:0000269|PubMed:15294961,
CC ECO:0000269|PubMed:16887996, ECO:0000269|PubMed:19251634}.
CC -!- INTERACTION:
CC Q9QUJ0; Q9R007: Clec5a; NbExp=3; IntAct=EBI-15761243, EBI-15761206;
CC Q9QUJ0; O54885: Tyrobp; NbExp=4; IntAct=EBI-15761243, EBI-15687058;
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000269|PubMed:17100879}; Single-
CC pass type I membrane protein {ECO:0000269|PubMed:17100879}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9QUJ0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9QUJ0-2; Sequence=VSP_033023;
CC -!- PTM: Phosphorylated; PIK3R1 and GRB2 associate specifically with
CC tyrosine-phosphorylated HCST. {ECO:0000269|PubMed:10528161}.
CC -!- PTM: O-glycosylated. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Mice exhibit low expression of KLRK1 in NK cells,
CC but no expression in resting T-cells. KLRK1 expression is not induced
CC upon T-cell activation, while it is up-regulated in activated NK cells;
CC NK cells promote KLRK1-mediated tumor rejection due to substitution of
CC HCST by DAP12/TYROBP. Mice lacking HCST exhibit antitumor phenotype;
CC they show enhanced immunity against melanoma malignancies due to
CC hyperactive functioning of a group of T-cells that share properties of
CC both T-cells and NK cells (NKT cells). NKT cells exhibit increased
CC cytokine production and cytotoxicity, leading to efficient killing of
CC melanoma tumors. Upon activation, T regulatory cells (Tregs) maintain
CC higher levels of IL2 and produced significantly lower amounts of IL10
CC and IFN-gamma cytokines. NKT cells activated by IL2 efficiently lyse
CC B16-melanoma tumors in vitro in an KLRK1-independent way; The
CC hyperactivity of NKT cells in these mice is not related to signaling of
CC KLRK1. {ECO:0000269|PubMed:12426564, ECO:0000269|PubMed:17100879,
CC ECO:0000269|PubMed:17785813}.
CC -!- MISCELLANEOUS: Immune reactivity to healthy cells that express KLRK1
CC ligands can happen under physiological conditions; NK cells are able to
CC reject syngeneic bone marrow grafts when the bone marrow cells
CC expressed sufficient KLRK1 ligand.
CC -!- SIMILARITY: Belongs to the DAP10 family. {ECO:0000305}.
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DR EMBL; AF172930; AAD50294.1; -; mRNA.
DR EMBL; AF072846; AAD46988.1; -; mRNA.
DR EMBL; AF122905; AAD47912.1; -; mRNA.
DR EMBL; AF358138; AAK52752.1; -; Genomic_DNA.
DR EMBL; AK008005; BAB25404.1; -; mRNA.
DR EMBL; BC069220; AAH69220.1; -; mRNA.
DR EMBL; BC145824; AAI45825.1; -; mRNA.
DR EMBL; BC145826; AAI45827.1; -; mRNA.
DR CCDS; CCDS39882.1; -. [Q9QUJ0-1]
DR RefSeq; NP_035957.2; NM_011827.3. [Q9QUJ0-1]
DR AlphaFoldDB; Q9QUJ0; -.
DR SMR; Q9QUJ0; -.
DR BioGRID; 204784; 3.
DR CORUM; Q9QUJ0; -.
DR DIP; DIP-48776N; -.
DR IntAct; Q9QUJ0; 2.
DR STRING; 10090.ENSMUSP00000074573; -.
DR iPTMnet; Q9QUJ0; -.
DR PhosphoSitePlus; Q9QUJ0; -.
DR PaxDb; Q9QUJ0; -.
DR PRIDE; Q9QUJ0; -.
DR ProteomicsDB; 269725; -. [Q9QUJ0-1]
DR ProteomicsDB; 269726; -. [Q9QUJ0-2]
DR Antibodypedia; 29605; 159 antibodies from 22 providers.
DR DNASU; 23900; -.
DR Ensembl; ENSMUST00000075062; ENSMUSP00000074573; ENSMUSG00000064109. [Q9QUJ0-1]
DR Ensembl; ENSMUST00000208740; ENSMUSP00000146793; ENSMUSG00000064109. [Q9QUJ0-2]
DR GeneID; 23900; -.
DR KEGG; mmu:23900; -.
DR UCSC; uc009geg.1; mouse. [Q9QUJ0-1]
DR UCSC; uc009geh.1; mouse. [Q9QUJ0-2]
DR CTD; 10870; -.
DR MGI; MGI:1344360; Hcst.
DR VEuPathDB; HostDB:ENSMUSG00000064109; -.
DR eggNOG; ENOG502TKP3; Eukaryota.
DR GeneTree; ENSGT00390000012777; -.
DR HOGENOM; CLU_196934_0_0_1; -.
DR InParanoid; Q9QUJ0; -.
DR OMA; YINMPAR; -.
DR OrthoDB; 1625802at2759; -.
DR PhylomeDB; Q9QUJ0; -.
DR TreeFam; TF338335; -.
DR Reactome; R-MMU-198933; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell.
DR BioGRID-ORCS; 23900; 1 hit in 70 CRISPR screens.
DR ChiTaRS; Hcst; mouse.
DR PRO; PR:Q9QUJ0; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; Q9QUJ0; protein.
DR Bgee; ENSMUSG00000064109; Expressed in granulocyte and 68 other tissues.
DR Genevisible; Q9QUJ0; MM.
DR GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; ISS:MGI.
DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; ISO:MGI.
DR GO; GO:0005102; F:signaling receptor binding; ISO:MGI.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; ISO:MGI.
DR GO; GO:0050776; P:regulation of immune response; IEA:InterPro.
DR InterPro; IPR009861; HCST.
DR PANTHER; PTHR21409; PTHR21409; 1.
DR Pfam; PF07213; DAP10; 1.
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..17
FT /evidence="ECO:0000255"
FT CHAIN 18..79
FT /note="Hematopoietic cell signal transducer"
FT /id="PRO_0000330290"
FT TOPO_DOM 18..35
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 36..56
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 57..79
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 72..75
FT /note="PIK3R1 binding site"
FT REGION 72..74
FT /note="GRB2 binding site"
FT MOD_RES 72
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q9UBK5"
FT VAR_SEQ 15..22
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10426994,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_033023"
SQ SEQUENCE 79 AA; 8114 MW; B411985277D601E3 CRC64;
MDPPGYLLFL LLLPVAASQT SAGSCSGCGT LSLPLLAGLV AADAVMSLLI VGVVFVCMRP
HGRPAQEDGR VYINMPGRG
