DOK5

Summary

DOK5 (docking protein 5, HGNC:16173) is a protein-coding gene on chromosome 20q13.2, encoding Docking protein 5 (Q9P104). DOK proteins are enzymatically inert adaptor or scaffolding proteins.

The protein encoded by this gene is a member of the DOK family of membrane proteins, which are adapter proteins involved in signal transduction. The encoded protein interacts with phosphorylated receptor tyrosine kinases to mediate neurite outgrowth and activation of the MAP kinase pathway. Unlike other DOK family proteins, this protein does not interact with RASGAP. This protein is up-regulated in patients with systemic sclerosis and is associated with fibrosis induced by insulin-like growth factor binding protein 5. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 55816 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 57 total
• MANE Select transcript: NM_018431

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16173
Approved symbol	DOK5
Name	docking protein 5
Location	20q13.2
Locus type	gene with protein product
Status	Approved
Aliases	dJ805C22.1
Ensembl gene	ENSG00000101134
Ensembl biotype	protein_coding
OMIM	608334
Entrez	55816

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000262593, ENST00000395939, ENST00000484860, ENST00000491469, ENST00000939307, ENST00000959731

RefSeq mRNA: 3 — MANE Select: NM_018431 NM_001294161, NM_018431, NM_177959

CCDS: CCDS13446, CCDS13447

Canonical transcript exons

ENST00000262593 — 8 exons

Exon	Start	End
ENSE00000662863	54591616	54591805
ENSE00000845676	54610388	54610523
ENSE00000845677	54643458	54643578
ENSE00001455163	54650415	54651169
ENSE00001921899	54475593	54476012
ENSE00003520503	54588483	54588597
ENSE00003551742	54588687	54588806
ENSE00003595338	54554933	54555040

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 99.32.

FANTOM5 (CAGE): breadth broad, TPM avg 7.1786 / max 532.0638, expressed in 874 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185400	2.3355	623
185402	2.2083	716
185403	2.1113	671
185401	0.5236	227

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.32	gold quality
ganglionic eminence	UBERON:0004023	97.44	gold quality
pancreatic ductal cell	CL:0002079	96.86	gold quality
vastus lateralis	UBERON:0001379	94.91	gold quality
cortical plate	UBERON:0005343	94.74	gold quality
cartilage tissue	UBERON:0002418	94.68	gold quality
quadriceps femoris	UBERON:0001377	94.16	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.28	gold quality
biceps brachii	UBERON:0001507	93.14	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.56	gold quality
deltoid	UBERON:0001476	92.39	gold quality
skeletal muscle tissue	UBERON:0001134	90.94	gold quality
Brodmann (1909) area 46	UBERON:0006483	90.67	gold quality
diaphragm	UBERON:0001103	89.99	gold quality
triceps brachii	UBERON:0001509	89.93	gold quality
tibialis anterior	UBERON:0001385	89.62	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.44	gold quality
entorhinal cortex	UBERON:0002728	89.19	gold quality
germinal epithelium of ovary	UBERON:0001304	89.16	gold quality
muscle tissue	UBERON:0002385	89.16	gold quality
gluteal muscle	UBERON:0002000	88.82	gold quality
Brodmann (1909) area 23	UBERON:0013554	88.58	gold quality
secondary oocyte	CL:0000655	88.11	gold quality
endothelial cell	CL:0000115	88.05	gold quality
muscle organ	UBERON:0001630	87.61	gold quality
choroid plexus epithelium	UBERON:0003911	87.18	gold quality
epithelial cell of pancreas	CL:0000083	87.07	gold quality
cardiac muscle of right atrium	UBERON:0003379	87.00	gold quality
oocyte	CL:0000023	86.97	gold quality
cranial nerve II	UBERON:0000941	86.94	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-75140	yes	301.60
E-HCAD-5	yes	54.43
E-MTAB-10485	no	432.05
E-ANND-3	no	3.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO3

miRNA regulators (miRDB)

18 targeting DOK5, 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-3163	100.00	77.23	8605
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-4260	98.78	65.37	848
HSA-MIR-589-5P	98.72	66.96	927
HSA-MIR-6869-5P	97.17	67.06	634
HSA-MIR-4689	96.97	65.79	1209
HSA-MIR-6858-5P	96.05	64.59	1020

