DOK3

Summary

DOK3 (docking protein 3, HGNC:24583) is a protein-coding gene on chromosome 5q35.3, encoding Docking protein 3 (Q7L591). DOK proteins are enzymatically inert adaptor or scaffolding proteins.

Predicted to be involved in Ras protein signal transduction and cell surface receptor protein tyrosine kinase signaling pathway. Predicted to be located in ficolin-1-rich granule membrane and plasma membrane. Predicted to be active in cytoplasm. Implicated in colorectal adenocarcinoma.

Source: NCBI Gene 79930 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 125 total
• MANE Select transcript: NM_001308236

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24583
Approved symbol	DOK3
Name	docking protein 3
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22570
Ensembl gene	ENSG00000146094
Ensembl biotype	protein_coding
OMIM	611435
Entrez	79930

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 18 protein_coding, 3 retained_intron

ENST00000312943, ENST00000357198, ENST00000377112, ENST00000500323, ENST00000501403, ENST00000502380, ENST00000502885, ENST00000506493, ENST00000509310, ENST00000510380, ENST00000510389, ENST00000510898, ENST00000512660, ENST00000882744, ENST00000882745, ENST00000882746, ENST00000882747, ENST00000882748, ENST00000882749, ENST00000965969, ENST00000965970

RefSeq mRNA: 14 — MANE Select: NM_001308236 NM_001144875, NM_001144876, NM_001308235, NM_001308236, NM_001375794, NM_001375795, NM_001375796, NM_001375797, NM_001375798, NM_001375799, NM_001384137, NM_001384138, NM_001384139, NM_024872

CCDS: CCDS47349, CCDS47350, CCDS78098

Canonical transcript exons

ENST00000510898 — 6 exons

Exon	Start	End
ENSE00001472811	177508237	177508542
ENSE00002045307	177509758	177509826
ENSE00003470690	177505011	177505110
ENSE00003621580	177509475	177509657
ENSE00003660804	177504743	177504915
ENSE00003819459	177501904	177504660

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 96.71.

FANTOM5 (CAGE): breadth broad, TPM avg 10.3256 / max 707.9629, expressed in 548 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65134	5.2548	428
65135	1.9316	336
65136	1.2958	331
65137	1.2880	231
65131	0.2779	112
65132	0.1678	75
65138	0.0861	44
65133	0.0237	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	96.71	gold quality
blood	UBERON:0000178	96.36	gold quality
mononuclear cell	CL:0000842	96.29	gold quality
leukocyte	CL:0000738	96.28	gold quality
granulocyte	CL:0000094	96.17	gold quality
spleen	UBERON:0002106	95.79	gold quality
right lung	UBERON:0002167	90.08	gold quality
lymph node	UBERON:0000029	89.46	gold quality
bone marrow	UBERON:0002371	89.24	gold quality
upper lobe of left lung	UBERON:0008952	88.45	gold quality
upper lobe of lung	UBERON:0008948	87.74	gold quality
trabecular bone tissue	UBERON:0002483	87.69	gold quality
vermiform appendix	UBERON:0001154	86.39	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.80	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.37	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.97	gold quality
bone marrow cell	CL:0002092	82.86	gold quality
left uterine tube	UBERON:0001303	81.62	gold quality
small intestine	UBERON:0002108	81.28	gold quality
right coronary artery	UBERON:0001625	81.22	gold quality
tonsil	UBERON:0002372	81.11	gold quality
caecum	UBERON:0001153	80.63	gold quality
omental fat pad	UBERON:0010414	80.07	gold quality
peritoneum	UBERON:0002358	79.96	gold quality
right testis	UBERON:0004534	79.73	gold quality
transverse colon	UBERON:0001157	79.51	gold quality
right adrenal gland cortex	UBERON:0035827	79.47	gold quality
lower lobe of lung	UBERON:0008949	79.45	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.32	gold quality
right adrenal gland	UBERON:0001233	78.73	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.68

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting DOK3, 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-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-6773-5P	97.04	64.30	595
HSA-MIR-6724-5P	96.41	63.11	507

Literature-anchored findings (GeneRIF, showing 12)

