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Protein

Hematopoietic cell signal transducer

Gene

HCST

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Transmembrane adapter protein which associates with KLRK1 to form an activation receptor KLRK1-HCST in lymphoid and myeloid cells; this receptor plays a major role in triggering cytotoxicity against target cells expressing cell surface ligands such as MHC class I chain-related MICA and MICB, and UL16-binding proteins (ULBPs); these ligands are up-regulated by stress conditions and pathological state such as viral infection and tumor transformation. Functions as docking site for PI3-kinase PIK3R1 and GRB2. Interaction of ULBPs with KLRK1-HCST triggers calcium mobilization and activation of the PIK3R1, MAP2K/ERK, and JAK2/STAT5 signaling pathways. Both PIK3R1 and GRB2 are required for full KLRK1-HCST-mediated activation and ultimate killing of target cells. In NK cells, KLRK1-HCST signaling directly induces cytotoxicity and enhances cytokine production initiated via DAP12/TYROBP-associated receptors. In T-cells, it provides primarily costimulation for TCR-induced signals. KLRK1-HCST receptor plays a role in immune surveillance against tumors and is required for cytolysis of tumors cells; indeed, melanoma cells that do not express KLRK1 ligands escape from immune surveillance mediated by NK cells.10 Publications

GO - Molecular functioni

  • phosphatidylinositol 3-kinase binding Source: UniProtKB
  • receptor binding Source: UniProtKB

GO - Biological processi

  • positive regulation of phosphatidylinositol 3-kinase signaling Source: UniProtKB
  • protein phosphorylation Source: CACAO
  • regulation of immune response Source: Reactome
Complete GO annotation...

Enzyme and pathway databases

ReactomeiR-HSA-198933. Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell.

Names & Taxonomyi

Protein namesi
Recommended name:
Hematopoietic cell signal transducer
Alternative name(s):
DNAX-activation protein 10
Membrane protein DAP10
Transmembrane adapter protein KAP10
Gene namesi
Name:HCST
Synonyms:DAP10, KAP10, PIK3AP
ORF Names:UNQ587/PRO1157
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:16977. HCST.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini19 – 4830ExtracellularSequence analysisAdd
BLAST
Transmembranei49 – 6921HelicalSequence analysisAdd
BLAST
Topological domaini70 – 9324CytoplasmicSequence analysisAdd
BLAST

GO - Cellular componenti

  • cell surface Source: UniProtKB
  • integral component of membrane Source: UniProtKB-KW
  • plasma membrane Source: Reactome
Complete GO annotation...

Keywords - Cellular componenti

Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi57 – 571D → A: Abolishes stable interaction with KLRK1. 1 Publication
Mutagenesisi88 – 881N → Q: Abrogates cell killing and interaction with GRB2. No effect on interaction with PIK3R1. 1 Publication
Mutagenesisi89 – 891M → Q: Abrogates cell killing and interaction with PIK3R1. No effect on interaction with GRB2. 1 Publication

Organism-specific databases

PharmGKBiPA134956649.

Polymorphism and mutation databases

BioMutaiHCST.
DMDMi74734930.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 1818Sequence analysisAdd
BLAST
Chaini19 – 9375Hematopoietic cell signal transducerPRO_0000330287Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei86 – 861Phosphotyrosine1 Publication

Post-translational modificationi

Phosphorylated; PIK3R1 and GRB2 associate specifically with tyrosine-phosphorylated HCST.3 Publications
O-glycosylated.1 Publication

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiQ9UBK5.
PRIDEiQ9UBK5.

PTM databases

iPTMnetiQ9UBK5.

Expressioni

Tissue specificityi

Predominantly expressed in hemopoietic cells such as NK cells, subset of T-cells and monocytes. Detected in leukocytes, spleen, and thymus.1 Publication

Inductioni

By T-cell receptor (TCR) ligation, which leads to enhanced KLRK1-HCST cell surface expression. Down-regulated by IL21/interleukin-21 in T-cells and NK cells.2 Publications

Gene expression databases

BgeeiQ9UBK5.
CleanExiHS_HCST.
GenevisibleiQ9UBK5. HS.

Organism-specific databases

HPAiCAB034435.

Interactioni

Subunit structurei

Interacts with CLEC5A (By similarity). Forms an CLEC5A/TYROBP/HCST trimolecular complex depending almost solely on TYROBP (By similarity). Homodimer; Disulfide-linked. Heterohexamer composed of four subunits of HCST/DAP10 and two subunits of KLRK1. Interacts (via transmembrane domain) with KLRK1 (via transmembrane domain); the interaction is required for KLRK1 NK cell surface and induces NK cell-mediated cytotoxicity. Interacts with PIK3R1 and GRB2.By similarity6 Publications

GO - Molecular functioni

  • phosphatidylinositol 3-kinase binding Source: UniProtKB
  • receptor binding Source: UniProtKB

Protein-protein interaction databases

BioGridi116079. 3 interactions.
IntActiQ9UBK5. 2 interactions.
STRINGi9606.ENSP00000246551.

