ADAM15

Summary

ADAM15 (ADAM metallopeptidase domain 15, HGNC:193) is a protein-coding gene on chromosome 1q21.3, encoding Disintegrin and metalloproteinase domain-containing protein 15 (Q13444). Active metalloproteinase with gelatinolytic and collagenolytic activity.

The protein encoded by this gene is a member of the ADAM (a disintegrin and metalloproteinase) protein family. ADAM family members are type I transmembrane glycoproteins known to be involved in cell adhesion and proteolytic ectodomain processing of cytokines and adhesion molecules. This protein contains multiple functional domains including a zinc-binding metalloprotease domain, a disintegrin-like domain, as well as a EGF-like domain. Through its disintegrin-like domain, this protein specifically interacts with the integrin beta chain, beta 3. It also interacts with Src family protein-tyrosine kinases in a phosphorylation-dependent manner, suggesting that this protein may function in cell-cell adhesion as well as in cellular signaling. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed.

Source: NCBI Gene 8751 — RefSeq curated summary.

At a glance

• GWAS associations: 23
• Clinical variants (ClinVar): 204 total — 4 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_207197

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:193
Approved symbol	ADAM15
Name	ADAM metallopeptidase domain 15
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	MDC15
Ensembl gene	ENSG00000143537
Ensembl biotype	protein_coding
OMIM	605548
Entrez	8751

Gene structure

Transcript identifiers

Ensembl transcripts: 68 — 46 protein_coding, 14 protein_coding_CDS_not_defined, 6 retained_intron, 2 nonsense_mediated_decay

ENST00000271836, ENST00000355956, ENST00000356955, ENST00000359280, ENST00000360674, ENST00000368412, ENST00000368413, ENST00000447332, ENST00000449910, ENST00000461234, ENST00000461564, ENST00000462116, ENST00000464824, ENST00000468053, ENST00000470779, ENST00000472434, ENST00000473905, ENST00000474709, ENST00000477533, ENST00000480331, ENST00000485346, ENST00000487956, ENST00000498481, ENST00000525020, ENST00000526491, ENST00000527418, ENST00000529473, ENST00000531455, ENST00000531703, ENST00000531831, ENST00000533732, ENST00000534019, ENST00000876982, ENST00000876983, ENST00000876984, ENST00000876985, ENST00000876986, ENST00000876987, ENST00000876988, ENST00000876989, ENST00000876990, ENST00000876991, ENST00000876992, ENST00000876993, ENST00000876994, ENST00000876995, ENST00000876996, ENST00000876997, ENST00000876998, ENST00000876999, ENST00000877000, ENST00000877001, ENST00000877002, ENST00000877003, ENST00000877004, ENST00000877005, ENST00000877006, ENST00000877007, ENST00000877008, ENST00000877009, ENST00000911991, ENST00000911992, ENST00000960269, ENST00000960270, ENST00000960271, ENST00000960272, ENST00000960273, ENST00000960274

RefSeq mRNA: 9 — MANE Select: NM_207197 NM_001261464, NM_001261465, NM_001261466, NM_003815, NM_207191, NM_207194, NM_207195, NM_207196, NM_207197

CCDS: CCDS1084, CCDS1085, CCDS1086, CCDS1087, CCDS1088, CCDS44236, CCDS58031, CCDS58032, CCDS60282

Canonical transcript exons

ENST00000356955 — 23 exons

Exon	Start	End
ENSE00003496245	155061415	155061489
ENSE00003504300	155051316	155051465
ENSE00003509732	155060763	155060832
ENSE00003520289	155058246	155058441
ENSE00003527163	155062245	155062369
ENSE00003537750	155052671	155052777
ENSE00003598333	155059902	155059974
ENSE00003620114	155060205	155060343
ENSE00003637430	155062460	155062775
ENSE00003639515	155058710	155058787
ENSE00003677858	155061904	155061975
ENSE00003687591	155053417	155053493
ENSE00003694777	155056080	155056249
ENSE00003696095	155055932	155056000
ENSE00003696133	155056386	155056470
ENSE00003698549	155056953	155057101
ENSE00003699096	155057851	155058155
ENSE00003699190	155055790	155055852
ENSE00003699780	155057637	155057729
ENSE00003700918	155054150	155054226
ENSE00003701182	155057188	155057362
ENSE00003701711	155053910	155053988
ENSE00003702171	155054314	155054506