• findings indicate that Dok-3 sequesters Grb2 from Shc and inhibits the Ras-Erk pathway downstream of PTKs (PMID:16436051)
• The novel platelet adapter Dok-3 is tyrosine phosphorylated in an Src kinase-independent manner downstream of alphaIIbbeta3 in human platelets, leading to an interaction with Grb2 and SHIP-1. (PMID:19682241)
• Identification of DOK genes as lung tumor suppressors. (PMID:20139980)
• absence of DOK3 increases LPS signaling, contributing to LPS-induced tolerance. Thus, DOK3 plays a role in TLR signaling during both naive and endotoxin-induced tolerant conditions (PMID:22761938)
• The Dok-3/Grb2 protein signal module attenuates Lyn kinase-dependent activation of Syk kinase in B cell antigen receptor microclusters (PMID:23223229)
• Mutations in DOK3 gene is associated with prostate cancer (PMID:26585945)
• DOK2 and DOK3 expression was significantly reduced in HTLV-1-infected T cells. (PMID:27265473)
• Elevated expression of DOK3 indicates high suppressive immune cell infiltration and unfavorable prognosis of gliomas. (PMID:32193105)
• Dok3 restrains neutrophil production of calprotectin during TLR4 sensing of SARS-CoV-2 spike protein. (PMID:36172386)
• Porphyromonas gingivalis Activation of Tumor-Associated Macrophages via DOK3 Promotes Recurrence of Oral Squamous Cell Carcinoma. (PMID:36210538)
• Expression and clinical significance of DOK3 in renal clear cell carcinoma. (PMID:37235715)
• DOK3 promotes atopic dermatitis by enabling the phosphatase PP4C to inhibit the T cell signaling mediator CARD11. (PMID:37906628)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dok3	ENSMUSG00000035711
rattus_norvegicus	Dok3	ENSRNOG00000013564
drosophila_melanogaster	Dok	FBGN0029944
drosophila_melanogaster	CG13398	FBGN0032042
caenorhabditis_elegans		WBGENE00018819

Paralogs (7): DOK5 (ENSG00000101134), DOK1 (ENSG00000115325), DOK4 (ENSG00000125170), FRS3 (ENSG00000137218), DOK2 (ENSG00000147443), FRS2 (ENSG00000166225), DOK6 (ENSG00000206052)

Protein

Protein identifiers

Docking protein 3 — Q7L591 (reviewed: Q7L591)

Alternative names: Downstream of tyrosine kinase 3

All UniProt accessions (8): Q7L591, A0A6M4C8X9, D6R951, D6R977, D6RAM3, D6RAZ9, D6RC22, D6RF29

UniProt curated annotations — full annotation on UniProt →

Function. DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK3 is a negative regulator of JNK signaling in B-cells through interaction with INPP5D/SHIP1. May modulate ABL1 function.

Subunit / interactions. On tyrosine phosphorylation, interacts with CSK and INPP5D/SHIP1 via their SH2 domains. Both Tyr-381 and Tyr-398 are required for interaction with INPP5D. Only Tyr-381 is required for interaction with CSK. Binds ABL1 through the PTB domain and in a kinase-dependent manner. Does not interact with RasGAP.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Expressed in spleen.

Post-translational modifications. Constitutively tyrosine-phosphorylated. On IL2 stimulation, phosphorylated on C-terminal tyrosine residues possibly by Src kinases. Can also be phosphorylated by ABL1 kinase.

Domain organisation. PTB domain mediates receptor interaction.

Similarity. Belongs to the DOK family. Type A subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q7L591-1	1	yes
Q7L591-2	2
Q7L591-3	3
Q7L591-4	4

RefSeq proteins (14): NP_001138347, NP_001138348, NP_001295164, NP_001295165, NP_001362723, NP_001362724, NP_001362725, NP_001362726, NP_001362727, NP_001362728, NP_001371066, NP_001371067, NP_001371068, NP_079148 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR002404	IRS_PTB	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR037751	Dok1/2/3_PTB	Domain
IPR050996	Docking_Protein_DOK	Family

Pfam: PF02174

UniProt features (22 total): modified residue 5, splice variant 5, sequence conflict 4, region of interest 3, domain 2, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7L591-F1	65.94	0.35

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 (5): 425, 194, 330, 364, 381

