DLK2

Summary

DLK2 (delta like non-canonical Notch ligand 2, HGNC:21113) is a protein-coding gene on chromosome 6p21.1, encoding Protein delta homolog 2 (Q6UY11). Regulates adipogenesis.

Predicted to enable Notch binding activity. Involved in negative regulation of Notch signaling pathway. Predicted to be located in membrane.

Source: NCBI Gene 65989 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 22 total
• MANE Select transcript: NM_023932

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21113
Approved symbol	DLK2
Name	delta like non-canonical Notch ligand 2
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC2487
Ensembl gene	ENSG00000171462
Ensembl biotype	protein_coding
OMIM	621120
Entrez	65989

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

ENST00000357338, ENST00000372485, ENST00000372488, ENST00000430324, ENST00000854535, ENST00000854536, ENST00000854537, ENST00000854538, ENST00000952222, ENST00000952223

RefSeq mRNA: 4 — MANE Select: NM_023932 NM_001286655, NM_001286656, NM_023932, NM_206539

CCDS: CCDS4897, CCDS75461

Canonical transcript exons

ENST00000372488 — 6 exons

Exon	Start	End
ENSE00001405680	43454411	43454474
ENSE00001421230	43453005	43453135
ENSE00001431243	43451940	43452084
ENSE00001436422	43454750	43454880
ENSE00001457931	43450352	43451274
ENSE00003845267	43455395	43455548

Expression profiles

Bgee: expression breadth ubiquitous, 182 present calls, max score 85.17.

FANTOM5 (CAGE): breadth broad, TPM avg 1.6280 / max 59.8272, expressed in 560 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73683	0.7263	337
73684	0.5053	241
73682	0.2078	108
73685	0.1887	72

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.17	gold quality
pancreatic ductal cell	CL:0002079	83.17	silver quality
cervix squamous epithelium	UBERON:0006922	81.37	gold quality
lower esophagus mucosa	UBERON:0035834	81.03	gold quality
esophagus mucosa	UBERON:0002469	80.07	gold quality
skin of leg	UBERON:0001511	79.98	gold quality
skin of abdomen	UBERON:0001416	79.65	gold quality
cortical plate	UBERON:0005343	78.96	gold quality
right hemisphere of cerebellum	UBERON:0014890	78.91	gold quality
cerebellar hemisphere	UBERON:0002245	78.65	gold quality
cerebellar cortex	UBERON:0002129	78.49	gold quality
zone of skin	UBERON:0000014	78.13	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	77.84	gold quality
prefrontal cortex	UBERON:0000451	77.59	gold quality
right frontal lobe	UBERON:0002810	77.32	gold quality
diaphragm	UBERON:0001103	77.25	gold quality
cerebellum	UBERON:0002037	77.13	gold quality
minor salivary gland	UBERON:0001830	76.43	gold quality
tongue squamous epithelium	UBERON:0006919	76.23	gold quality
apex of heart	UBERON:0002098	76.18	gold quality
mouth mucosa	UBERON:0003729	75.46	gold quality
nucleus accumbens	UBERON:0001882	75.12	gold quality
anterior cingulate cortex	UBERON:0009835	75.00	gold quality
cingulate cortex	UBERON:0003027	74.95	gold quality
squamous epithelium	UBERON:0006914	74.95	silver quality
esophagus squamous epithelium	UBERON:0006920	74.94	silver quality
Brodmann (1909) area 9	UBERON:0013540	74.83	gold quality
prostate gland	UBERON:0002367	74.78	gold quality
epithelium of esophagus	UBERON:0001976	74.67	silver quality
frontal cortex	UBERON:0001870	74.19	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	148.24
E-ANND-3	yes	11.04

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): KLF4, SP1

miRNA regulators (miRDB)

18 targeting DLK2, 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-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-223-5P	99.24	68.82	1206
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-6738-5P	96.33	63.61	815

Literature-anchored findings (GeneRIF, showing 3)

