LY6K

Summary

LY6K (lymphocyte antigen 6 family member K, HGNC:24225) is a protein-coding gene on chromosome 8q24.3, encoding Lymphocyte antigen 6K (Q17RY6). Required for sperm migration into the oviduct and male fertility by controlling binding of sperm to zona pellucida.

Predicted to be involved in binding activity of sperm to zona pellucida. Predicted to act upstream of or within flagellated sperm motility. Predicted to be located in cell surface and plasma membrane. Predicted to be active in acrosomal vesicle.

Source: NCBI Gene 54742 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 23 total
• Druggable target: yes
• MANE Select transcript: NM_017527

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24225
Approved symbol	LY6K
Name	lymphocyte antigen 6 family member K
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	HSJ001348, FLJ35226, CT97
Ensembl gene	ENSG00000160886
Ensembl biotype	protein_coding
OMIM	615093
Entrez	54742

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000292430, ENST00000518841, ENST00000519387, ENST00000519390, ENST00000522591

RefSeq mRNA: 3 — MANE Select: NM_017527 NM_001160354, NM_001160355, NM_017527

CCDS: CCDS59114, CCDS6385

Canonical transcript exons

ENST00000292430 — 3 exons

Exon	Start	End
ENSE00001055210	142701600	142701713
ENSE00001390209	142703091	142705127
ENSE00002094746	142700111	142700630

Expression profiles

Bgee: expression breadth ubiquitous, 184 present calls, max score 92.29.

FANTOM5 (CAGE): breadth broad, TPM avg 7.7629 / max 298.5130, expressed in 712 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
91358	4.9603	552
91359	0.9125	190
91361	0.8462	145
91357	0.7030	286
91355	0.2265	91
91360	0.0662	31
91356	0.0482	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	92.29	gold quality
left testis	UBERON:0004533	91.54	gold quality
lower esophagus mucosa	UBERON:0035834	89.95	gold quality
testis	UBERON:0000473	89.52	gold quality
pancreatic ductal cell	CL:0002079	88.81	silver quality
esophagus squamous epithelium	UBERON:0006920	88.17	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.06	gold quality
amniotic fluid	UBERON:0000173	87.39	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	86.77	silver quality
decidua	UBERON:0002450	85.49	gold quality
vastus lateralis	UBERON:0001379	85.40	silver quality
adult organism	UBERON:0007023	85.17	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	84.91	silver quality
biceps brachii	UBERON:0001507	83.19	silver quality
quadriceps femoris	UBERON:0001377	83.17	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.56	gold quality
oral cavity	UBERON:0000167	81.44	gold quality
esophagus mucosa	UBERON:0002469	81.21	gold quality
upper arm skin	UBERON:0004263	80.49	gold quality
buccal mucosa cell	CL:0002336	79.08	gold quality
hindlimb stylopod muscle	UBERON:0004252	78.76	gold quality
skeletal muscle tissue	UBERON:0001134	78.49	gold quality
mammalian vulva	UBERON:0000997	78.20	gold quality
placenta	UBERON:0001987	76.97	gold quality
endothelial cell	CL:0000115	76.45	silver quality
skin of abdomen	UBERON:0001416	76.06	gold quality
seminal vesicle	UBERON:0000998	75.97	gold quality
muscle tissue	UBERON:0002385	75.66	gold quality
mammary gland	UBERON:0001911	74.76	gold quality
thoracic mammary gland	UBERON:0005200	74.72	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	807.53
E-CURD-11	yes	194.16
E-MTAB-6701	yes	79.57
E-ANND-3	no	1.85

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CREB1, FOSL1, JUND

miRNA regulators (miRDB)

28 targeting LY6K, 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-570-3P	99.96	72.41	4910
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-4464	98.95	67.73	820
HSA-MIR-4748	98.95	67.53	810
HSA-MIR-4424	98.91	70.33	1145
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-6715B-3P	98.80	68.07	1204
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-676-5P	98.49	68.87	1492
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-624-3P	98.37	67.06	1067
HSA-MIR-561-5P	98.25	68.13	1365
HSA-MIR-6769A-5P	97.99	64.16	851
HSA-MIR-647	97.73	67.79	927
HSA-MIR-510-5P	97.66	65.82	916
HSA-MIR-6802-3P	97.29	65.42	613
HSA-MIR-3622A-3P	97.06	66.43	1000
HSA-MIR-3622B-3P	96.82	66.36	988
HSA-MIR-4529-5P	96.74	65.77	569
HSA-MIR-8081	96.42	67.75	738

