DOK4

Summary

DOK4 (docking protein 4, HGNC:19868) is a protein-coding gene on chromosome 16q21, encoding Docking protein 4 (Q8TEW6). DOK proteins are enzymatically inert adaptor or scaffolding proteins.

Predicted to be involved in cell surface receptor protein tyrosine kinase signaling pathway. Predicted to act upstream of or within nervous system development and positive regulation of MAPK cascade. Predicted to be located in cytosol. Predicted to be active in cytoplasm.

Source: NCBI Gene 55715 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 68 total
• MANE Select transcript: NM_018110

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19868
Approved symbol	DOK4
Name	docking protein 4
Location	16q21
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10488
Ensembl gene	ENSG00000125170
Ensembl biotype	protein_coding
OMIM	608333
Entrez	55715

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 41 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000340099, ENST00000561659, ENST00000561918, ENST00000562008, ENST00000562737, ENST00000563483, ENST00000564378, ENST00000566588, ENST00000566705, ENST00000566936, ENST00000567175, ENST00000567214, ENST00000567276, ENST00000568617, ENST00000569010, ENST00000569250, ENST00000569538, ENST00000569548, ENST00000880391, ENST00000880392, ENST00000880393, ENST00000880394, ENST00000880395, ENST00000880396, ENST00000880397, ENST00000880398, ENST00000880399, ENST00000880400, ENST00000880401, ENST00000880402, ENST00000880403, ENST00000880404, ENST00000880405, ENST00000880406, ENST00000925001, ENST00000925002, ENST00000925003, ENST00000925004, ENST00000925005, ENST00000972046, ENST00000972047, ENST00000972048, ENST00000972049, ENST00000972050

RefSeq mRNA: 16 — MANE Select: NM_018110 NM_001330556, NM_001369618, NM_001369619, NM_001369620, NM_001369621, NM_001394652, NM_001394653, NM_001394654, NM_001394655, NM_001394656, NM_001394657, NM_001394658, NM_001394659, NM_001394660, NM_001394661, NM_018110

CCDS: CCDS10783, CCDS81986

Canonical transcript exons

ENST00000340099 — 9 exons

Exon	Start	End
ENSE00000852935	57473613	57473736
ENSE00000921061	57474793	57474982
ENSE00001231924	57486305	57486493
ENSE00001382198	57479442	57479688
ENSE00003551152	57475850	57475957
ENSE00003621145	57475506	57475620
ENSE00003660872	57475100	57475219
ENSE00003784137	57473901	57474039
ENSE00003978330	57471922	57473495

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 95.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.5286 / max 196.1607, expressed in 1511 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157532	6.8096	1431
157531	1.2761	635
157530	0.4430	215

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	95.79	gold quality
cortical plate	UBERON:0005343	95.78	gold quality
tendon of biceps brachii	UBERON:0008188	94.51	gold quality
right coronary artery	UBERON:0001625	92.97	gold quality
lower esophagus mucosa	UBERON:0035834	92.93	gold quality
duodenum	UBERON:0002114	92.05	gold quality
descending thoracic aorta	UBERON:0002345	91.71	gold quality
rectum	UBERON:0001052	91.07	gold quality
ganglionic eminence	UBERON:0004023	91.04	gold quality
thoracic aorta	UBERON:0001515	90.76	gold quality
metanephros cortex	UBERON:0010533	90.74	gold quality
dorsal root ganglion	UBERON:0000044	90.72	gold quality
ascending aorta	UBERON:0001496	90.66	gold quality
transverse colon	UBERON:0001157	90.43	gold quality
skin of leg	UBERON:0001511	90.34	gold quality
left coronary artery	UBERON:0001626	89.74	gold quality
coronary artery	UBERON:0001621	89.68	gold quality
jejunal mucosa	UBERON:0000399	89.43	gold quality
body of stomach	UBERON:0001161	89.42	gold quality
adult mammalian kidney	UBERON:0000082	89.39	gold quality
buccal mucosa cell	CL:0002336	89.35	silver quality
esophagus mucosa	UBERON:0002469	89.34	gold quality
embryo	UBERON:0000922	89.33	gold quality
trigeminal ganglion	UBERON:0001675	89.14	gold quality
skin of abdomen	UBERON:0001416	89.13	gold quality
aorta	UBERON:0000947	88.88	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.80	gold quality
zone of skin	UBERON:0000014	88.79	gold quality
small intestine	UBERON:0002108	88.57	gold quality
cerebellar hemisphere	UBERON:0002245	88.54	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.54
E-MTAB-8271	yes	8.46
E-MTAB-8205	no	248.33
E-MTAB-7052	no	57.08

