MDK

Summary

MDK (midkine, HGNC:6972) is a protein-coding gene on chromosome 11p11.2, encoding Midkine (P21741). Secreted protein that functions as a cytokine and growth factor and mediates its signal through cell-surface proteoglycan and non-proteoglycan receptors.

This gene encodes a member of a small family of secreted growth factors that binds heparin and responds to retinoic acid. The encoded protein promotes cell growth, migration, and angiogenesis, in particular during tumorigenesis. This gene has been targeted as a therapeutic for a variety of different disorders. Alternatively spliced transcript variants encoding multiple isoforms have been observed.

Source: NCBI Gene 4192 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 13 total
• Druggable target: yes
• MANE Select transcript: NM_002391

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6972
Approved symbol	MDK
Name	midkine
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Aliases	MK, FLJ27379
Ensembl gene	ENSG00000110492
Ensembl biotype	protein_coding
OMIM	162096
Entrez	4192

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 24 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000359803, ENST00000395565, ENST00000395566, ENST00000395569, ENST00000405308, ENST00000407067, ENST00000441869, ENST00000481047, ENST00000489525, ENST00000490240, ENST00000533283, ENST00000533952, ENST00000855479, ENST00000855480, ENST00000855481, ENST00000855482, ENST00000855483, ENST00000927241, ENST00000927242, ENST00000927243, ENST00000927244, ENST00000927245, ENST00000927246, ENST00000927247, ENST00000927248, ENST00000927249, ENST00000927250, ENST00000927251

RefSeq mRNA: 6 — MANE Select: NM_002391 NM_001012333, NM_001012334, NM_001270550, NM_001270551, NM_001270552, NM_002391

CCDS: CCDS59226, CCDS7919

Canonical transcript exons

ENST00000395566 — 5 exons

Exon	Start	End
ENSE00001522129	46381669	46381758
ENSE00003461624	46382294	46382461
ENSE00003570455	46382057	46382133
ENSE00003601039	46383469	46383801
ENSE00003652867	46382587	46382748

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 116.2406 / max 1225.6403, expressed in 1617 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114129	54.7964	1567
114130	19.8558	1354
114125	14.8912	1380
114131	13.5176	1192
114134	5.6688	1166
114123	1.8551	814
114132	1.5720	452
114124	0.7434	413
114127	0.7181	462
114135	0.7081	260

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.33	gold quality
stromal cell of endometrium	CL:0002255	99.30	gold quality
pituitary gland	UBERON:0000007	99.24	gold quality
left ovary	UBERON:0002119	99.21	gold quality
endocervix	UBERON:0000458	99.17	gold quality
adenohypophysis	UBERON:0002196	99.17	gold quality
ovary	UBERON:0000992	99.15	gold quality
right uterine tube	UBERON:0001302	99.09	gold quality
ganglionic eminence	UBERON:0004023	99.04	gold quality
duodenum	UBERON:0002114	98.99	gold quality
right ovary	UBERON:0002118	98.98	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.58	gold quality
fallopian tube	UBERON:0003889	98.46	gold quality
gall bladder	UBERON:0002110	98.39	gold quality
adrenal tissue	UBERON:0018303	97.94	gold quality
uterine cervix	UBERON:0000002	97.77	gold quality
body of uterus	UBERON:0009853	97.72	gold quality
left uterine tube	UBERON:0001303	97.66	gold quality
prostate gland	UBERON:0002367	97.61	gold quality
tibial nerve	UBERON:0001323	97.27	gold quality
right adrenal gland cortex	UBERON:0035827	97.17	gold quality
ectocervix	UBERON:0012249	97.03	gold quality
myometrium	UBERON:0001296	96.98	gold quality
minor salivary gland	UBERON:0001830	96.78	gold quality
saliva-secreting gland	UBERON:0001044	96.75	gold quality
right adrenal gland	UBERON:0001233	96.66	gold quality
left adrenal gland	UBERON:0001234	96.38	gold quality
left adrenal gland cortex	UBERON:0035825	96.11	gold quality
adrenal gland	UBERON:0002369	95.99	gold quality
small intestine	UBERON:0002108	95.84	gold quality

Single-cell (SCXA)