• Studies in mouse showed that dlk2, highly homologous to dlk1 (also known as pref-1, and FA-1) appears to modulate adipogenesis in vitro in an opposite way to that of dlk1. (PMID:17320102)
• EGFL9 promotes breast cancer metastasis by inducing cMET activation and metabolic reprogramming. (PMID:31695034)
• Different Expression Levels of DLK2 Inhibit NOTCH Signaling and Inversely Modulate MDA-MB-231 Breast Cancer Tumor Growth In Vivo. (PMID:35163478)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	dlk2	ENSDARG00000076247
mus_musculus	Dlk2	ENSMUSG00000047428
rattus_norvegicus	Dlk2	ENSRNOG00000018949
caenorhabditis_elegans		WBGENE00000168
caenorhabditis_elegans		WBGENE00012018
caenorhabditis_elegans		WBGENE00013480
caenorhabditis_elegans		WBGENE00013486
caenorhabditis_elegans		WBGENE00013487
caenorhabditis_elegans		WBGENE00018906
caenorhabditis_elegans		WBGENE00019901
caenorhabditis_elegans		WBGENE00022858

Paralogs (8): DLL3 (ENSG00000090932), CD93 (ENSG00000125810), FBLN7 (ENSG00000144152), WIF1 (ENSG00000156076), CRELD1 (ENSG00000163703), CD248 (ENSG00000174807), CLEC14A (ENSG00000176435), CRELD2 (ENSG00000184164)

Protein

Protein identifiers

Protein delta homolog 2 — Q6UY11 (reviewed: Q6UY11)

Alternative names: Epidermal growth factor-like protein 9

All UniProt accessions (3): Q6UY11, H0Y5P1, Q5T3T9

UniProt curated annotations — full annotation on UniProt →

Function. Regulates adipogenesis.

Subcellular location. Membrane.

Miscellaneous. Splicing acceptor site not canonical.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6UY11-1	1	yes
Q6UY11-2	2

RefSeq proteins (4): NP_001273584, NP_001273585, NP_076421, NP_996262 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR051022

Pfam: PF00008, PF21700

UniProt features (31 total): disulfide bond 17, domain 6, topological domain 2, signal peptide 1, chain 1, glycosylation site 1, splice variant 1, transmembrane region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UY11-F1	74.43	0.46

Functional residue map

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

Disulfide bonds (17): 29–40, 33–46, 48–57, 66–71, 79–88, 95–107, 101–117, 119–128, 135–148, 142–160, 162–171, 178–189, 183–198, 200–209, 216–227, 221–236, 238–247

Glycosylation sites (1): 157

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 73 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, BENPORATH_ES_WITH_H3K27ME3, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, TGACCTY_ERR1_Q2, GOBP_NEGATIVE_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, GOBP_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, GOBP_FAT_CELL_DIFFERENTIATION, GOMF_SIGNALING_RECEPTOR_BINDING, GOMF_NOTCH_BINDING, ER_Q6_01, DAVICIONI_MOLECULAR_ARMS_VS_ERMS_UP, LU_EZH2_TARGETS_UP, LEE_BMP2_TARGETS_DN

GO Biological Process (3): regulation of fat cell differentiation (GO:0045598), negative regulation of Notch signaling pathway (GO:0045746), regulation of Notch signaling pathway (GO:0008593)

GO Molecular Function (3): Notch binding (GO:0005112), calcium ion binding (GO:0005509), identical protein binding (GO:0042802)

GO Cellular Component (1): membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
Notch signaling pathway	2
fat cell differentiation	1
regulation of cell differentiation	1
regulation of Notch signaling pathway	1
negative regulation of signal transduction	1
regulation of signal transduction	1
signaling receptor binding	1
metal ion binding	1
protein binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