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 8)

• DOK4 expression in human T cells has been demonstrated, and its genomic structure has been predicted. (PMID:12595900)
• IRS5/DOK4 and IRS6/DOK5 represent two new signaling proteins with potential roles in insulin and IGF-1 action (PMID:12730241)
• Results suggest that Dok-4, through activation of the Rap1-ERK1/2 pathway, regulates GDNF-mediated neurite outgrowth during neuronal development. (PMID:16820412)
• IRS-5 (DOK4) is significantly upregulated in 90% of examined clear cell RCCs. Studies on this gene has shown that it is regulated through chromatin remodeling in kidney cells (PMID:17443497)
• Epigenetic regulation of DOK4 expression is associated with non-small-cell lung cancer. (PMID:19073520)
• Dok-4 represents a novel negative regulator of T cells (PMID:19494292)
• the current study have explored in more detail the structure and function of the Dok-4 PTB domain. (PMID:22982678)
• Study of DOK4 gene expression and promoter methylation in sporadic breast cancer. (PMID:32386480)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	dok4	ENSDARG00000073731
mus_musculus	Dok4	ENSMUSG00000040631
rattus_norvegicus	Dok4	ENSRNOG00000015679
drosophila_melanogaster	Dok	FBGN0029944
drosophila_melanogaster	CG13398	FBGN0032042
caenorhabditis_elegans		WBGENE00018819

Paralogs (7): DOK5 (ENSG00000101134), DOK1 (ENSG00000115325), FRS3 (ENSG00000137218), DOK3 (ENSG00000146094), DOK2 (ENSG00000147443), FRS2 (ENSG00000166225), DOK6 (ENSG00000206052)

Protein

Protein identifiers

Docking protein 4 — Q8TEW6 (reviewed: Q8TEW6)

Alternative names: Downstream of tyrosine kinase 4, Insulin receptor substrate 5

All UniProt accessions (13): Q8TEW6, A0A1B0GX86, H3BN90, H3BPY9, H3BQ19, H3BS85, H3BSK0, H3BST9, H3BTI4, H3BTI7, H3BTK2, H3BV67, H3BVB4

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. DOK4 functions in RET-mediated neurite outgrowth and plays a positive role in activation of the MAP kinase pathway. Putative link with downstream effectors of RET in neuronal differentiation. May be involved in the regulation of the immune response induced by T-cells.

Subunit / interactions. Interacts with RET and TEK/TIE2. Interaction with RET is mediated through the PTB domain and requires phosphorylation of RET ‘Tyr-1062’.

Tissue specificity. Widely expressed. High expression in skeletal muscle, heart, kidney and liver. Weaker expression in spleen, lung and small intestine, brain, heart and. Expressed in both resting and activated peripheral blood T-cells.

Post-translational modifications. Phosphorylated on tyrosine residues in response to insulin, IGF1 or RET stimulation.

Domain organisation. PTB domain mediates receptor interaction.

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

RefSeq proteins (16): NP_001317485, NP_001356547, NP_001356548, NP_001356549, NP_001356550, NP_001381581, NP_001381582, NP_001381583, NP_001381584, NP_001381585, NP_001381586, NP_001381587, NP_001381588, NP_001381589, NP_001381590, NP_060580* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR002404	IRS_PTB	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR037816	DOK4/5/6_PH	Domain
IPR050996	Docking_Protein_DOK	Family

Pfam: PF00169, PF02174

UniProt features (6 total): domain 2, sequence conflict 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TEW6-F1	75.73	0.47

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8853659	RET signaling

MSigDB gene sets: 106 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, PEREZ_TP63_TARGETS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, TGACCTY_ERR1_Q2, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, TGCTGAY_UNKNOWN, GROSS_HYPOXIA_VIA_ELK3_UP, GROSS_HYPOXIA_VIA_ELK3_ONLY_DN, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, chr16q21

GO Biological Process (3): cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), nervous system development (GO:0007399), positive regulation of MAPK cascade (GO:0043410)

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

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Axon guidance	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
system development	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
binding	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