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 99.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 62.0226 / max 602.1137, expressed in 1818 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5561	62.0226	1818

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.21	gold quality
skin of leg	UBERON:0001511	99.06	gold quality
skin of abdomen	UBERON:0001416	99.03	gold quality
apex of heart	UBERON:0002098	98.84	gold quality
peripheral nervous system	UBERON:0000010	98.38	gold quality
left uterine tube	UBERON:0001303	98.38	gold quality
tibial nerve	UBERON:0001323	98.38	gold quality
mucosa of stomach	UBERON:0001199	98.23	gold quality
minor salivary gland	UBERON:0001830	98.17	gold quality
upper lobe of left lung	UBERON:0008952	98.15	gold quality
right lung	UBERON:0002167	98.05	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.05	gold quality
mucosa of transverse colon	UBERON:0004991	98.03	gold quality
body of stomach	UBERON:0001161	98.00	gold quality
ectocervix	UBERON:0012249	97.99	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.99	gold quality
body of uterus	UBERON:0009853	97.97	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.94	gold quality
lower esophagus	UBERON:0013473	97.93	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.91	gold quality
omental fat pad	UBERON:0010414	97.88	gold quality
right lobe of thyroid gland	UBERON:0001119	97.78	gold quality
peritoneum	UBERON:0002358	97.77	gold quality
right coronary artery	UBERON:0001625	97.76	gold quality
cerebellar hemisphere	UBERON:0002245	97.62	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.58	gold quality
transverse colon	UBERON:0001157	97.51	gold quality
granulocyte	CL:0000094	97.43	gold quality
cerebellar cortex	UBERON:0002129	97.39	gold quality
endocervix	UBERON:0000458	97.19	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-11	yes	43.19
E-HCAD-10	yes	33.89
E-MTAB-8410	yes	26.78
E-ANND-3	yes	16.21
E-MTAB-6678	yes	13.06

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IL1B, SP1

miRNA regulators (miRDB)

1 targeting ADAM15, 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-4443	98.02	66.25	1928

Literature-anchored findings (GeneRIF, showing 40)