Detected in 36 experiment(s), a significant marker in 25.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	5606.93
E-MTAB-10485	yes	3233.85
E-MTAB-7407	yes	3145.60
E-CURD-98	yes	3140.97
E-CURD-112	yes	3079.15
E-CURD-79	yes	2499.50
E-MTAB-10287	yes	1842.14
E-MTAB-10042	yes	1729.33
E-HCAD-5	yes	1554.13
E-MTAB-6308	yes	1285.34
E-MTAB-8410	yes	1051.45
E-MTAB-8884	yes	597.40
E-GEOD-98556	yes	366.09
E-MTAB-9067	yes	358.51
E-HCAD-4	yes	61.69

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, NKX2-1, NR3C1, TP53

miRNA regulators (miRDB)

37 targeting MDK, 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-190A-3P	100.00	80.35	5520
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-7109-5P	99.18	66.13	1057
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-6769A-5P	97.99	64.16	851
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-4642	97.52	67.60	916
HSA-MIR-4253	97.48	65.11	692

Literature-anchored findings (GeneRIF, showing 40)

• Requirement of chondroitin sulfate/dermatan sulfate recognition in midkine-dependent migration of macrophages (PMID:11925507)
• In a blood vessel model, midkine induced stratification of endothelial cells and increased their proliferation and glycosaminoglycan synthesis. Increased proliferation of endothelium also occurred by coculture with smooth muscle cells and midkine. (PMID:12077357)
• midkine binds to ALK and has a role in signal transduction for cell growth and survival (PMID:12122009)
• Midkine is expressed in astrocytes during the early period of human brain ischemia. (PMID:12127679)
• results suggest that the cell surface-expressed nucleolin serves as a low affinity receptor for midkine and could be implicated in its entry process (PMID:12147681)
• Increased midkine expression is associated with superficial esophageal cancer (PMID:12579281)
• Increased preoperative serum midkine in patients with esophageal squamous cell carcinoma is associated with poor survival. (PMID:12841873)
• nuclear targeting growth factor midkine undergoes proteasomal degradation (PMID:14970216)
• a G to T substitution at the 62nd site of intron 3 in the midkine gene enhances the expression of truncated midkine in colon cancer (PMID:15050737)
• data showed that the midkine promoter activated a therapeutic gene in a wider range of human breast cancer than the c-erbB-2 promoter and suggest that MK promoter-mediated gene therapy is potentially more favorable in clinical settings (PMID:15138367)
• MK participates in each of the two distinct phases of rheumatoid arthritis development, namely, migration of inflammatory leukocytes and osteoclast differentiation, and is a key molecule in pathogenesis (PMID:15146411)
• Midkine promoter-based conditionally replicative adenovirus might be a promising new modality of gene therapy for malignant glioma. (PMID:15201962)
• Increased midkine levels are associated with tumorigenesis in neurofibromatosis type 1 (PMID:15355893)
• MK may play roles, such as stimulation of endometriotic cell proliferation, in the development of endometriosis. (PMID:15734764)
• reported that human MK exclusively localized to the nucleus and nucleolus in HepG2 cells by using GFP as a tracking molecule (PMID:15781266)
• A survival molecule, midkine, was identified by cDNA array to be expressed only in drug-resistant neuroblastoma cells. (PMID:15897897)
• Midkine likely plays a key role in human fetal adrenal glandcdevelopment. (PMID:16895951)