504 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DOK4	PLEK2	Q9NYT0	702
DOK4	PLEK	P08567	698
DOK4	CRK	P46108	653
DOK4	IRS4	O14654	621
DOK4	H3BTC1	H3BTC1	621
DOK4	FYN	P06241	614
DOK4	TMEM184B	Q9Y519	604
DOK4	SRC	P12931	596
DOK4	ADAMTSL5	Q6ZMM2	549
DOK4	DOK7	Q18PE1	513
DOK4	CSK	P41240	485
DOK4	IGF1	P01343	462
DOK4	CCDC102A	Q96A19	459
DOK4	EFR3A	Q14156	437
DOK4	IRS2	Q9Y4H2	431

IntAct

38 interactions, top by confidence:

A	B	Type	Score
OPRM1	DOK4	psi-mi:“MI:0915”(physical association)	0.580
DOK4	OPRM1	psi-mi:“MI:0915”(physical association)	0.580
DOK4	CCM2	psi-mi:“MI:0915”(physical association)	0.570
DOK4	DOK3	psi-mi:“MI:0915”(physical association)	0.570
CCM2	DOK4	psi-mi:“MI:0915”(physical association)	0.570
DOK4	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560
INCA1	DOK4	psi-mi:“MI:0915”(physical association)	0.560
DOK4	PFDN5	psi-mi:“MI:0915”(physical association)	0.560
PAX8	DOK4	psi-mi:“MI:0915”(physical association)	0.560
DOK4	KDM1A	psi-mi:“MI:0914”(association)	0.530
DOK4	PTK2	psi-mi:“MI:0915”(physical association)	0.490
DOK4	STAT2	psi-mi:“MI:0915”(physical association)	0.490
PTK2	DOK4	psi-mi:“MI:0915”(physical association)	0.490
STAT2	DOK4	psi-mi:“MI:0915”(physical association)	0.490
DOK4	ERBB2	psi-mi:“MI:0407”(direct interaction)	0.440
DOK4	EGFR	psi-mi:“MI:0407”(direct interaction)	0.440
DOK4	OLIG1	psi-mi:“MI:0915”(physical association)	0.370
DOK4	MAPRE3	psi-mi:“MI:0915”(physical association)	0.370
RBP7	DOK4	psi-mi:“MI:0915”(physical association)	0.370
LIX1	DOK4	psi-mi:“MI:0915”(physical association)	0.370
DOK4	SUPT5H	psi-mi:“MI:0914”(association)	0.350

BioGRID (109): DOK4 (Two-hybrid), OPRM1 (Reconstituted Complex), DOK4 (Reconstituted Complex), DOK4 (Affinity Capture-Western), DOK4 (Affinity Capture-Western), DOK4 (Affinity Capture-Western), KDM1A (Affinity Capture-MS), GSE1 (Affinity Capture-MS), PHKA2 (Affinity Capture-MS), SMARCAD1 (Affinity Capture-MS), PBK (Affinity Capture-MS), RCOR1 (Affinity Capture-MS), RCOR3 (Affinity Capture-MS), PHKB (Affinity Capture-MS), AHCYL2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JTR4, A1A4S6, A2AWA9, A4FUD6, A4II46, A6H6A9, A6QNS3, A6QQZ7, O60890, P09851, P0CAX5, P20936, P23727, P26450, P27986, P50904, Q08DP6, Q12979, Q5R372, Q5R5M3, Q5R685, Q5R6F2, Q5R8I6, Q5RCC1, Q5RCW6, Q5SSL4, Q5T2T1, Q5U2Y3, Q5ZJ17, Q5ZLX4, Q5ZMW5, Q62696, Q63787, Q6Y5D8, Q6ZQ82, Q7YQL5, Q7YQL6, Q8AVG0, Q8BPU7, Q8K0F1

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

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
DOK4	up-regulates	CRK	binding
DOK4	up-regulates	FYN	binding
DOK4	up-regulates	SRC	binding
INSR	up-regulates	DOK4
RET	up-regulates	DOK4	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1587 predictions. Top by Δscore:

Variant	Effect	Δscore
16:57473605:CGACT:C	donor_loss	1.0000
16:57473606:GACTC:G	donor_loss	1.0000
16:57473607:ACT:A	donor_loss	1.0000
16:57473608:CTCA:C	donor_loss	1.0000
16:57473609:TCA:T	donor_loss	1.0000
16:57473610:CACCA:C	donor_loss	1.0000
16:57473611:A:AC	donor_gain	1.0000
16:57473611:A:AG	donor_loss	1.0000
16:57473611:AC:A	donor_gain	1.0000
16:57473611:ACCAG:A	donor_gain	1.0000
16:57473612:C:CA	donor_gain	1.0000
16:57473612:CC:C	donor_gain	1.0000
16:57473612:CCAG:C	donor_gain	1.0000
16:57473612:CCAGC:C	donor_gain	1.0000
16:57473732:AGCAG:A	acceptor_gain	1.0000
16:57473733:GCAG:G	acceptor_gain	1.0000
16:57473734:CAG:C	acceptor_gain	1.0000
16:57473734:CAGC:C	acceptor_gain	1.0000
16:57473735:AG:A	acceptor_gain	1.0000
16:57473736:GC:G	acceptor_loss	1.0000
16:57473737:C:CC	acceptor_gain	1.0000
16:57473739:G:C	acceptor_gain	1.0000
16:57473739:G:GC	acceptor_gain	1.0000
16:57473745:C:CT	acceptor_gain	1.0000
16:57473746:A:T	acceptor_gain	1.0000
16:57473899:AC:A	donor_gain	1.0000
16:57473900:CC:C	donor_gain	1.0000
16:57473906:CGTT:C	donor_gain	1.0000
16:57474035:ACATC:A	acceptor_gain	1.0000
16:57474036:CATC:C	acceptor_gain	1.0000

AlphaMissense

2125 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:57473948:C:G	A231P	1.000
16:57473956:A:G	L228P	1.000
16:57473963:C:G	A226P	1.000
16:57473971:A:T	V223D	1.000
16:57473981:A:C	Y220D	1.000
16:57473983:A:C	I219S	1.000
16:57473993:C:A	G216W	1.000
16:57473993:C:G	G216R	1.000
16:57473993:C:T	G216R	1.000
16:57474007:A:G	F211S	1.000
16:57474020:C:G	G207R	1.000
16:57474020:C:T	G207R	1.000
16:57474796:C:T	G199D	1.000
16:57474797:C:G	G199R	1.000
16:57474801:C:A	E197D	1.000
16:57474801:C:G	E197D	1.000
16:57474803:C:T	E197K	1.000
16:57474805:A:G	F196S	1.000
16:57474810:A:C	F194L	1.000
16:57474810:A:T	F194L	1.000
16:57474811:A:C	F194C	1.000
16:57474811:A:G	F194S	1.000
16:57474812:A:G	F194L	1.000
16:57474829:C:T	G188D	1.000
16:57474830:C:G	G188R	1.000
16:57474833:A:C	Y187D	1.000
16:57474833:A:G	Y187H	1.000
16:57474835:C:G	R186P	1.000
16:57474836:G:T	R186S	1.000
16:57474839:G:C	R185G	1.000

dbSNP variants (sampled 300 via entrez): RS1000010483 (16:57475658 G>A,C), RS1000699086 (16:57485290 G>A), RS1000751131 (16:57485724 C>T), RS1000809451 (16:57486091 G>C,T), RS1001312316 (16:57480140 G>A), RS1001414737 (16:57489093 G>A,C), RS1001527623 (16:57482300 C>T), RS1001626408 (16:57476944 G>A), RS1001681800 (16:57477294 T>C), RS1001977003 (16:57482591 T>C), RS1002927886 (16:57473551 A>G), RS1003259951 (16:57483754 G>A), RS1003319793 (16:57478310 G>C), RS1003372269 (16:57478566 G>A), RS1003524325 (16:57472551 G>A,T)

Disease associations

OMIM: gene MIM:608333 | 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

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	increases expression	2
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
kojic acid	decreases expression	1
ciglitazone	affects binding, increases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	increases expression	1
Temozolomide	increases expression	1
Decitabine	increases expression	1
Sunitinib	decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	increases phosphorylation	1
Calcitriol	increases expression, affects cotreatment	1
Cisplatin	affects cotreatment, increases expression	1
Cytarabine	decreases expression	1
Diazinon	increases methylation	1
Diethylhexyl Phthalate	increases expression	1
Diethylstilbestrol	increases expression	1
Formaldehyde	increases expression	1
Rotenone	increases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Testosterone	affects cotreatment, increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases expression	1
Vincristine	increases expression	1

Clinical trials (associated diseases)

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