678 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DLK2	TTC28	Q96AY4	576
DLK2	KTN1	Q86UP2	531
DLK2	EGFL8	Q99944	507
DLK2	MEGF9	Q9H1U4	483
DLK2	KARS1	Q15046	406
DLK2	EGFL7	Q9UHF1	400
DLK2	NKAIN1	Q4KMZ8	393
DLK2	NGFR	P08138	381
DLK2	JAG1	P78504	380
DLK2	EIF1AX	P47813	362
DLK2	IGFL1	Q6UW32	355
DLK2	HEY1	Q9Y5J3	350
DLK2	TP53BP1	Q12888	345
DLK2	MEGF6	O75095	344
DLK2	LAMB3	Q13751	341
DLK2	SDR16C5	Q8N3Y7	341

IntAct

7 interactions, top by confidence:

A	B	Type	Score
DLK2	SCRIB	psi-mi:“MI:0915”(physical association)	0.400
DLK2	IDE	psi-mi:“MI:0915”(physical association)	0.400
DLK2	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.370
PLSCR1	DLK2	psi-mi:“MI:0915”(physical association)	0.370
DLK2	KRTAP4-12	psi-mi:“MI:0915”(physical association)	0.370
DLK2	RABGAP1L	psi-mi:“MI:0914”(association)	0.350

BioGRID (58): DLK2 (Two-hybrid), DLK2 (Two-hybrid), KRTAP4-12 (Two-hybrid), RNF213 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), RABGAP1L (Affinity Capture-MS), TARBP1 (Affinity Capture-MS), SLC22A23 (Affinity Capture-MS), VEZT (Affinity Capture-MS), ASPHD2 (Affinity Capture-MS), NOTCH3 (Affinity Capture-MS), NOTCH1 (Affinity Capture-MS), ZDHHC18 (Affinity Capture-MS), SLC7A2 (Affinity Capture-MS), LDLR (Affinity Capture-MS)

ESM2 similar proteins: A4FV93, A5A8Y8, B2LW77, D3ZUK3, O00468, O70534, O75074, O88204, O88839, O95407, P06579, P07204, P15306, P60882, P80370, Q09163, Q13444, Q14162, Q3SWY4, Q501P1, Q53RD9, Q5ND28, Q5VY43, Q5W7P8, Q61810, Q6AZ60, Q6GUQ1, Q6MG84, Q6UY11, Q71U07, Q75N90, Q7Z7M0, Q8K1E3, Q8K1S7, Q8K4G1, Q8NCW0, Q8ND94, Q8VIK5, Q8WUT4, Q93038

Diamond homologs: A0A096LNW5, A2RUV0, B4DH59, G3I6Z6, O35474, O35516, O75095, O89019, P07207, P0DPK3, P0DPK4, P13508, P20749, P21783, P31695, P46530, P46531, P82279, Q01705, Q04721, Q07008, Q20911, Q499M5, Q502K3, Q5RBP1, Q61982, Q6UXI9, Q6UY11, Q7Z3S9, Q810B6, Q8AVH7, Q8IUX8, Q91V88, Q99466, Q9FY48, Q9JJZ5, Q9P2R3, Q9QW30, Q9QXT5, Q9R172

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
DLK2	down-regulates	NOTCH1	binding
DLK2	“down-regulates activity”	NOTCH1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1056 predictions. Top by Δscore:

Variant	Effect	Δscore
6:43451275:C:CC	acceptor_gain	1.0000
6:43451270:GGGAG:G	acceptor_gain	0.9900
6:43451271:GGAG:G	acceptor_gain	0.9900
6:43451272:GAG:G	acceptor_gain	0.9900
6:43451275:C:CG	acceptor_loss	0.9900
6:43451276:T:A	acceptor_loss	0.9900
6:43451277:G:C	acceptor_gain	0.9900
6:43454408:TAC:T	donor_loss	0.9900
6:43454409:A:C	donor_loss	0.9900
6:43455389:CCTCA:C	donor_loss	0.9900
6:43455390:CTCAC:C	donor_loss	0.9900
6:43455391:TCA:T	donor_loss	0.9900
6:43455392:CA:C	donor_loss	0.9900
6:43455393:ACC:A	donor_loss	0.9900
6:43455394:C:CG	donor_loss	0.9900
6:43455396:T:TA	donor_gain	0.9900
6:43451273:AG:A	acceptor_gain	0.9800
6:43451280:G:GC	acceptor_gain	0.9800
6:43452081:TCATC:T	acceptor_loss	0.9800
6:43452083:ATC:A	acceptor_loss	0.9800
6:43452084:TCT:T	acceptor_loss	0.9800
6:43452085:C:CG	acceptor_loss	0.9800
6:43453133:CAC:C	acceptor_gain	0.9800
6:43453136:C:CG	acceptor_loss	0.9800
6:43453137:T:A	acceptor_loss	0.9800
6:43454471:TCGG:T	acceptor_gain	0.9800
6:43454472:CGGC:C	acceptor_gain	0.9800
6:43454475:C:CC	acceptor_gain	0.9800
6:43455393:ACCT:A	donor_gain	0.9800
6:43455394:CCT:C	donor_gain	0.9800