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 133 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, CAGCTG_AP4_Q5, GOBP_RAS_PROTEIN_SIGNAL_TRANSDUCTION, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, OCT1_B, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, ZHAN_MULTIPLE_MYELOMA_CD1_DN, GOCC_SECRETORY_VESICLE, GOCC_SECRETORY_GRANULE_MEMBRANE, GARY_CD5_TARGETS_UP, YATGNWAAT_OCT_C, HEB_Q6, GOMF_SIGNALING_ADAPTOR_ACTIVITY

GO Biological Process (2): cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), Ras protein signal transduction (GO:0007265)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), plasma membrane (GO:0005886), secretory granule membrane (GO:0030667), ficolin-1-rich granule membrane (GO:0101003), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
enzyme-linked receptor protein signaling pathway	1
small GTPase-mediated signal transduction	1
binding	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
secretory granule	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
secretory granule membrane	1
tertiary granule	1
ficolin-1-rich granule	1

Protein interactions and networks

STRING

1008 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DOK3	CSK	P41240	922
DOK3	TYROBP	O43914	787
DOK3	GRB2	P29354	771
DOK3	INPP5D	Q92835	750
DOK3	RASA1	P20936	621
DOK3	CBL	P22681	541
DOK3	LYN	P07948	501
DOK3	ABL1	P00519	469
DOK3	DOK7	Q18PE1	454
DOK3	VAV3	Q9UKW4	453
DOK3	CD86	P42081	439
DOK3	SYK	P43405	426
DOK3	PTPRD	P23468	424
DOK3	LRP1B	Q9NZR2	424
DOK3	BLNK	Q8WV28	413

IntAct

31 interactions, top by confidence:

A	B	Type	Score
TRAF1	DOK3	psi-mi:“MI:0915”(physical association)	0.670
DOK3	TRAF1	psi-mi:“MI:0915”(physical association)	0.670
RBPMS	DOK3	psi-mi:“MI:0915”(physical association)	0.560
DOK3	RBPMS	psi-mi:“MI:0915”(physical association)	0.560
DOK3	TPP2	psi-mi:“MI:0914”(association)	0.530
DOK3	EGFR	psi-mi:“MI:0915”(physical association)	0.510
DOK3	H1-4	psi-mi:“MI:0915”(physical association)	0.400
DOK3	GRB2	psi-mi:“MI:0915”(physical association)	0.400
GRB2	DOK3	psi-mi:“MI:0915”(physical association)	0.400
INPP5D	DOK3	psi-mi:“MI:0915”(physical association)	0.400
DOK3	DOK3	psi-mi:“MI:0915”(physical association)	0.400
DOK3	Shc1	psi-mi:“MI:0914”(association)	0.350
DOK3	Ppfibp1	psi-mi:“MI:0914”(association)	0.350
DOK3	Ptpn6	psi-mi:“MI:0914”(association)	0.350
apa	NUDT21	psi-mi:“MI:0914”(association)	0.350
DOK3	BLTP3B	psi-mi:“MI:0914”(association)	0.350
DOK3	HSPA8	psi-mi:“MI:0914”(association)	0.350
BLNK	PLCG2	psi-mi:“MI:0914”(association)	0.350
GRB2	DOK3	psi-mi:“MI:0914”(association)	0.350
RPS11	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
YWHAG	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
	DOK3	psi-mi:“MI:0915”(physical association)	0.000
DOK3		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (65): DOK3 (Two-hybrid), DOK3 (Two-hybrid), AMD1 (Affinity Capture-MS), TPP2 (Affinity Capture-MS), DPP9 (Affinity Capture-MS), MIOS (Affinity Capture-MS), WDR34 (Affinity Capture-MS), UHRF1BP1L (Affinity Capture-MS), DPP8 (Affinity Capture-MS), WDR54 (Affinity Capture-MS), DOK3 (Two-hybrid), DOK3 (Two-hybrid), DOK3 (Two-hybrid), DOK3 (Two-hybrid), DOK3 (Two-hybrid)

ESM2 similar proteins: A3R064, A7MBB8, B2RYG7, D3ZZN9, E1BDF2, O60496, O70469, O94989, O95153, P97465, P97680, P98077, Q13671, Q14B98, Q1RMU7, Q3MIN7, Q3UR97, Q3UYI5, Q494U1, Q4QQV2, Q58EX7, Q5EA84, Q5FWH6, Q6ICB4, Q6PGG2, Q6ZW31, Q7L591, Q7TNF8, Q8BH49, Q8BWA8, Q8IW93, Q8IYJ3, Q8N878, Q8NAG6, Q8NFA2, Q91WA6, Q921Q7, Q92502, Q969H4, Q969T3