• These data demonstrate selective, phosphorylation-dependent interactions of ADAM15 with Src family PTKs and Grb2, which highlight the potential for integration of ADAM functions and cellular signaling (PMID:11741929)
• Atrial fibrillation is associated with an increase in the expression of ADAM15 in the heart atrium (PMID:11839628)
• structure determined by X ray chrystallography (PMID:11840679)
• functional classification based on a conserved motif for bining intergrinalpha9beta1 (PMID:11882657)
• ADAM 15 IS involved in the restructuring of the mesangial matrix and in the migration of MC in disease. (PMID:12091380)
• Data suggest that ADAM15, whose expression may be driven by VE-cadherin, may be a component of adherens junctions and play a role in endothelial functions mediated by these cell contacts. (PMID:12243749)
• ADAM8, ADAM15, and MDC-L, but not ADAM17, catalyzed ectodomain shedding of CD23, the low affinity IgE receptor. (PMID:12777399)
• ADAM15 has a role in pathological neovascularization in mice (PMID:12897135)
• ADAM 15 was detected in perinatal cortical pyramidal cells; during aging there was also an increase in intracellular staining and the number of stained cells per volume (cell density). In AD brains ADAM 15 was seen in a few diffuse plaques (PMID:14707550)
• In humans, the cytoplasmic domain of ADAM15v2 strongly interacts with Lck and Hck and regulates leukocyte function. (PMID:15263807)
• The expression and the role of ADAMs in intestinal epithelial cells, including its role in wound healing in human cell lines and cultured colonic cells. (PMID:15358598)
• Altered regulation of alternative exon usage in ADAM15 gene may provide a useful target for cancer diagnostics development (PMID:15384173)
• ADAM15 decreases integrin alphavbeta3/vitronectin-mediated ovarian neoplasm cell adhesion and movement in an RGD-dependent fashion. (PMID:15618016)
• Lung carcinoma cell lines and tissues were frequently ADAM15 positive. (PMID:15756594)
• ADAM15 is generally overexpressed in adenocarcinoma and is highly associated with metastatic progression of prostate and breast cancers (PMID:16756724)
• ADAM15 is upregulated in epithelial cells during inflammatory bowel disease compared with the normal colon epithelial cells. (PMID:16894352)
• the ADAM-15 disintegrin-like domain and a number of mutants in which the RGD-containing loop was substituted by cognate regions from ADAM-2, -12 and -19 were tested in terms of integrin-binding activity (PMID:17080222)
• ADAM-15-mediated cell-cell interactions are involved in mechanisms of epithelial restitution and production of pro-inflammatory mediators (PMID:17416588)
• disintegrin domain of ADAM-15 inhibits ASMC adhesion and migration through the beta(1)-integrin, without modulating signaling pathways involved in ASMC migratory responses (PMID:17575078)
• the alternative exon use is a physiological post-transcriptional mechanism regulating ADAM15 expression in human tissues. (PMID:17937806)
• Loss of ADAM15 significantly attenuated the metastatic spread of PC-3 cells to bone. Data strongly support a functional role for ADAM15 in prostate tumor cell interaction with vascular endothelium and the metastatic progression of human prostate cancer. (PMID:18281484)
• Four ADAM-15 variants are differentially expressed in human mammary carcinoma tissues compared with normal breast. (PMID:18296648)
• This presents a novel mechanism by which ADAM15 regulates cell-matrix adhesion and migration. (PMID:18387333)
• ADAM15 catalyzes the cleavage of E-cadherin to generate a soluble fragment that in turn binds to and stimulates ErbB receptor signaling (PMID:18434311)
• Recombinant ADAM15 disintegrin domain inhibits melanoma cell proliferation partly through p38 kinase activation. (PMID:18695922)
• cytoplasmic tail of ADAM15 confers a modulatory effect on the autophosphorylation site Y397 of the focal adhesion kinase (FAK) during chondrocyte-collagen interaction (PMID:18774960)
• results define key catalytic properties of ADAM15 in cells and its response to stimulators and inhibitors of ectodomain shedding. (PMID:19207106)
• involved in advanced atherosclerosis, in catalytically active form, most notably associated with cells of monocytic origin (PMID:19253070)
• Insights into the mechanism of how a splice variant linked to clinical agressiveness in breast cancer causes increased activity of ADAM15B. (PMID:19487280)
• analysis of the ADAM15 disintegrin domain and its binding properties (PMID:19550037)
• Alternative splicing of ADAM15 regulates its interactions with cellular SH3 proteins SNX33 and nephrocystin (PMID:19718658)
• The effects of ADAM15 on endothelial hyperpermeability and neutrophil transmigration are mediated by intracellular signalling involving Src and ERK1/2 activation. (PMID:20189953)
• ADAM15 conveys antiapoptotic properties to osteoarthritis chondrocytes that might sustain their potential to better resist the influence of death-inducing stimuli under pathophysiologic conditions (PMID:20213810)
• the downregulation of ADAM15 plays an important role in melanoma progression and ADAM15 act as a tumorsuppressor in melanoma. (PMID:20851104)
• Promoter methylation of ADAM15 was examined as well as the microsatellite instability status. Thirty-six percent of colorectal carcinomas displayed a reduced expression of ADAM15. (PMID:21190186)
• demonstrate the intrinsic promoter activity of ADAM15 in quiescent mesangial cells and show the involvement of Sp1 in its regulation (PMID:21196774)
• gene expressions for ADAM8 and ADAM15 were notably lower in ascending aorta as compared with aortic dissection (PMID:21728902)
• Exosomes rich in ADAM15 display enhanced binding affinity for integrin alphavbeta3 in an RGD-dependent manner and suppress vitronectin- and fibronectin-induced cell adhesion, growth, and migration, as well as in vivo tumor growth. (PMID:22505472)
• ADAM15 tail can transduce a percepted extracellular signal to enhance FAK and Src phosphorylation. (PMID:22544741)
• dispensable for cutaneous wound healing and B16F1 melanoma growth, but significantly contributes to metastasis formation (PMID:22621184)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adam15	ENSDARG00000089213
mus_musculus	Adam15	ENSMUSG00000028041
rattus_norvegicus	Adam15	ENSRNOG00000020590