Structurei

3D structure databases

ProteinModelPortaliQ9UBK5.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni86 – 894PIK3R1 binding site
Regioni86 – 883GRB2 binding site

Sequence similaritiesi

Belongs to the DAP10 family.Curated

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410J782. Eukaryota.
ENOG4111C1J. LUCA.
GeneTreeiENSGT00390000012777.
HOGENOMiHOG000112856.
HOVERGENiHBG106666.
InParanoidiQ9UBK5.
KOiK07988.
OMAiHPGHILF.
OrthoDBiEOG7PP5B3.
PhylomeDBiQ9UBK5.
TreeFamiTF338335.

Family and domain databases

InterProiIPR009861. HCST.
[Graphical view]
PANTHERiPTHR21409. PTHR21409. 1 hit.
PfamiPF07213. DAP10. 2 hits.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9UBK5-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MIHLGHILFL LLLPVAAAQT TPGERSSLPA FYPGTSGSCS GCGSLSLPLL
60 70 80 90
AGLVAADAVA SLLIVGAVFL CARPRRSPAQ EDGKVYINMP GRG
Length:93
Mass (Da):9,489
Last modified:May 1, 2000 - v1
Checksum:i97786F24F8A2EE44
GO
Isoform 2 (identifier: Q9UBK5-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     81-81: Missing.

Show »
Length:92
Mass (Da):9,360
Checksum:i5D257437153A4FB4
GO

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei81 – 811Missing in isoform 2. 2 PublicationsVSP_033022

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF172929 mRNA. Translation: AAD50293.1.
AF072844 mRNA. Translation: AAD46986.1.
AF072845 Genomic DNA. Translation: AAD46987.1.
AF122904 mRNA. Translation: AAD47911.1.
AF285447 mRNA. Translation: AAG29425.1.
AY359058 mRNA. Translation: AAQ89417.1.
AL050163 mRNA. Translation: CAB43303.2.
BC035931 mRNA. Translation: AAH35931.1.
BC046348 mRNA. Translation: AAH46348.1.
BC065224 mRNA. Translation: AAH65224.1.
CCDSiCCDS32998.1. [Q9UBK5-1]
CCDS46057.1. [Q9UBK5-2]
PIRiT08788.
RefSeqiNP_001007470.1. NM_001007469.1. [Q9UBK5-2]
NP_055081.1. NM_014266.3. [Q9UBK5-1]
UniGeneiHs.117339.

Genome annotation databases

EnsembliENST00000246551; ENSP00000246551; ENSG00000126264. [Q9UBK5-1]
ENST00000437550; ENSP00000400516; ENSG00000126264. [Q9UBK5-2]
GeneIDi10870.
KEGGihsa:10870.
UCSCiuc002ock.2. human. [Q9UBK5-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF172929 mRNA. Translation: AAD50293.1.
AF072844 mRNA. Translation: AAD46986.1.
AF072845 Genomic DNA. Translation: AAD46987.1.
AF122904 mRNA. Translation: AAD47911.1.
AF285447 mRNA. Translation: AAG29425.1.
AY359058 mRNA. Translation: AAQ89417.1.
AL050163 mRNA. Translation: CAB43303.2.
BC035931 mRNA. Translation: AAH35931.1.
BC046348 mRNA. Translation: AAH46348.1.
BC065224 mRNA. Translation: AAH65224.1.
CCDSiCCDS32998.1. [Q9UBK5-1]
CCDS46057.1. [Q9UBK5-2]
PIRiT08788.
RefSeqiNP_001007470.1. NM_001007469.1. [Q9UBK5-2]
NP_055081.1. NM_014266.3. [Q9UBK5-1]
UniGeneiHs.117339.

3D structure databases

ProteinModelPortaliQ9UBK5.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi116079. 3 interactions.
IntActiQ9UBK5. 2 interactions.
STRINGi9606.ENSP00000246551.

PTM databases

iPTMnetiQ9UBK5.

Polymorphism and mutation databases

BioMutaiHCST.
DMDMi74734930.

Proteomic databases

PaxDbiQ9UBK5.
PRIDEiQ9UBK5.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000246551; ENSP00000246551; ENSG00000126264. [Q9UBK5-1]
ENST00000437550; ENSP00000400516; ENSG00000126264. [Q9UBK5-2]
GeneIDi10870.
KEGGihsa:10870.
UCSCiuc002ock.2. human. [Q9UBK5-1]

Organism-specific databases

CTDi10870.
GeneCardsiHCST.
HGNCiHGNC:16977. HCST.
HPAiCAB034435.
MIMi604089. gene.
neXtProtiNX_Q9UBK5.
PharmGKBiPA134956649.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410J782. Eukaryota.
ENOG4111C1J. LUCA.
GeneTreeiENSGT00390000012777.
HOGENOMiHOG000112856.
HOVERGENiHBG106666.
InParanoidiQ9UBK5.
KOiK07988.
OMAiHPGHILF.
OrthoDBiEOG7PP5B3.
PhylomeDBiQ9UBK5.
TreeFamiTF338335.

Enzyme and pathway databases

ReactomeiR-HSA-198933. Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell.