Diamond homologs: A3R064, A7MBB8, B2RYG7, O43559, O60496, O70469, P97465, Q4QQV2, Q52RG8, Q5EA84, Q7L591, Q8C180, Q8WU20, Q91WJ0, Q99704, Q9QZK7, Q5RA30, Q8TEW6, Q99KE3, Q2MHE5, Q6PKX4, Q91ZM9, Q9P104

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
LYN	“up-regulates activity”	DOK3	phosphorylation
DOK3	“up-regulates activity”	GRB2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	106
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1000 predictions. Top by Δscore:

Variant	Effect	Δscore
5:177504740:CAC:C	donor_loss	1.0000
5:177504742:C:CA	donor_loss	1.0000
5:177504912:CCCA:C	acceptor_gain	1.0000
5:177504913:CCAC:C	acceptor_gain	1.0000
5:177504914:CA:C	acceptor_gain	1.0000
5:177504915:ACTG:A	acceptor_loss	1.0000
5:177504916:C:CA	acceptor_loss	1.0000
5:177504916:C:CC	acceptor_gain	1.0000
5:177505006:CTTA:C	donor_loss	1.0000
5:177505008:TACCT:T	donor_loss	1.0000
5:177505009:A:AC	donor_gain	1.0000
5:177505009:A:T	donor_loss	1.0000
5:177505009:ACCTT:A	donor_gain	1.0000
5:177505010:C:CC	donor_gain	1.0000
5:177505010:CCTT:C	donor_gain	1.0000
5:177505010:CCTTC:C	donor_gain	1.0000
5:177505013:T:A	donor_gain	1.0000
5:177505107:TCCC:T	acceptor_gain	1.0000
5:177505108:CCC:C	acceptor_gain	1.0000
5:177505108:CCCC:C	acceptor_gain	1.0000
5:177505109:CC:C	acceptor_gain	1.0000
5:177505109:CCC:C	acceptor_gain	1.0000
5:177505110:CC:C	acceptor_gain	1.0000
5:177505111:C:CC	acceptor_gain	1.0000
5:177505112:T:A	acceptor_loss	1.0000
5:177508233:TCA:T	donor_loss	1.0000
5:177508234:CA:C	donor_loss	1.0000
5:177508363:C:CT	acceptor_gain	1.0000
5:177508364:G:T	acceptor_gain	1.0000
5:177504657:CGCC:C	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000621375 (5:177507446 C>T), RS1001407768 (5:177508708 C>T), RS1001480774 (5:177504383 C>T), RS1001551167 (5:177502601 C>T), RS1002158511 (5:177506313 T>C), RS1002425691 (5:177508230 C>T), RS1003438850 (5:177507168 ATTTC>A), RS1003527286 (5:177510249 G>A), RS1003542386 (5:177502369 A>C), RS1003664615 (5:177510052 C>T), RS1003723083 (5:177511450 G>A,T), RS1004214493 (5:177508167 G>A), RS1004650395 (5:177503594 C>G,T), RS1004668882 (5:177508997 C>A,G,T), RS1004689901 (5:177510360 C>T)

Disease associations

OMIM: gene MIM:611435 | 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
GCST001725_86	Inflammatory bowel disease	2.000000e-08
GCST005194_201	Coronary artery disease	1.000000e-06
GCST005956_15	Waist-to-hip ratio adjusted for BMI	1.000000e-07
GCST005957_13	Waist-to-hip ratio adjusted for BMI (age <50)	3.000000e-07
GCST005962_42	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-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
Estradiol	affects cotreatment, increases expression	2
Nickel	increases expression	2
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
ethyl-p-hydroxybenzoate	increases expression	1
2-butenal	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
jinfukang	affects cotreatment, decreases expression	1
trametinib	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases reaction, affects binding	1
Air Pollutants	increases abundance, affects expression	1
Cisplatin	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Ozone	increases abundance, affects expression	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Testosterone	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tretinoin	increases expression	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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