• Resultsd suggested that truncated MK (tMK) has a greater ability of malignant transformation than full-length MK, and whether tMK is expressed or not will be useful information for improving cancer chemotherapy. (PMID:17066487)
• localized exclusively to the nucleus and accumulated in the nucleolus in the three kinds of cancer cell lines (PMID:17171794)
• Overexpression of midkine is associated with childhood B-precursor acute lymphoblastic leukemia (PMID:17267033)
• Midkine, pleiotrophin (PTN), and their receptors syndecan-3 and receptor protein tyrosine phosphatase beta/zeta, were highly expressed in the striatum during developmen (PMID:17368428)
• Antisense oligonucleotide targeting midkine suppressed the angiogenesis both in human hepatocellular carcinoma cell line (HEPG2)-induced chick chorioallantoic membrane and in situ human HCC tissues. (PMID:17451201)
• MK expression was increased along with tumor progression. (PMID:17493173)
• Midkine expression was detected in the glomeruli, tubular epithelium and interstitium of kidneys from patients with diabetic nephropathy (PMID:17607302)
• MK is involved in granulosa cell proliferation and estradiol production in developing follicles and may play a role as a local regulator in the human ovary. (PMID:17845207)
• IL-6 and IL-8, and probably midkine and VEGF-A, appear to participate in the development of cancer-related cachexia in gastroesophageal malignancies. (PMID:17931612)
• These data demonstrate a crucial role of MK-LRP1 signaling in anchorage-independent cell growth. (PMID:17971413)
• Midkine has anti-apoptotic and cytoprotective role during cadmium toxicity in hepatocytes (PMID:18176965)
• Midkine was expressed in choroid plexus of normal brain and released there; CSF MK levels were not high in patients with cerebral infarction but were increased in patients with meningitis (PMID:18195496)
• MK is considered to mediate growth activity of odontogenic tumors and cell differentiation of odontogenic mixed tumors through molecular mechanisms similar to those involved in morphogenesis of the tooth. (PMID:18329695)
• higher serum MK protein concentration was correlated with the presence of lymph node metastases and prognosis of endometrial carcinomas (PMID:18422745)
• Midkine induces epithelial-mesenchymal transition through Notch2/Jak2-Stat3 signaling in human keratinocytes. (PMID:18469519)
• Both TP and MK are important for angiogenesis in laryngeal squamous cell carcinoma. The expression of TP, MK and CD105 were all correlated with T-stage and lymph node metastasis. (PMID:18476626)
• increased expression in the prefrontal cortex of chronic alcoholics (PMID:18657127)
• Increased serum midkine is associated with oral squamous cell carcinoma. (PMID:18682710)
• midkine enhances soft-tissue sarcoma tumor growth (PMID:18698021)
• Quantitative analysis of MK mRNA may be a promising modality for the diagnosis of pancreatic cancer and the prediction of its prognosis. (PMID:18712601)
• The major finding of this study is a novel MK-triggered signaling mechanism implicated in migration and invasiveness of head and neck squamous cell carcinoma cells. (PMID:18851943)
• midkine-mRNA expression was found in the majority of the neuroblastoma tissues. No correlation of MK status with survival, risk factors or disease stage was observed. (PMID:18956201)
• Midkine accumulated in nucleolus of HepG2 cells involved in rRNA transcription. (PMID:18985819)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mdkb	ENSDARG00000020708
danio_rerio	mdka	ENSDARG00000036036
mus_musculus	Mdk	ENSMUSG00000027239
rattus_norvegicus	Mdk	ENSRNOG00000017560