AlphaMissense

2485 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:43451064:G:C	C209W	0.999
6:43451065:C:G	C209S	0.999
6:43451065:C:T	C209Y	0.999
6:43451066:A:T	C209S	0.999
6:43451080:A:C	F204C	0.999
6:43451084:C:A	G203C	0.999
6:43451104:A:C	F196C	0.999
6:43451189:C:A	G168C	0.999
6:43451193:A:C	F166L	0.999
6:43451193:A:T	F166L	0.999
6:43451194:A:C	F166C	0.999
6:43451195:A:G	F166L	0.999
6:43451198:C:A	G165C	0.999
6:43453027:C:A	W83C	0.999
6:43453027:C:G	W83C	0.999
6:43453120:C:A	W52C	0.999
6:43453120:C:G	W52C	0.999
6:43450990:A:C	F234C	0.998
6:43451011:C:G	C227S	0.998
6:43451012:A:T	C227S	0.998
6:43451044:C:G	C216S	0.998
6:43451045:A:T	C216S	0.998
6:43451066:A:G	C209R	0.998
6:43451079:A:C	F204L	0.998
6:43451079:A:T	F204L	0.998
6:43451081:A:G	F204L	0.998
6:43451103:G:C	F196L	0.998
6:43451103:G:T	F196L	0.998
6:43451105:A:G	F196L	0.998
6:43451125:C:G	C189S	0.998

dbSNP variants (sampled 300 via entrez): RS1000752713 (6:43454561 G>C), RS1000838366 (6:43454578 A>G), RS1000908391 (6:43454252 A>G), RS1001140674 (6:43457942 CCAT>C), RS1001274998 (6:43457673 T>TA), RS1002704673 (6:43455389 C>T), RS1002859603 (6:43451395 T>C), RS1003480085 (6:43450135 A>G), RS1003547735 (6:43456087 TATC>T), RS1004211991 (6:43453314 A>G), RS1004605470 (6:43450637 C>T), RS1004996518 (6:43450278 C>A), RS1005141210 (6:43457468 C>G), RS1005260167 (6:43453771 A>G), RS1005502174 (6:43458066 T>G)

Disease associations

OMIM: gene MIM:621120 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005956_58	Waist-to-hip ratio adjusted for BMI	7.000000e-26
GCST005957_1	Waist-to-hip ratio adjusted for BMI (age <50)	2.000000e-14
GCST005958_2	Waist-to-hip ratio adjusted for BMI (age >50)	2.000000e-19
GCST005962_2	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	3.000000e-31
GCST006585_2774	Blood protein levels	8.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	2
lead acetate	decreases expression	1
decabromobiphenyl ether	affects expression	1
sulforaphane	decreases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
cupric chloride	decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Amiodarone	increases expression	1
Calcitriol	decreases expression	1
Carbamazepine	affects expression	1
Estradiol	affects cotreatment, decreases expression	1
Gasoline	increases expression, affects cotreatment, increases abundance	1
Plant Extracts	affects cotreatment, decreases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases expression	1
Sodium Selenite	increases expression	1

Clinical trials (associated diseases)

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