Literature-anchored findings (GeneRIF, showing 7)

• DOK5 expression in human T cells, its genomic structure characterized, and its regulation upon T cell activation has been demonstrated. (PMID:12595900)
• IRS5/DOK4 and IRS6/DOK5 represent two new signaling proteins with potential roles in insulin and IGF-1 action (PMID:12730241)
• identified DOK5 as a novel susceptibility gene for obesity and type 2 diabetes in North Indian subjects (PMID:20187968)
• Although preliminary, these data suggest that DOK5 and perhaps several other genes influence the magnitude of amygdala activation during face processing, particularly in those with BD. (PMID:20215924)
• IGFBP-5 induces its pro-fibrotic effects, at least in part, via DOK5. IGFBP-5 and DOK5 are both increased in systemic sclerosis fibroblasts and tissues and may thus be acting in concert to promote fibrosis. (PMID:24551065)
• DOK5 as a Prognostic Biomarker of Gastric Cancer Immunoinvasion: A Bioinformatics Analysis. (PMID:35036444)
• Dok5 regulates proliferation and differentiation of osteoblast via canonical Wnt/beta-catenin signaling. (PMID:35234166)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dok5	ENSMUSG00000027560
rattus_norvegicus	Dok5	ENSRNOG00000013196
drosophila_melanogaster	Dok	FBGN0029944
drosophila_melanogaster	CG13398	FBGN0032042
caenorhabditis_elegans		WBGENE00018819

Paralogs (7): DOK1 (ENSG00000115325), DOK4 (ENSG00000125170), FRS3 (ENSG00000137218), DOK3 (ENSG00000146094), DOK2 (ENSG00000147443), FRS2 (ENSG00000166225), DOK6 (ENSG00000206052)

Protein

Protein identifiers

Docking protein 5 — Q9P104 (reviewed: Q9P104)

Alternative names: Downstream of tyrosine kinase 5, Insulin receptor substrate 6

All UniProt accessions (1): Q9P104

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. DOK5 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.

Subunit / interactions. Interacts with phosphorylated RET. In contrast to other DOK proteins, it does not interact with RASGAP.

Tissue specificity. Highest expression in skeletal muscle, lower in brain, heart and kidney. Also detected in activated peripheral blood T-lymphocytes.

Post-translational modifications. Phosphorylated on tyrosine residues in response to insulin, IGF1 and GDNF.

Domain organisation. PTB domain mediates receptor interaction.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q9P104-1	1	yes
Q9P104-2	2

RefSeq proteins (2): NP_060901, NP_808874 (=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: PF02174

UniProt features (16 total): strand 8, domain 2, helix 2, chain 1, short sequence motif 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1J0W	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P104-F1	78.32	0.50

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8853659	RET signaling

MSigDB gene sets: 97 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEUROGENESIS, MORF_IL4, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_RESPONSE_TO_GROWTH_FACTOR, SASAKI_ADULT_T_CELL_LEUKEMIA, GOBP_NEUROTROPHIN_TRK_RECEPTOR_SIGNALING_PATHWAY, GOBP_NEUROTROPHIN_SIGNALING_PATHWAY, GOBP_CELL_SURFACE_RECEPTOR_PROTEIN_TYROSINE_KINASE_SIGNALING_PATHWAY, BOQUEST_STEM_CELL_CULTURED_VS_FRESH_UP, GOMF_SIGNALING_ADAPTOR_ACTIVITY, NIKOLSKY_BREAST_CANCER_20Q12_Q13_AMPLICON

GO Biological Process (4): cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), neuron differentiation (GO:0030182), positive regulation of MAPK cascade (GO:0043410), regulation of neurotrophin TRK receptor signaling pathway (GO:0051386)

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
cell differentiation	1
generation of neurons	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
regulation of signal transduction	1
neurotrophin TRK receptor signaling pathway	1
regulation of cellular response to growth factor stimulus	1
binding	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