Paralogs (1): PTN (ENSG00000105894)

Protein

Protein identifiers

Midkine — P21741 (reviewed: P21741)

Alternative names: Amphiregulin-associated protein, Midgestation and kidney protein, Neurite outgrowth-promoting factor 2, Neurite outgrowth-promoting protein

All UniProt accessions (4): P21741, C9JHA4, E9PLM6, E9PPJ5

UniProt curated annotations — full annotation on UniProt →

Function. Secreted protein that functions as a cytokine and growth factor and mediates its signal through cell-surface proteoglycan and non-proteoglycan receptors. Binds cell-surface proteoglycan receptors via their chondroitin sulfate (CS) groups. Thereby regulates many processes like inflammatory response, cell proliferation, cell adhesion, cell growth, cell survival, tissue regeneration, cell differentiation and cell migration. Participates in inflammatory processes by exerting two different activities. Firstly, mediates neutrophils and macrophages recruitment to the sites of inflammation both by direct action by cooperating namely with ITGB2 via LRP1 and by inducing chemokine expression. This inflammation can be accompanied by epithelial cell survival and smooth muscle cell migration after renal and vessel damage, respectively. Secondly, suppresses the development of tolerogenic dendric cells thereby inhibiting the differentiation of regulatory T cells and also promote T cell expansion through NFAT signaling and Th1 cell differentiation. Promotes tissue regeneration after injury or trauma. After heart damage negatively regulates the recruitment of inflammatory cells and mediates cell survival through activation of anti-apoptotic signaling pathways via MAPKs and AKT pathways through the activation of angiogenesis. Also facilitates liver regeneration as well as bone repair by recruiting macrophage at trauma site and by promoting cartilage development by facilitating chondrocyte differentiation. Plays a role in brain by promoting neural precursor cells survival and growth through interaction with heparan sulfate proteoglycans. Binds PTPRZ1 and promotes neuronal migration and embryonic neurons survival. Binds SDC3 or GPC2 and mediates neurite outgrowth and cell adhesion. Binds chondroitin sulfate E and heparin leading to inhibition of neuronal cell adhesion induced by binding with GPC2. Binds CSPG5 and promotes elongation of oligodendroglial precursor-like cells. Also binds ITGA6:ITGB1 complex; this interaction mediates MDK-induced neurite outgrowth. Binds LRP1; promotes neuronal survival. Binds ITGA4:ITGB1 complex; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation. Binds anaplastic lymphoma kinase (ALK) which induces ALK activation and subsequent phosphorylation of the insulin receptor substrate (IRS1), followed by the activation of mitogen-activated protein kinase (MAPK) and PI3-kinase, and the induction of cell proliferation. Promotes epithelial to mesenchymal transition through interaction with NOTCH2. During arteriogenesis, plays a role in vascular endothelial cell proliferation by inducing VEGFA expression and release which in turn induces nitric oxide synthase expression. Moreover activates vasodilation through nitric oxide synthase activation. Negatively regulates bone formation in response to mechanical load by inhibiting Wnt/beta-catenin signaling in osteoblasts. In addition plays a role in hippocampal development, working memory, auditory response, early fetal adrenal gland development and the female reproductive system.

Subunit / interactions. Homodimer. Interacts with ALK. Interacts with LRP1; promotes neuronal survival. Interacts with LRP2. Interacts with NCAM1. Interacts (via C-terminal) with PTPRZ1 (via chondroitin sulfate chains); this interaction is inhibited by PTN; this interaction promotes neuronal migration. Interacts with NCL; this interaction promotes NCL clustering and lateral movements of this complex into lipid rafts leading to MDK internalization. Interacts with LRP6 and LRP8: this interaction is calcium dependent. Interacts with ITGA4. Interacts with ITGA6. Interacts with ITGB1. Interacts with ITGA4:ITGB1 complex; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation. Interacts with ITGA6:ITGB1 complex; this interaction mediates MDK-induced neurite outgrowth. Interacts with NOTCH2; this interaction mediates a nuclear accumulation of NOTCH2 and therefore activation of NOTCH2 signaling leading to interaction between HES1 and STAT3. Interacts with GPC2 (via heparan sulfate chain); this interaction is inhibited by heparin followed by chondroitin sulfate E; this interaction induces GPC2 clustering through heparan sulfate chain; this interaction induces neuronal cell adhesion and neurite outgrowth. Interacts with SDC3; this interaction induces SDC3 clustering; this interaction induces neuronal cell adhesion and neurite outgrowth. Interacts with SDC1. Interacts with CSPG5; this interaction promotes elongation of oligodendroglial precursor-like cells.

Subcellular location. Secreted.

Tissue specificity. Expressed in various tumor cell lines. In insulinoma tissue predominantly expressed in precancerous lesions.

Induction. By heparin and retinoic acid.

Miscellaneous. Found in cancer tissues with expression in the tumor bodies and surrounding normal cells.

Similarity. Belongs to the pleiotrophin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P21741-1	1	yes
P21741-2	2, tMKA

RefSeq proteins (6): NP_001012333, NP_001012334, NP_001257479, NP_001257480, NP_001257481, NP_002382* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000762	Midkine_heparin-bd_GF	Family
IPR020089	PTN/MK_N_dom	Domain
IPR020090	PTN/MK_C_dom	Domain
IPR020091	PTN/MK_diS_sf	Homologous_superfamily
IPR020092	PTN_MK_heparin-bd_GF_CS	Conserved_site
IPR037122	PTN/MK_N_dom_sf	Homologous_superfamily
IPR038130	PTN/MK_C_dom_sf	Homologous_superfamily

Pfam: PF01091, PF05196

UniProt features (19 total): strand 9, disulfide bond 5, signal peptide 1, chain 1, site 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1MKC	SOLUTION NMR
1MKN	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P21741-F1	72.96	0.17

Functional residue map

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

Catalytic / active sites (1): 103 (required for high affinity binding to ptrz1 by interacting with the chondroitin sulfate chains of ptrz1)