Miscellaneous databases

ChiTaRSiHCST. human.
GeneWikiiHCST_(gene).
GenomeRNAii10870.
PROiQ9UBK5.
SOURCEiSearch...

Gene expression databases

BgeeiQ9UBK5.
CleanExiHS_HCST.
GenevisibleiQ9UBK5. HS.

Family and domain databases

InterProiIPR009861. HCST.
[Graphical view]
PANTHERiPTHR21409. PTHR21409. 1 hit.
PfamiPF07213. DAP10. 2 hits.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "KAP10, a novel transmembrane adapter protein genetically linked to DAP12 but with unique signaling properties."
    Chang C., Dietrich J., Harpur A.G., Lindquist J.A., Haude A., Loke Y.W., King A., Colonna M., Trowsdale J., Wilson M.J.
    J. Immunol. 163:4651-4654(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, INTERACTION WITH PIK3R1 AND GRB2, PHOSPHORYLATION.
  2. "An activating immunoreceptor complex formed by NKG2D and DAP10."
    Wu J., Song Y., Bakker A.B.H., Bauer S., Spies T., Lanier L.L., Phillips J.H.
    Science 285:730-732(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, INTERACTION WITH KLRK1 AND PIK3R1, GLYCOSYLATION, SUBCELLULAR LOCATION, PHOSPHORYLATION, MUTAGENESIS OF ASP-57.
  3. "Molecular cloning and characterization of pig immunoreceptor DAP10 and NKG2D."
    Yim D., Jie H.-B., Sotiriadis J., Kim Y.-S., Kim K.-S., Rothschild M.F., Lanier L.L., Kim Y.B.
    Immunogenetics 53:243-249(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
  4. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
  5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Tissue: Uterus.
  6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Tissue: Lung and Pancreas.
  7. "DAP10 and DAP12 form distinct, but functionally cooperative, receptor complexes in natural killer cells."
    Wu J., Cherwinski H., Spies T., Phillips J.H., Lanier L.L.
    J. Exp. Med. 192:1059-1068(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH KLRK1.
  8. "UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells."
    Sutherland C.L., Chalupny N.J., Schooley K., VandenBos T., Kubin M., Cosman D.
    J. Immunol. 168:671-679(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  9. "NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway."
    Billadeau D.D., Upshaw J.L., Schoon R.A., Dick C.J., Leibson P.J.
    Nat. Immunol. 4:557-564(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  10. "NKG2D triggers cytotoxicity in mouse NK cells lacking DAP12 or Syk family kinases."
    Zompi S., Hamerman J.A., Ogasawara K., Schweighoffer E., Tybulewicz V.L.J., Di Santo J.P., Lanier L.L., Colucci F.
    Nat. Immunol. 4:565-572(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  11. "A Structural basis for the association of DAP12 with mouse, but not human, NKG2D."
    Rosen D.B., Araki M., Hamerman J.A., Chen T., Yamamura T., Lanier L.L.
    J. Immunol. 173:2470-2478(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH KLRK1.
  12. "Systemic NKG2D down-regulation impairs NK and CD8 T cell responses in vivo."
    Wiemann K., Mittruecker H.-W., Feger U., Welte S.A., Yokoyama W.M., Spies T., Rammensee H.-G., Steinle A.
    J. Immunol. 175:720-729(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  13. "Silencing human NKG2D, DAP10, and DAP12 reduces cytotoxicity of activated CD8+ T cells and NK cells."
    Karimi M., Cao T.M., Baker J.A., Verneris M.R., Soares L., Negrin R.S.
    J. Immunol. 175:7819-7828(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  14. "The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure."
    Garrity D., Call M.E., Feng J., Wucherpfennig K.W.
    Proc. Natl. Acad. Sci. U.S.A. 102:7641-7646(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBUNIT.
  15. "IL-21 down-regulates NKG2D/DAP10 expression on human NK and CD8+ T cells."
    Burgess S.J., Marusina A.I., Pathmanathan I., Borrego F., Coligan J.E.
    J. Immunol. 176:1490-1497(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION.
  16. "NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells."
    Upshaw J.L., Arneson L.N., Schoon R.A., Dick C.J., Billadeau D.D., Leibson P.J.
    Nat. Immunol. 7:524-532(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH GRB2-VAV1 AND PIK3R1, PHOSPHORYLATION AT TYR-86, MUTAGENESIS OF ASN-88 AND MET-89.
  17. "Regulation of human DAP10 gene expression in NK and T cells by Ap-1 transcription factors."
    Marusina A.I., Burgess S.J., Pathmanathan I., Borrego F., Coligan J.E.
    J. Immunol. 180:409-417(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INDUCTION.

Entry informationi

Entry nameiHCST_HUMAN
AccessioniPrimary (citable) accession number: Q9UBK5
Secondary accession number(s): Q9UBS1, Q9Y3Y0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 29, 2008
Last sequence update: May 1, 2000
Last modified: June 8, 2016
This is version 111 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Miscellaneous

Silencing of HCST suppresses cytolytic activity of T-cells and NK cells.

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.