594 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DOK5	PLEK2	Q9NYT0	665
DOK5	H3BTC1	H3BTC1	661
DOK5	IRS4	O14654	661
DOK5	CRK	P46108	640
DOK5	PLEK	P08567	637
DOK5	FYN	P06241	551
DOK5	NTRK2	Q16620	524
DOK5	NTRK3	Q16288	523
DOK5	IGF1	P01343	518
DOK5	IRS2	Q9Y4H2	507
DOK5	IRS1	P35568	477
DOK5	SRC	P12931	446
DOK5	GDNF	P39905	443
DOK5	DOCK1	Q14185	425
DOK5	CDH4	P55283	420

IntAct

6 interactions, top by confidence:

A	B	Type	Score
DOK5	EGFR	psi-mi:“MI:0407”(direct interaction)	0.440
DOK5	OPRM1	psi-mi:“MI:0915”(physical association)	0.370
OPRM1	DOK5	psi-mi:“MI:0915”(physical association)	0.370
BNIP3L	DOK5	psi-mi:“MI:0915”(physical association)	0.370
CCDC85B	DOK5	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (18): DOK5 (Two-hybrid), DOK5 (Two-hybrid), DOK5 (Two-hybrid), DOK3 (Two-hybrid), SCOC (Two-hybrid), OLIG1 (Two-hybrid), WIZ (Two-hybrid), AHDC1 (Two-hybrid), ATF3 (Two-hybrid), CDCA4 (Two-hybrid), FANCG (Two-hybrid), RAI2 (Two-hybrid), TSC1 (Two-hybrid), RET (Affinity Capture-Western), PFDN5 (Two-hybrid)

ESM2 similar proteins: A1L2W9, B2RQE8, B5XG43, G9CGD6, O08969, O88387, P59113, Q0V987, Q0VC85, Q1KKW7, Q1KKZ1, Q32LP0, Q3UUV5, Q3ZBA3, Q4V7G1, Q503L1, Q53GA4, Q5FVW6, Q5PQT7, Q5R8M5, Q5U597, Q5XGP7, Q5ZL23, Q6P0G8, Q6PG29, Q7Z628, Q7Z6J4, Q80VL0, Q80YS6, Q86UX7, Q86WV1, Q8AW35, Q8BY35, Q8IZC4, Q8K1B8, Q8N556, Q8VH46, Q91ZM9, Q91ZT5, Q925E0

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

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
INSR	up-regulates	DOK5
RET	up-regulates	DOK5	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	50
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2229 predictions. Top by Δscore:

Variant	Effect	Δscore
20:54554928:TCCA:T	acceptor_loss	1.0000
20:54554929:CCA:C	acceptor_loss	1.0000
20:54554930:CAGA:C	acceptor_loss	1.0000
20:54554931:AGATT:A	acceptor_loss	1.0000
20:54588478:TTCA:T	acceptor_loss	1.0000
20:54588480:CAGGT:C	acceptor_loss	1.0000
20:54588593:ATCAG:A	donor_loss	1.0000
20:54588594:TCAGG:T	donor_loss	1.0000
20:54588595:CAG:C	donor_loss	1.0000
20:54588596:AGGT:A	donor_loss	1.0000
20:54588597:GGTT:G	donor_loss	1.0000
20:54588598:GTTT:G	donor_loss	1.0000
20:54588599:T:A	donor_loss	1.0000
20:54588677:A:AG	acceptor_gain	1.0000
20:54588683:A:AG	acceptor_gain	1.0000
20:54588683:ACAG:A	acceptor_loss	1.0000
20:54588684:C:G	acceptor_gain	1.0000
20:54588684:CA:C	acceptor_loss	1.0000
20:54588685:A:AG	acceptor_gain	1.0000
20:54588685:A:C	acceptor_loss	1.0000
20:54588686:G:GA	acceptor_gain	1.0000
20:54588686:GA:G	acceptor_gain	1.0000
20:54588686:GAT:G	acceptor_gain	1.0000
20:54588686:GATC:G	acceptor_gain	1.0000
20:54588686:GATCT:G	acceptor_gain	1.0000
20:54588802:GAGTG:G	donor_gain	1.0000
20:54588804:GTG:G	donor_gain	1.0000
20:54588805:TG:T	donor_gain	1.0000
20:54588806:GG:G	donor_gain	1.0000
20:54588807:G:GA	donor_loss	1.0000

