HCST

Summary

HCST (hematopoietic cell signal transducer, HGNC:16977) is a protein-coding gene on chromosome 19q13.12, encoding Hematopoietic cell signal transducer (Q9UBK5). 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 M….

This gene encodes a transmembrane signaling adaptor that contains a YxxM motif in its cytoplasmic domain. The encoded protein may form part of the immune recognition receptor complex with the C-type lectin-like receptor NKG2D. As part of this receptor complex, this protein may activate phosphatidylinositol 3-kinase dependent signaling pathways through its intracytoplasmic YxxM motif. This receptor complex may have a role in cell survival and proliferation by activation of NK and T cell responses. Alternative splicing results in two transcript variants encoding different isoforms.

Source: NCBI Gene 10870 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 18 total
• MANE Select transcript: NM_014266

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16977
Approved symbol	HCST
Name	hematopoietic cell signal transducer
Location	19q13.12
Locus type	gene with protein product
Status	Approved
Aliases	DAP10, DKFZP586C1522, KAP10
Ensembl gene	ENSG00000126264
Ensembl biotype	protein_coding
OMIM	604089
Entrez	10870

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000246551, ENST00000437550, ENST00000864003, ENST00000864004, ENST00000930206

RefSeq mRNA: 2 — MANE Select: NM_014266 NM_001007469, NM_014266

CCDS: CCDS32998, CCDS46057

Canonical transcript exons

ENST00000246551 — 4 exons

Exon	Start	End
ENSE00000699089	35903772	35903903
ENSE00000862898	35902529	35902636
ENSE00000862899	35903351	35903416
ENSE00002856716	35904120	35904377

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 99.50.

FANTOM5 (CAGE): breadth broad, TPM avg 63.7603 / max 2100.7130, expressed in 652 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175437	37.1682	577
175436	18.2977	517
175435	6.4201	414
175434	1.7748	339
175433	0.0994	31

Top tissues by expression

240 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.50	gold quality
leukocyte	CL:0000738	98.44	gold quality
monocyte	CL:0000576	98.38	gold quality
bone marrow	UBERON:0002371	97.05	gold quality
blood	UBERON:0000178	96.90	gold quality
bone marrow cell	CL:0002092	96.84	gold quality
spleen	UBERON:0002106	96.46	gold quality
vermiform appendix	UBERON:0001154	94.61	gold quality
lymph node	UBERON:0000029	92.45	gold quality
thymus	UBERON:0002370	91.74	gold quality
caecum	UBERON:0001153	89.28	gold quality
trabecular bone tissue	UBERON:0002483	89.27	gold quality
right lung	UBERON:0002167	89.22	gold quality
upper lobe of left lung	UBERON:0008952	89.22	gold quality
right coronary artery	UBERON:0001625	89.12	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.31	gold quality
upper lobe of lung	UBERON:0008948	88.09	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.29	gold quality
omental fat pad	UBERON:0010414	86.93	gold quality
peritoneum	UBERON:0002358	86.88	gold quality
adipose tissue of abdominal region	UBERON:0007808	86.21	gold quality
ileal mucosa	UBERON:0000331	86.02	gold quality
spinal cord	UBERON:0002240	85.65	gold quality
left coronary artery	UBERON:0001626	85.09	gold quality
coronary artery	UBERON:0001621	84.85	gold quality
small intestine Peyer’s patch	UBERON:0003454	84.70	gold quality
thoracic aorta	UBERON:0001515	84.41	gold quality
tibial nerve	UBERON:0001323	84.32	gold quality
subcutaneous adipose tissue	UBERON:0002190	84.31	gold quality
ascending aorta	UBERON:0001496	84.26	gold quality

Single-cell (SCXA)

Detected in 32 experiment(s), a significant marker in 28.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	1854.53
E-MTAB-8530	yes	1672.31
E-MTAB-8495	yes	1585.69
E-MTAB-8410	yes	1523.75
E-HCAD-24	yes	1518.09
E-MTAB-9221	yes	1295.95
E-MTAB-8221	yes	1218.31
E-MTAB-10287	yes	945.06
E-HCAD-4	yes	206.18
E-HCAD-1	yes	160.15
E-MTAB-6701	yes	145.86
E-MTAB-10553	yes	71.69
E-CURD-122	yes	70.18
E-MTAB-9467	yes	64.33
E-HCAD-10	yes	60.15

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

1 targeting HCST, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1178-5P	95.83	64.12	504

Literature-anchored findings (GeneRIF, showing 13)

• NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. (PMID:12740575)
• both activated and expanded CD8+ T cells and NK cells use DAP10 for cytolysis (PMID:16339517)
• Downstream targets of DAP10 and DAP12 are constitutively activated in large granular lymphocyte leukemia cells, and expression of dominant-negative DAP10 and DAP12 dramatically reduces their lytic capacity. (PMID:19075187)
• the rapid degradation of NKG2D/DAP10 observed coincident with recruitment of the receptor to the cytotoxic immune synapse may explain the loss of NKG2D receptor expression after chronic exposure to NKG2D ligands (PMID:19329438)
• A transgenic mouse model demonstrates that induction of tolerance in Ly49H-positive natural killer (NK) cells by chronic exposure to virus-encoded ligand m157 requires signaling through the Ly49H adaptor protein DAP12, not the DAP10 adaptor protein. (PMID:21263069)
• HMBOX1 negatively regulates the expression of NKG2D and the activation of the NKG2D/DAP10 signaling pathway in NK cells. (PMID:21706044)
• TGF-BETA1 down-modulates surface NKG2D expression by controlling the transcriptional and translational levels of DAP10. (PMID:21789015)
• Other gamma(c) cytokines act similarly to IL-2 in up-regulating DAP10 expression and NKG2D-DAP10 surface expression. (PMID:21816829)
• TGF-beta1 may reduce the expression of NKG2D/DAP10 and 2B4/SAPin patients with hepatitis B. (PMID:22438812)
• findings indicate that the functional interaction between RAGE and DAP10 coordinately regulates S100A8/A9-mediated survival and/or apoptotic response of keratinocytes (PMID:25002577)
• These results suggest that NKG2D-DAP10 endocytosis represents a means to decrease cell surface receptor abundance, as well as to control signaling outcome in cytotoxic lymphocytes. (PMID:26508790)
• NKG2D-DAP10 signaling recruits EVL to the cytotoxic synapse to generate F-actin and promote NK cell cytotoxicity. (PMID:31235500)
• CSF1R and HCST: Novel Candidate Biomarkers Predicting the Response to Immunotherapy in Non-Small Cell Lung Cancer. (PMID:33153411)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hcst	ENSMUSG00000064109
rattus_norvegicus	Hcst	ENSRNOG00000020849

Protein

Protein identifiers

Hematopoietic cell signal transducer — Q9UBK5 (reviewed: Q9UBK5)

Alternative names: DNAX-activation protein 10, Membrane protein DAP10, Transmembrane adapter protein KAP10

All UniProt accessions (1): Q9UBK5

UniProt curated annotations — full annotation on UniProt →

Function. 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 a 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.

Subunit / interactions. Interacts with CLEC5A. Forms an CLEC5A/TYROBP/HCST trimolecular complex depending almost solely on TYROBP. 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. Interacts with CD300H.

Subcellular location. Membrane.

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

Post-translational modifications. Phosphorylated; PIK3R1 and GRB2 associate specifically with tyrosine-phosphorylated HCST. O-glycosylated.

Induction. 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.

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

Similarity. Belongs to the DAP10 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UBK5-1	1	yes
Q9UBK5-2	2

RefSeq proteins (2): NP_001007470, NP_055081* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009861	HCST	Family

Pfam: PF07213

UniProt features (12 total): mutagenesis site 3, topological domain 2, region of interest 2, signal peptide 1, chain 1, transmembrane region 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBK5-F1	66.95	0.07

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 86

Mutagenesis-validated functional residues (3):

Position	Phenotype
88	abrogates cell killing and interaction with grb2. no effect on interaction with pik3r1.
89	abrogates cell killing and interaction with pik3r1. no effect on interaction with grb2.
57	abolishes stable interaction with klrk1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell

MSigDB gene sets: 161 (showing top): CREL_01, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOCC_CELL_SURFACE, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, GOBP_PHOSPHATIDYLINOSITOL_3_KINASE_PROTEIN_KINASE_B_SIGNAL_TRANSDUCTION, ZIC1_01, GOBP_NATURAL_KILLER_CELL_MEDIATED_IMMUNITY, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, ATF4_Q2, GOBP_POSITIVE_REGULATION_OF_PHOSPHATIDYLINOSITOL_3_KINASE_PROTEIN_KINASE_B_SIGNAL_TRANSDUCTION

GO Biological Process (4): protein phosphorylation (GO:0006468), natural killer cell mediated cytotoxicity (GO:0042267), regulation of immune response (GO:0050776), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897)

GO Molecular Function (4): signaling receptor binding (GO:0005102), protein-macromolecule adaptor activity (GO:0030674), phosphatidylinositol 3-kinase binding (GO:0043548), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
cellular anatomical structure	2
phosphorylation	1
protein modification process	1
leukocyte mediated cytotoxicity	1
natural killer cell mediated immunity	1
regulation of immune system process	1
immune response	1
regulation of response to stimulus	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
molecular adaptor activity	1
binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1276 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HCST	KLRK1	P26718	999
HCST	TYROBP	O43914	978
HCST	GRB2	P29354	953
HCST	VAV1	P15498	947
HCST	SYK	P43405	933
HCST	MICB	P79525	930
HCST	CD247	P20963	918
HCST	FCER1G	P30273	881
HCST	CLEC5A	Q9NY25	875
HCST	ULBP1	Q9BZM6	864
HCST	ULBP2	Q9BZM5	862
HCST	NCR1	O76036	857
HCST	ULBP3	Q9BZM4	857
HCST	NCR2	O95944	852
HCST	CD300LB	A8K4G0	795
HCST	FCGR3A	P08637	795

IntAct

19 interactions, top by confidence:

A	B	Type	Score
VSTM1	HCST	psi-mi:“MI:0915”(physical association)	0.560
STARD3NL	HCST	psi-mi:“MI:0915”(physical association)	0.560
SEC22A	HCST	psi-mi:“MI:0915”(physical association)	0.560
HCST	BDNF	psi-mi:“MI:0915”(physical association)	0.560
HCST	KLRK1	psi-mi:“MI:0915”(physical association)	0.400
FCN1	HCST	psi-mi:“MI:0915”(physical association)	0.370
CD300H	TYROBP	psi-mi:“MI:0914”(association)	0.350
HCST	TMEM120B	psi-mi:“MI:0914”(association)	0.350
HCST	B3GAT3	psi-mi:“MI:0914”(association)	0.350
STARD3NL	HCST	psi-mi:“MI:0915”(physical association)	0.000
SEC22A	HCST	psi-mi:“MI:0915”(physical association)	0.000
HCST	katG	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (202): HCST (Two-hybrid), HCST (Two-hybrid), VSTM1 (Two-hybrid), HCST (Affinity Capture-RNA), ATP7A (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP1A3 (Affinity Capture-MS), CDS1 (Affinity Capture-MS), ADCK1 (Affinity Capture-MS), XPO6 (Affinity Capture-MS), TUBGCP4 (Affinity Capture-MS), TMEM120A (Affinity Capture-MS), ZDHHC17 (Affinity Capture-MS), KIAA0368 (Affinity Capture-MS), LARS2 (Affinity Capture-MS)

ESM2 similar proteins: A4F4L0, O00453, O14669, O43914, O54885, P04234, P04235, P07766, P0CAN6, P18438, P19377, P20963, P24161, P29328, P29329, P59646, Q13113, Q28072, Q28073, Q2KIP5, Q3TYX2, Q5R1Q1, Q5RA41, Q63113, Q64159, Q6AYD4, Q6ITQ4, Q6X9T7, Q764N2, Q8K1T1, Q8MII8, Q8N386, Q8NET5, Q8R182, Q8WNQ8, Q923S2, Q925F2, Q95J79, Q95LI5, Q95LI8

Diamond homologs: Q1XF11, Q6X9T8, Q70RD5, Q8WNQ9, Q9GJR5, Q9QUJ0, Q9UBK5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

18 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	9
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

571 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:35903826:C:A	A55D	0.968
19:35903834:G:C	A58P	0.950
19:35903853:T:A	I64N	0.950
19:35903835:C:A	A58E	0.946
19:35903829:C:A	A56D	0.944
19:35904142:C:A	N88K	0.944
19:35904142:C:G	N88K	0.944
19:35903816:G:C	G52R	0.935
19:35903858:G:A	G66R	0.935
19:35903858:G:C	G66R	0.935
19:35903850:T:A	L63H	0.928
19:35903820:T:A	L53H	0.925
19:35903831:G:C	D57H	0.920
19:35903850:T:G	L63R	0.920
19:35903847:T:G	L62R	0.919
19:35903817:G:A	G52D	0.903
19:35903844:C:G	S61W	0.902
19:35903828:G:C	A56P	0.901
19:35903831:G:T	D57Y	0.901
19:35903832:A:T	D57V	0.901
19:35903856:T:A	V65E	0.899
19:35903865:T:A	V68E	0.899
19:35903859:G:A	G66E	0.898
19:35904134:T:C	Y86H	0.897
19:35903832:A:C	D57A	0.891
19:35903838:T:A	V59E	0.890
19:35903847:T:A	L62Q	0.885
19:35904134:T:G	Y86D	0.885
19:35904141:A:T	N88I	0.881
19:35903825:G:C	A55P	0.866

dbSNP variants (sampled 300 via entrez): RS1000396552 (19:35903100 C>A,T), RS1000968616 (19:35901240 C>A,T), RS1001008950 (19:35900813 C>T), RS1001097633 (19:35900676 A>G), RS1003142437 (19:35903233 T>G), RS1004920442 (19:35900712 A>C), RS1005361110 (19:35900947 C>T), RS1005902803 (19:35903923 G>A), RS1007993023 (19:35902356 C>A,T), RS1009339097 (19:35904292 A>G), RS1009368496 (19:35904600 T>C), RS1010102924 (19:35900744 G>A), RS1011622197 (19:35904044 C>A,T), RS1011687865 (19:35902996 GT>G), RS1012631536 (19:35903136 G>A)

Disease associations

OMIM: gene MIM:604089 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Nickel	increases expression	2
Cyclosporine	increases expression	2
propionaldehyde	increases expression	1
butyraldehyde	increases expression	1
CGP 52608	affects binding, increases reaction	1
fenpyroximate	increases expression	1
pyrimidifen	increases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, decreases expression	1
(+)-JQ1 compound	decreases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Vehicle Emissions	decreases expression, decreases reaction	1
Benzo(a)pyrene	increases expression	1
Diethylhexyl Phthalate	increases expression	1
Diuron	decreases expression	1
Menthol	decreases expression	1
Rotenone	increases expression	1
Dronabinol	decreases expression	1
Tretinoin	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Okadaic Acid	increases expression	1
Genistein	decreases expression	1
Particulate Matter	decreases expression, decreases reaction	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.