Literature-anchored findings (GeneRIF, showing 14)

• Data show that TTK protein kinase, lymphocyte antigen 6 complex locus K and insulin-like growth factor (IGF)-II mRNA binding protein 3 are tumor-associated antigens recognized by cytotoxic T lymphocytes and HLA-A24-restricted epitope peptides. (PMID:17784873)
• Useful as a tumor biomarker and probably as a target for the development of new molecular therapies for cancer treatment. (PMID:18089789)
• it appears that LY6K is constitutively overexpressed either by copy number changes, or by yet unknown mechanisms in gingivobuccal squamous cell carcinoma (PMID:22072328)
• AP-1 activation has an important role in promoting LY6K gene expression that regulates cell mobility of breast cancer cells (PMID:22988241)
• LY6K overexpression is associated with Breast Cancer Progression, Immune Escape, and Drug Resistance. (PMID:27197181)
• miR-192-5p, induced by LY6K, downregulates ERalpha directly and induced tamoxifen resistance in ERalpha-positive breast cancer cells; re-expression of ERalpha in ERalpha-negative breast cancer cells increased miR-500a-3p expression and directly inhibits LY6K expression (PMID:27304060)
• breast cancer risk and metastasis were significantly associated with not only LY6K expression, but also methylation of CGI shore which induced by SNP242 mutation. (PMID:27494879)
• miR-500a-3p acts as a tumor suppressor in non-small cell lung cancer partially via down-regulation of LY6K expression (PMID:30249107)
• LY6K promotes glioblastoma tumorigenicity via CAV-1-mediated ERK1/2 signaling enhancement. (PMID:32055849)
• LY6K-AS lncRNA is a lung adenocarcinoma prognostic biomarker and regulator of mitotic progression. (PMID:33674747)
• Down-regulation of ZNF252P-AS1 alleviates ovarian cancer progression by binding miR-324-3p to downregulate LY6K. (PMID:34980214)
• Lymphocyte antigen 6K signaling to aurora kinase promotes advancement of the cell cycle and the growth of cancer cells, which is inhibited by LY6K-NSC243928 interaction. (PMID:36805500)
• LY6K depletion modulates TGF-beta and EGF signaling. (PMID:37076981)
• Upregulation of LY6K induced by FTO-mediated demethylation promotes the tumorigenesis and metastasis of oral squamous cell carcinoma via CAV-1-mediated ERK1/2 signaling activation. (PMID:38469708)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ly6k	ENSMUSG00000044678
rattus_norvegicus	Ly6k	ENSRNOG00000025725

Paralogs (1): GML (ENSG00000104499)

Protein

Protein identifiers

Lymphocyte antigen 6K — Q17RY6 (reviewed: Q17RY6)

All UniProt accessions (3): Q17RY6, E5RGJ8, H0YB07

UniProt curated annotations — full annotation on UniProt →

Function. Required for sperm migration into the oviduct and male fertility by controlling binding of sperm to zona pellucida. May play a role in cell growth.

Subunit / interactions. Interacts with TEX101.

Subcellular location. Secreted. Cytoplasm. Cell membrane. Cytoplasmic vesicle. Secretory vesicle. Acrosome. Membrane raft.

Tissue specificity. Specifically expressed in testis (at protein level).

Isoforms (2)

UniProt ID	Names	Canonical?
Q17RY6-1	1	yes
Q17RY6-2	2

RefSeq proteins (3): NP_001153826, NP_001153827, NP_059997* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR035076	Toxin/TOLIP	Domain
IPR045860	Snake_toxin-like_sf	Homologous_superfamily
IPR052874	Sperm-ZP_regulatory	Family

Pfam: PF00087

UniProt features (10 total): splice variant 2, sequence conflict 2, signal peptide 1, chain 1, propeptide 1, domain 1, lipid moiety-binding region 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q17RY6-F1	73.03	0.31