Disulfide bonds (5): 37–61, 45–70, 52–74, 84–116, 94–126

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-201556	Signaling by ALK
R-HSA-2979096	NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-9851151	MDK and PTN in ALK signaling
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1980145	Signaling by NOTCH2
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 518 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_MEMORY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_HEPATOCYTE_PROLIFERATION, GOBP_DENTATE_GYRUS_DEVELOPMENT, GOBP_EXCRETION, GOBP_DIGESTION, GOBP_HINDBRAIN_DEVELOPMENT, REACTOME_SIGNALING_BY_NOTCH, MODULE_52, MODULE_92, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT

GO Biological Process (63): behavioral fear response (GO:0001662), leukocyte chemotaxis involved in inflammatory response (GO:0002232), T cell activation involved in immune response (GO:0002286), positive regulation of leukocyte chemotaxis (GO:0002690), cytoskeleton organization (GO:0007010), negative regulation of cell adhesion (GO:0007162), signal transduction (GO:0007165), nervous system development (GO:0007399), short-term memory (GO:0007614), response to xenobiotic stimulus (GO:0009410), response to wounding (GO:0009611), negative regulation of cardiac muscle cell apoptotic process (GO:0010667), positive regulation of epithelial to mesenchymal transition (GO:0010718), positive regulation of macrophage chemotaxis (GO:0010759), positive regulation of keratinocyte proliferation (GO:0010838), positive regulation of neuron projection development (GO:0010976), response to auditory stimulus (GO:0010996), dentate gyrus development (GO:0021542), cerebellar granular layer development (GO:0021681), cerebral cortex development (GO:0021987), cell differentiation (GO:0030154), negative regulation of ossification (GO:0030279), adrenal gland development (GO:0030325), positive regulation of cell migration (GO:0030335), defecation (GO:0030421), regulation of chondrocyte differentiation (GO:0032330), positive regulation of interleukin-12 production (GO:0032735), intracellular signal transduction (GO:0035556), tissue regeneration (GO:0042246), negative regulation of neuron apoptotic process (GO:0043524), estrous cycle (GO:0044849), positive regulation of T cell differentiation (GO:0045582), negative regulation of regulatory T cell differentiation (GO:0045590), positive regulation of cell adhesion (GO:0045785), positive regulation of DNA-templated transcription (GO:0045893), regulation of bone remodeling (GO:0046850), oogenesis (GO:0048477), positive regulation of oligodendrocyte differentiation (GO:0048714), positive regulation of inflammatory response (GO:0050729), regulation of behavior (GO:0050795)

GO Molecular Function (5): growth factor activity (GO:0008083), heparin binding (GO:0008201), chondroitin sulfate binding (GO:0035374), heparan sulfate binding (GO:1904399), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), cell projection (GO:0042995), extracellular matrix (GO:0031012)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signal Transduction	2
Signaling by Receptor Tyrosine Kinases	1
Signaling by NOTCH2	1
Signaling by ALK	1
Signaling by NOTCH	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anatomical structure development	3
glycosaminoglycan binding	3
sulfur compound binding	3
leukocyte chemotaxis	2
cellular anatomical structure	2
behavioral defense response	1
fear response	1
leukocyte migration involved in inflammatory response	1
inflammatory response	1
lymphocyte activation involved in immune response	1
immune response	1
T cell activation	1
positive regulation of leukocyte migration	1
regulation of leukocyte chemotaxis	1
positive regulation of chemotaxis	1
organelle organization	1
cell adhesion	1
regulation of cell adhesion	1
negative regulation of cellular process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
system development	1
memory	1
response to chemical	1
response to stress	1
cardiac muscle cell apoptotic process	1
negative regulation of striated muscle cell apoptotic process	1
regulation of cardiac muscle cell apoptotic process	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
positive regulation of cell differentiation	1
positive regulation of multicellular organismal process	1
positive regulation of leukocyte chemotaxis	1
regulation of macrophage chemotaxis	1
macrophage chemotaxis	1
regulation of granulocyte chemotaxis	1
positive regulation of macrophage migration	1