AlphaMissense

2015 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:54475980:G:A	G12R	1.000
20:54475980:G:C	G12R	1.000
20:54475980:G:T	G12W	1.000
20:54475981:G:A	G12E	1.000
20:54554948:T:A	W28R	1.000
20:54554948:T:C	W28R	1.000
20:54554950:G:C	W28C	1.000
20:54554950:G:T	W28C	1.000
20:54554991:T:C	L42P	1.000
20:54554999:T:C	F45L	1.000
20:54555001:T:A	F45L	1.000
20:54555001:T:G	F45L	1.000
20:54588704:T:A	W103R	1.000
20:54588704:T:C	W103R	1.000
20:54588706:G:C	W103C	1.000
20:54588706:G:T	W103C	1.000
20:54591703:T:C	L166P	1.000
20:54591741:T:A	W179R	1.000
20:54591741:T:C	W179R	1.000
20:54591742:G:C	W179S	1.000
20:54591743:G:C	W179C	1.000
20:54591743:G:T	W179C	1.000
20:54591765:T:G	Y187D	1.000
20:54591769:G:A	G188E	1.000
20:54591787:T:C	F194S	1.000
20:54610420:T:C	F211S	1.000
20:54610456:T:A	V223D	1.000
20:54475976:G:C	K10N	0.999
20:54475976:G:T	K10N	0.999
20:54475981:G:T	G12V	0.999

dbSNP variants (sampled 300 via entrez): RS1000001690 (20:54499629 C>A), RS1000008789 (20:54538543 G>T), RS1000014517 (20:54519717 G>A), RS1000046173 (20:54584003 A>T), RS1000076827 (20:54544565 G>A), RS1000128926 (20:54489321 G>T), RS1000143938 (20:54628277 C>T), RS1000146225 (20:54597956 C>G,T), RS1000158933 (20:54583695 G>T), RS1000165618 (20:54551611 AC>A,ACC), RS1000187803 (20:54565275 T>A), RS1000202734 (20:54530346 C>A), RS1000203355 (20:54631163 C>T), RS1000214429 (20:54551409 G>A), RS1000220137 (20:54511535 G>A,T)

Disease associations

OMIM: gene MIM:608334 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000556_1	Functional MRI	5.000000e-07
GCST002112_9	Celiac disease	5.000000e-06
GCST006956_14	Erectile dysfunction	6.000000e-06
GCST011743_7	HDL cholesterol levels in HIV infection	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004550	amygdala reactivity measurement
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs117532069	Toxicity	3	cyclophosphamide;cytarabine;daunorubicin;dexamethasone;doxorubicin;methotrexate;pegaspargase;prednisone;thioguanine;vincristine	Acute lymphoblastic leukemia;Osteonecrosis

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs117532069	DOK5	3	0.00	1	cyclophosphamide;cytarabine;daunorubicin;dexamethasone;doxorubicin;methotrexate;pegaspargase;prednisone;thioguanine;vincristine

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation, increases expression	8
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression	3
Benzo(a)pyrene	affects methylation	2
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, decreases expression	1
lead acetate	decreases expression	1
testosterone undecanoate	affects cotreatment, increases expression	1
arsenite	increases methylation	1
aflatoxin B2	increases methylation	1
CGP 52608	increases reaction, affects binding	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
clothianidin	decreases expression	1
belinostat	increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Vorinostat	affects cotreatment, increases expression	1
Panobinostat	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Cadmium	decreases expression	1
Calcitriol	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Endosulfan	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Nickel	increases expression	1
Silicon Dioxide	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1

Cellosaurus cell lines

16 cell lines: 16 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0179	BT-474	Cancer cell line	Female
CVCL_4V65	BT474-5FU[r]	Cancer cell line	Female
CVCL_4Y08	BT-474/CMV-Luc	Cancer cell line	Female
CVCL_A2GH	LR-BT474	Cancer cell line	Female
CVCL_A4AK	BT-474 Tam2	Cancer cell line	Female
CVCL_A4CL	BT-474 Ecadherin EmGFP	Cancer cell line	Female
CVCL_AQ07	BT-474 Clone 5	Cancer cell line	Female
CVCL_AR86	BT-474 Tam1	Cancer cell line	Female
CVCL_AR96	BT-474 EEI	Cancer cell line	Female
CVCL_C9CU	BT-474-Luc2	Cancer cell line	Female

Clinical trials (associated diseases)

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