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): 138

Glycosylation sites (1): 20

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-163125	Post-translational modification: synthesis of GPI-anchored proteins
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 73 (showing top): GOBP_SINGLE_FERTILIZATION, GOCC_SECRETORY_GRANULE, GOBP_SPERM_EGG_RECOGNITION, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, GOBP_FERTILIZATION, GOBP_CELL_CELL_RECOGNITION, GOBP_BINDING_OF_SPERM_TO_ZONA_PELLUCIDA, DURCHDEWALD_SKIN_CARCINOGENESIS_DN, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_UP, GOCC_SECRETORY_VESICLE, GAVIN_FOXP3_TARGETS_CLUSTER_P2, GOCC_SIDE_OF_MEMBRANE, GOCC_ACROSOMAL_VESICLE, NIKOLSKY_BREAST_CANCER_8Q23_Q24_AMPLICON, REACTOME_POST_TRANSLATIONAL_PROTEIN_MODIFICATION

GO Biological Process (1): binding of sperm to zona pellucida (GO:0007339)

GO Molecular Function (0):

GO Cellular Component (8): acrosomal vesicle (GO:0001669), extracellular region (GO:0005576), plasma membrane (GO:0005886), membrane raft (GO:0045121), side of membrane (GO:0098552), cytoplasm (GO:0005737), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Post-translational protein modification	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
membrane	2
sperm-egg recognition	1
secretory granule	1
cell periphery	1
membrane microdomain	1
leaflet of membrane bilayer	1
intracellular anatomical structure	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

662 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LY6K	TEX101	Q9BY14	815
LY6K	LYPD2	Q6UXB3	795
LY6K	LY6H	O94772	736
LY6K	LYNX1	P0DP58	736
LY6K	SLURP1	P55000	717
LY6K	DEPDC1	Q5TB30	702
LY6K	NUF2	Q9BZD4	700
LY6K	TTK	P33981	693
LY6K	IGF2BP3	O00425	607
LY6K	LYPD6	Q86Y78	595
LY6K	LYPD4	Q6UWN0	592
LY6K	SPACA4	Q8TDM5	573
LY6K	GPIHBP1	Q8IV16	561
LY6K	LY6L	H3BQJ8	522
LY6K	PSCA	O43653	517

IntAct

5 interactions, top by confidence:

A	B	Type	Score
Npc1	ESYT2	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
MFSD14A	FAM171A2	psi-mi:“MI:0914”(association)	0.350
SLC4A5	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): LY6K (Affinity Capture-MS), LY6K (Positive Genetic), LY6K (Proximity Label-MS), LY6K (Affinity Capture-MS), LY6K (Affinity Capture-MS), LY6K (Affinity Capture-MS)

ESM2 similar proteins: A0JNL5, H2LID1, O55006, O55186, O62680, O77541, O95867, O95868, P05533, P0DP57, P0DP59, P0DP61, P0DPQ9, P13987, P27274, P35459, P35460, P35461, P46657, P51447, P55000, P58019, P81827, P81828, P83121, Q14210, Q17RY6, Q28216, Q28785, Q32PB3, Q5R510, Q63317, Q66H42, Q6MG58, Q6UWN5, Q6UXB3, Q7TQN2, Q80ZQ0, Q8BLC3, Q8N2G4

Diamond homologs: Q17RY6, Q9CWP4, P0DP61

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

453 predictions. Top by Δscore:

Variant	Effect	Δscore
8:142701714:G:GG	donor_gain	0.9900
8:142703111:AT:A	acceptor_gain	0.9900
8:142703112:T:G	acceptor_gain	0.9900
8:142703112:T:TA	acceptor_gain	0.9900
8:142700993:G:GT	donor_gain	0.9800
8:142701009:G:GT	donor_gain	0.9800
8:142701710:GTGA:G	donor_gain	0.9800
8:142701712:GA:G	donor_gain	0.9800
8:142703113:G:A	acceptor_gain	0.9800
8:142700354:A:G	donor_gain	0.9700
8:142703089:A:AG	acceptor_gain	0.9700
8:142703090:G:GG	acceptor_gain	0.9700
8:142703090:GAAAT:G	acceptor_gain	0.9700
8:142700629:GG:G	donor_gain	0.9600
8:142700630:GG:G	donor_gain	0.9600
8:142701706:GGCC:G	donor_gain	0.9600
8:142701707:GCC:G	donor_gain	0.9600
8:142701707:GCCG:G	donor_gain	0.9600
8:142703090:GAA:G	acceptor_gain	0.9600
8:142703111:ATG:A	acceptor_gain	0.9600
8:142700346:GCCC:G	donor_gain	0.9500
8:142700628:CGGG:C	donor_loss	0.9500
8:142700629:GGGT:G	donor_loss	0.9500
8:142700631:G:GA	donor_loss	0.9500
8:142700632:T:A	donor_loss	0.9500
8:142700720:GGCC:G	donor_gain	0.9500
8:142700721:GCCG:G	donor_gain	0.9500
8:142700760:G:GT	donor_gain	0.9400
8:142700633:GA:G	donor_loss	0.9300
8:142701670:G:GT	donor_gain	0.9300