Protein interactions and networks

STRING

1880 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MDK	ALK	Q9UM73	971
MDK	NUCLEOLIN	P19338	942
MDK	HDGF	P51858	933
MDK	NOTCH2	Q04721	910
MDK	PTPRZ1	P23471	909
MDK	PTPRB	P23467	826
MDK	SORL1	Q92673	818
MDK	SDC1	P18827	815
MDK	GPC2	Q8N158	791
MDK	AZU1	P20160	732
MDK	SDC4	P31431	714
MDK	TACSTD2	P09758	681
MDK	SDC3	O75056	674
MDK	SPP1	P10451	666
MDK	SLC2A1	P11166	639

IntAct

56 interactions, top by confidence:

A	B	Type	Score
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
TCEA2	MDK	psi-mi:“MI:0915”(physical association)	0.560
UBQLN2	MDK	psi-mi:“MI:0915”(physical association)	0.560
MIEF2	MDK	psi-mi:“MI:0915”(physical association)	0.560
AP1M1	MDK	psi-mi:“MI:0915”(physical association)	0.560
MDK	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
MDK	JOSD2	psi-mi:“MI:0915”(physical association)	0.560
MDK	TCEA2	psi-mi:“MI:0915”(physical association)	0.560
MDK	RBFA	psi-mi:“MI:0915”(physical association)	0.560
MDK	TMED8	psi-mi:“MI:0915”(physical association)	0.560
MDK	NFU1	psi-mi:“MI:0915”(physical association)	0.560
MDK	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
MDK	MIEF2	psi-mi:“MI:0915”(physical association)	0.560
MDK	AP1M1	psi-mi:“MI:0915”(physical association)	0.560
MDK	PBX3	psi-mi:“MI:0915”(physical association)	0.560
HCK	MDK	psi-mi:“MI:0915”(physical association)	0.560
MDK	SETD1A	psi-mi:“MI:0914”(association)	0.530
MDK	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
MAPK6	MDK	psi-mi:“MI:0915”(physical association)	0.370
KSR1	FBLL1	psi-mi:“MI:0914”(association)	0.350
APP	ESYT2	psi-mi:“MI:0914”(association)	0.350
NPM1	RPS3A	psi-mi:“MI:0914”(association)	0.350
PSMB10	DDX46	psi-mi:“MI:0914”(association)	0.350
RPL35	SRP72	psi-mi:“MI:0914”(association)	0.350
NOTCH2	ZNF320	psi-mi:“MI:0914”(association)	0.350

BioGRID (116): SETD1A (Affinity Capture-MS), CXXC1 (Affinity Capture-MS), TNRC18 (Affinity Capture-MS), NAF1 (Affinity Capture-MS), HIST1H1A (Affinity Capture-MS), AFF4 (Affinity Capture-MS), UBTF (Affinity Capture-MS), MLLT3 (Affinity Capture-MS), SRRM2 (Affinity Capture-MS), CHD9 (Affinity Capture-MS), BOD1L1 (Affinity Capture-MS), CWC22 (Affinity Capture-MS), RPS27A (Affinity Capture-MS), NOS1AP (Affinity Capture-MS), CLK2 (Affinity Capture-MS)

ESM2 similar proteins: A0A6I8RMG7, A5A6L1, A7E2Z9, B3F211, O00622, O54775, O95388, P0C5H9, P12025, P18406, P19336, P21741, P24052, P24593, P24594, P35446, P35447, P48530, P48531, P48532, P48533, P55145, P80513, Q05717, Q07079, Q28985, Q2MKA7, Q49AH0, Q4V7M2, Q5M7L6, Q5UE90, Q5XH36, Q6DDW2, Q6DHR0, Q6P8F3, Q6UXX9, Q8BFU0, Q8R553, Q8VCC9, Q8VDA1

Diamond homologs: P12025, P21246, P21741, P21782, P24052, P32760, P48530, P48531, P48532, P48533, P63089, P63090, P79281, Q6P8F3, Q9R1S9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MDK	up-regulates	NOTCH2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	10
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

734 predictions. Top by Δscore:

Variant	Effect	Δscore
11:46382130:A:T	donor_gain	1.0000
11:46382292:A:AG	acceptor_gain	1.0000
11:46382293:G:GG	acceptor_gain	1.0000
11:46382583:CCA:C	acceptor_loss	1.0000
11:46382584:CAGCC:C	acceptor_loss	1.0000
11:46382585:A:AG	acceptor_gain	1.0000
11:46382585:A:T	acceptor_loss	1.0000
11:46382586:G:GA	acceptor_gain	1.0000
11:46382586:GCC:G	acceptor_gain	1.0000
11:46382586:GCCGA:G	acceptor_gain	1.0000
11:46382744:CAAAG:C	donor_loss	1.0000
11:46382747:AGG:A	donor_loss	1.0000
11:46380788:A:T	donor_gain	0.9900
11:46381527:G:GT	donor_gain	0.9900
11:46381964:A:T	donor_gain	0.9900
11:46382052:CTCA:C	acceptor_loss	0.9900
11:46382054:CAGG:C	acceptor_loss	0.9900
11:46382055:A:C	acceptor_loss	0.9900
11:46382056:G:A	acceptor_loss	0.9900
11:46382129:GAAAG:G	donor_gain	0.9900
11:46382130:AAAG:A	donor_loss	0.9900
11:46382132:AGGTG:A	donor_loss	0.9900
11:46382133:GGTGA:G	donor_loss	0.9900
11:46382134:GT:G	donor_loss	0.9900
11:46382135:T:A	donor_loss	0.9900
11:46382286:C:CA	acceptor_gain	0.9900
11:46382290:GTA:G	acceptor_loss	0.9900
11:46382291:TAGAT:T	acceptor_loss	0.9900
11:46382292:A:C	acceptor_loss	0.9900
11:46382293:G:C	acceptor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000002643 (11:46380726 C>A,T), RS1000269356 (11:46380390 T>A,G), RS1001674189 (11:46381863 C>G), RS1001752631 (11:46383139 C>A,G,T), RS1002348853 (11:46382154 G>A,C), RS1003009117 (11:46381962 G>A), RS1003205224 (11:46380892 TG>T), RS1003315056 (11:46380548 TTTC>T), RS1003342698 (11:46380727 G>A,T), RS1003395780 (11:46383404 C>A,G,T), RS1003751040 (11:46383585 T>C,G), RS1003804717 (11:46380315 T>C), RS1004066567 (11:46380041 G>A,T), RS1004989965 (11:46382346 G>A,T), RS1005126297 (11:46381978 G>A,T)

Disease associations

OMIM: gene MIM:162096 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000763_2	Immunoglobulin A	2.000000e-06
GCST004521_122	Autism spectrum disorder or schizophrenia	3.000000e-13
GCST004521_165	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004946_84	Schizophrenia	7.000000e-12
GCST006803_20	Schizophrenia	3.000000e-13
GCST006943_7	Feeling miserable	2.000000e-08
GCST007201_238	Schizophrenia	2.000000e-10
GCST007825_4	Alzheimer’s disease or fasting glucose levels (pleiotropy)	3.000000e-16

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004747	protein measurement
EFO:0009598	feeling miserable measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1949490 (SINGLE PROTEIN)

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

ChEMBL bioactivities

9 potent at pChembl≥5 of 9 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.58	Kd	2.62	nM	CHEMBL1950106
7.94	Kd	11.6	nM	CHEMBL1950108
7.75	Kd	17.8	nM	CHEMBL1950107
7.28	Kd	52.3	nM	CHEMBL4540967
7.02	Kd	96.3	nM	CHEMBL4436421
6.69	IC50	206	nM	CHEMBL4209610
6.40	IC50	396	nM	CHEMBL4206352
5.89	IC50	1300	nM	CHEMBL4202957
5.69	Kd	2030	nM	CHEMBL1950105

