Q9UBK5 (HCST_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Hematopoietic cell signal transducer

Alternative name(s):
DNAX-activation protein 10
Membrane protein DAP10
Transmembrane adapter protein KAP10

Gene names

Name:	HCST
Synonyms:	DAP10, KAP10, PIK3AP
ORF Names:	UNQ587/PRO1157

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	93 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Transmembrane adapter protein which associates with NKG2D to form an activation receptor NKG2D-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 NKG2D-DAP10 triggers calcium mobilization and activation of the PIK3R1, MAP2K/ERK, and JAK2/STAT5 signaling pathways. Both PIK3R1 and GRB2 are required for full NKG2D-HCST-mediated activation and ultimate killing of target cells. In NK cells, NKG2D-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. NKG2D-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 NKG2D ligands escape from immune surveillance mediated by NK cells. Ref.1 Ref.2 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.14 Ref.15
Subunit structure	Interacts with CLEC5A By similarity. Forms an CLEC5A/TYROBP/HCST trimolecular complex depending almost solely on TYROBP By similarity. Homodimer; Disulfide-linked. Interacts with NKG2D to form a stable complex, which results in surface expression of both proteins, whereas alone, it is minimally expressed. Interacts with PIK3R1 and GRB2. Ref.1 Ref.2 Ref.14
Subcellular location	Membrane; Single-pass type I membrane protein Ref.2.
Tissue specificity	Predominantly expressed in hemopoietic cells such as NK cells, subset of T-cells and monocytes. Detected in leukocytes, spleen, and thymus. Ref.1
Induction	By T-cell receptor (TCR) ligation, which leads to enhanced NKG2D-HCST cell surface expression. Down-regulated by IL21/interleukin-21 in T-cells and NK cells. Ref.13 Ref.15
Post-translational modification	Phosphorylated; PIK3R1 and GRB2 associate specifically with tyrosine-phosphorylated HCST. Ref.1 Ref.2 Ref.14 O-glycosylated. Ref.2
Miscellaneous	Silencing of HCST suppresses cytolytic activity of T-cells and NK cells.
Sequence similarities	Belongs to the DAP10 family.

Ontologies

Keywords
Cellular component	Membrane
Coding sequence diversity	Alternative splicing
Domain	Signal Transmembrane Transmembrane helix
PTM	Disulfide bond Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	positive regulation of phosphatidylinositol 3-kinase cascade Inferred from direct assay Ref.2. Source: UniProtKB regulation of immune response Traceable author statement. Source: Reactome
Cellular_component	cell surface Inferred from direct assay Ref.2. Source: UniProtKB integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW plasma membrane Traceable author statement. Source: Reactome
Molecular_function	phosphatidylinositol 3-kinase binding Inferred from direct assay Ref.2. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q9UBK5-1)

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.

Isoform 2 (identifier: Q9UBK5-2)

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

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 18	18	Potential
	Chain	19 – 93	75	Hematopoietic cell signal transducer		PRO_0000330287
Regions
	Topological domain	19 – 48	30	Extracellular Potential
	Transmembrane	49 – 69	21	Helical; Potential
	Topological domain	70 – 93	24	Cytoplasmic Potential
	Region	86 – 89	4	PIK3R1 binding site
	Region	86 – 88	3	GRB2 binding site
Amino acid modifications
	Modified residue	86	1	Phosphotyrosine Ref.14
Natural variations
	Alternative sequence	81	1	Missing in isoform 2.		VSP_033022
Experimental info
	Mutagenesis	57	1	D → A: Abolishes stable interaction with NKG2D. Ref.2
	Mutagenesis	88	1	N → Q: Abrogates cell killing and interaction with GRB2. No effect on interaction with PIK3R1. Ref.14
	Mutagenesis	89	1	M → Q: Abrogates cell killing and interaction with PIK3R1. No effect on interaction with GRB2. Ref.14

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 1, 2000. Version 1. Checksum: 97786F24F8A2EE44	FASTA	93	9,489
	10 20 30 40 50 60 MIHLGHILFL LLLPVAAAQT TPGERSSLPA FYPGTSGSCS GCGSLSLPLL AGLVAADAVA 70 80 90 SLLIVGAVFL CARPRRSPAQ EDGKVYINMP GRG
	Isoform 2 [UniParc]. Checksum: 5D257437153A4FB4	FASTA	92	9,360
	10 20 30 40 50 60 MIHLGHILFL LLLPVAAAQT TPGERSSLPA FYPGTSGSCS GCGSLSLPLL AGLVAADAVA 70 80 90 SLLIVGAVFL CARPRRSPAQ DGKVYINMPG RG

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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 NKG2D 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]	"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment." Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E. , Heldens S., Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M. Genome Res. 13:2265-2270(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
[5]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract] 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.
[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]	"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.
[12]	"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.
[13]	"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.
[14]	"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.
[15]	"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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	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.
IPI	IPI00464987. IPI00514454.
PIR	T08788.
RefSeq	NP_001007470.1. NM_001007469.1. NP_055081.1. NM_014266.3.
UniGene	Hs.117339.
3D structure databases
ProteinModelPortal	Q9UBK5.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9UBK5. 2 interactions.
STRING	9606.ENSP00000246551.
Polymorphism databases
DMDM	74734930.
Proteomic databases
PaxDb	Q9UBK5.
PRIDE	Q9UBK5.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000246551; ENSP00000246551; ENSG00000126264. ENST00000437550; ENSP00000400516; ENSG00000126264.
GeneID	10870.
KEGG	hsa:10870.
UCSC	uc002ock.1. human. uc002ocl.1. human.
Organism-specific databases
CTD	10870.
GeneCards	GC19P036393.
HGNC	HGNC:16977. HCST.
HPA	CAB034435.
MIM	604089. gene.
neXtProt	NX_Q9UBK5.
PharmGKB	PA134956649.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG42800.
HOGENOM	HOG000112856.
HOVERGEN	HBG106666.
InParanoid	Q9UBK5.
KO	K07988.
OMA	HPGHILF.
OrthoDB	EOG4W9J5P.
Enzyme and pathway databases
Reactome	REACT_6900. Immune System.
Gene expression databases
Bgee	Q9UBK5.
CleanEx	HS_HCST.
Genevestigator	Q9UBK5.
Family and domain databases
InterPro	IPR009861. DAP10. [Graphical view]
PANTHER	PTHR21409. PTHR21409. 1 hit.
Pfam	PF07213. DAP10. 2 hits. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	HCST. human.
GenomeRNAi	10870.
NextBio	41275.
SOURCE	Search...

Entry information

Entry name

HCST_HUMAN

Accession

Primary (citable) accession number: Q9UBK5
Secondary accession number(s): Q9UBS1, Q9Y3Y0

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 29, 2008
Last sequence update:	May 1, 2000
Last modified:	May 1, 2013
This is version 88 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.