AlphaMissense

1068 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:142703122:G:C	K83N	0.992
8:142703122:G:T	K83N	0.992
8:142701623:T:A	C43S	0.989
8:142701624:G:C	C43S	0.989
8:142701651:T:G	F52C	0.989
8:142703239:T:A	N122K	0.986
8:142703239:T:G	N122K	0.986
8:142701696:G:A	C67Y	0.984
8:142701697:C:G	C67W	0.983
8:142703202:T:G	F110C	0.983
8:142701695:T:A	C67S	0.982
8:142701696:G:C	C67S	0.982
8:142703105:T:C	F78L	0.982
8:142703107:T:A	F78L	0.982
8:142703107:T:G	F78L	0.982
8:142701708:C:A	A71D	0.981
8:142703201:T:C	F110L	0.980
8:142703203:C:A	F110L	0.980
8:142703203:C:G	F110L	0.980
8:142701656:T:A	C54S	0.978
8:142701657:G:C	C54S	0.978
8:142701632:T:A	C46S	0.977
8:142701633:G:C	C46S	0.977
8:142703126:T:A	C85S	0.977
8:142703127:G:C	C85S	0.977
8:142701674:T:A	C60S	0.976
8:142701675:G:C	C60S	0.976
8:142703235:G:A	C121Y	0.976
8:142701633:G:A	C46Y	0.975
8:142701656:T:C	C54R	0.975

dbSNP variants (sampled 300 via entrez): RS1000116237 (8:142703276 G>A,T), RS1000454977 (8:142702038 C>T), RS1000505378 (8:142701801 G>A,T), RS1001119397 (8:142704577 C>T), RS1001173648 (8:142704261 C>G), RS1002349094 (8:142699501 G>C), RS1002811502 (8:142699254 G>T), RS1003063872 (8:142701458 T>G), RS1004014929 (8:142703039 T>A,C), RS1004067436 (8:142702721 A>C,G), RS1006414542 (8:142703962 A>G), RS1006469896 (8:142698383 C>G), RS1006662820 (8:142698675 G>A), RS1007136882 (8:142701016 G>C,T), RS1007253049 (8:142699962 G>C)

Disease associations

OMIM: gene MIM:615093 | 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: yes

ChEMBL targets (1): CHEMBL5291516 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.52	Kd	300	nM	CHEMBL5281008
5.33	Kd	4700	nM	CHEMBL108454

PubChem BioAssay actives

2 with measured affinity, of 10 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[2-[2-[2-[2-[2-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-9-[4-(ethylsulfonylamino)-2-methoxyanilino]acridine-3-carboxamide	1922908: Binding affinity to human wild type LY6K assessed as dissociation constant measured upto 250 sec by SPR assay	kd	0.3000	uM
N-[4-(acridin-9-ylamino)-3-methoxyphenyl]ethanesulfonamide	1922908: Binding affinity to human wild type LY6K assessed as dissociation constant measured upto 250 sec by SPR assay	kd	4.7000	uM

CTD chemical–gene interactions

49 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, decreases expression, decreases reaction, increases abundance, affects cotreatment	3
Benzo(a)pyrene	affects methylation, increases expression	3
mercuric bromide	affects cotreatment, increases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Smoke	increases expression	2
Tobacco Smoke Pollution	increases expression	2
Valproic Acid	increases expression, increases methylation	2
Particulate Matter	increases abundance, decreases reaction, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, decreases expression	1
ginger extract	decreases expression, decreases reaction, increases abundance	1
methylmercuric chloride	increases expression	1
propionaldehyde	increases expression	1
lead acetate	increases expression	1
trichostatin A	increases expression	1
2-butenal	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
cupric chloride	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
pentanal	increases expression	1
phenethyl isothiocyanate	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
ormosil	affects binding, increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Air Pollutants	increases expression, increases abundance	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5225872	Binding	Binding affinity to human wild type LY6K at 1.25 to 5 uM measured upto 250 sec by SPR assay	Development of fluorophore labeled or biotinylated anticancer small molecule NSC243928. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1WA	Abcam HeLa LY6K KO	Cancer cell line	Female

Clinical trials (associated diseases)

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