PubChem BioAssay actives

7 with measured affinity, of 12 total; 7 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
tetrasodium;[(2R,3R,4R,5R,6S)-6-[(2S,3S,4R,5R,6R)-6-[2-[3-[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]propanoylamino]ethoxy]-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-acetamido-4-[(2R,3R,4R,5S,6S)-5-[(2S,3R,4R,5R,6R)-3-acetamido-4-hydroxy-5-sulfonatooxy-6-(sulfonatooxymethyl)oxan-2-yl]oxy-6-carboxy-3,4-dihydroxyoxan-2-yl]oxy-2-(sulfonatooxymethyl)oxan-3-yl] sulfate	647575: Binding affinity to recombinant midkine after 3 mins	kd	0.0026	uM
trisodium;[(2R,3R,4R,5R,6S)-6-[(2S,3S,4R,5R,6R)-6-[2-[3-[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]propanoylamino]ethoxy]-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-acetamido-4-[(2R,3R,4R,5S,6S)-5-[(2S,3R,4R,5R,6R)-3-acetamido-4-hydroxy-5-sulfonatooxy-6-(sulfonatooxymethyl)oxan-2-yl]oxy-6-carboxy-3,4-dihydroxyoxan-2-yl]oxy-2-(hydroxymethyl)oxan-3-yl] sulfate	647575: Binding affinity to recombinant midkine after 3 mins	kd	0.0116	uM
disodium;[(2R,3R,4R,5R,6S)-6-[(2S,3S,4R,5R,6R)-6-[2-[3-[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]propanoylamino]ethoxy]-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-acetamido-4-[(2R,3R,4R,5S,6S)-5-[(2S,3R,4R,5R,6R)-3-acetamido-4-hydroxy-6-(hydroxymethyl)-5-sulfonatooxyoxan-2-yl]oxy-6-carboxy-3,4-dihydroxyoxan-2-yl]oxy-2-(hydroxymethyl)oxan-3-yl] sulfate	647575: Binding affinity to recombinant midkine after 3 mins	kd	0.0178	uM
(2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2-(6-azidohexoxy)-5-hydroxy-6-(sulfooxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(sulfooxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid	1612775: Binding affinity to MDK (unknown origin) by SPR assay	kd	0.0523	uM
(2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5R,6R)-3-acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5R,6R)-3-acetamido-2-(6-azidohexoxy)-5-sulfooxy-6-(sulfooxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-sulfooxy-6-(sulfooxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid	1612775: Binding affinity to MDK (unknown origin) by SPR assay	kd	0.0963	uM
benzyl (2S,3S,4S,5R,6R)-5-benzoyloxy-6-[(2S,3R,4R,5S,6R)-2-[(2S,3S,4S,5R,6S)-5-benzoyloxy-6-(4-methoxyphenoxy)-4-phenylmethoxy-2-phenylmethoxycarbonyloxan-3-yl]oxy-5-sulfooxy-6-(sulfooxymethyl)-3-[(2,2,2-trifluoroacetyl)amino]oxan-4-yl]oxy-3-[(2S,3R,4R,5S,6R)-4-(4-oxopentanoyloxy)-5-sulfooxy-6-(sulfooxymethyl)-3-[(2,2,2-trifluoroacetyl)amino]oxan-2-yl]oxy-4-phenylmethoxyoxane-2-carboxylate	1374217: Inhibition of fluorescein labelled heparin-like hexasaccharide probe binding to recombinant human midkine after 5 mins by fluorescence polarization assay	ic50	1.3000	uM
(2S,3S,4R,5R,6R)-6-[2-[3-[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]propanoylamino]ethoxy]-3-[(2S,3R,4R,5R,6R)-3-acetamido-4-[(2R,3R,4R,5S,6S)-5-[(2S,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-carboxy-3,4-dihydroxyoxan-2-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5-dihydroxyoxane-2-carboxylic acid	647575: Binding affinity to recombinant midkine after 3 mins	kd	2.0300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression	3
Tretinoin	increases expression	3
Particulate Matter	increases expression, affects cotreatment, decreases expression, decreases reaction, increases abundance	3
sodium arsenite	decreases expression, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
Chondroitin Sulfates	affects binding	2
Doxorubicin	increases expression, decreases response to substance	2
Tobacco Smoke Pollution	affects expression, increases expression	2
aristolochic acid I	increases expression	1
lly-283	decreases expression	1
methyleugenol	increases expression	1
bisphenol A	affects expression	1
beta-lapachone	increases expression	1
arsenite	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	increases expression	1
nickel sulfate	decreases expression	1
bicalutamide	increases expression	1
tamibarotene	increases expression	1
seocalcitol	decreases expression	1
azoxystrobin	increases expression	1
fenpyroximate	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
pyrimidifen	increases expression	1
nutlin 3	affects cotreatment, increases expression	1
ICG 001	increases expression	1
thifluzamide	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
pyrachlostrobin	increases expression	1
enzalutamide	affects expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1952884	Binding	Binding affinity to recombinant midkine after 3 mins	Synthesis and interaction with midkine of biotinylated chondroitin sulfate tetrasaccharides. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C6Y2	HAP1 MDK (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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