Paralogs (20): ADAM22 (ENSG00000008277), ADAM28 (ENSG00000042980), ADAM7 (ENSG00000069206), ADAM11 (ENSG00000073670), ADAM2 (ENSG00000104755), ADAM23 (ENSG00000114948), ADAM20 (ENSG00000134007), ADAMDEC1 (ENSG00000134028), ADAM30 (ENSG00000134249), ADAM19 (ENSG00000135074), ADAM10 (ENSG00000137845), ADAM21 (ENSG00000139985), ADAM12 (ENSG00000148848), ADAM33 (ENSG00000149451), ADAM8 (ENSG00000151651), ADAM17 (ENSG00000151694), ADAM29 (ENSG00000168594), ADAM9 (ENSG00000168615), ADAM18 (ENSG00000168619), ADAM32 (ENSG00000197140)

Protein

Protein identifiers

Disintegrin and metalloproteinase domain-containing protein 15 — Q13444 (reviewed: Q13444)

Alternative names: Metalloprotease RGD disintegrin protein, Metalloproteinase-like, disintegrin-like, and cysteine-rich protein 15, Metargidin

All UniProt accessions (1): Q13444

UniProt curated annotations — full annotation on UniProt →

Function. Active metalloproteinase with gelatinolytic and collagenolytic activity. Plays a role in the wound healing process. Mediates both heterotypic intraepithelial cell/T-cell interactions and homotypic T-cell aggregation. Inhibits beta-1 integrin-mediated cell adhesion and migration of airway smooth muscle cells. Suppresses cell motility on or towards fibronectin possibly by driving alpha-v/beta-1 integrin (ITAGV-ITGB1) cell surface expression via ERK1/2 inactivation. Cleaves E-cadherin in response to growth factor deprivation. Plays a role in glomerular cell migration. Plays a role in pathological neovascularization. May play a role in cartilage remodeling. May be proteolytically processed, during sperm epididymal maturation and the acrosome reaction. May play a role in sperm-egg binding through its disintegrin domain.

Subunit / interactions. Interacts with ITAGV-ITGB3 (vitronectin receptor). Interacts with SH3GL2 and SNX9; this interaction occurs preferentially with ADAM15 precursor, rather than the processed form, suggesting it occurs in a secretory pathway compartment prior to the medial Golgi. Interacts with ITAG9-ITGB1. Interacts specifically with Src family protein-tyrosine kinases (PTKs). Interacts with SH3PXD2A. Interacts with ITAGV-ITGB1. Interacts with GRB2, HCK, ITSN1, ITSN2, LYN, MAPK1, MAPK3, NCF1, NCK1, nephrocystin, PTK6, SNX33, LCK and SRC.

Subcellular location. Endomembrane system. Cell junction. Adherens junction. Cell projection. Cilium. Flagellum. Cytoplasmic vesicle. Secretory vesicle. Acrosome.

Tissue specificity. Expressed in colon and small intestine. Expressed in airway smooth muscle and glomerular mesangial cells (at protein level). Ubiquitously expressed. Overexpressed in atherosclerotic lesions. Constitutively expressed in cultured endothelium and smooth muscle. Expressed in chondrocytes. Expressed in airway smooth muscle and glomerular mesangial cells.

Post-translational modifications. The precursor is cleaved by a furin endopeptidase. Phosphorylation increases association with PTKs.

Activity regulation. Inhibited by hydroxamate-type metalloproteinase inhibitors such as marimastat. Inhibited by metalloproteinase inhibitor 2 (TIMP-2) and TIMP-3 at nanomolar concentrations. Not significantly inhibited by TIMP-1 at concentrations of up to 100 nM. Not activated by PMA or ionomycin.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The cytoplasmic domain is required for SH3GL2- and SNX9-binding. Disintegrin domain binds to integrin alphaV-beta3. The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.

Isoforms (13)

UniProt ID	Names	Canonical?
Q13444-1	1, 6b	yes
Q13444-2	2
Q13444-3	3, 6a
Q13444-4	4, 4a
Q13444-5	5
Q13444-6	6, 7b
Q13444-7	7, 7a
Q13444-8	8
Q13444-9	9, 3a
Q13444-10	10, 1
Q13444-11	11
Q13444-12	12
Q13444-13	13

RefSeq proteins (9): NP_001248393, NP_001248394, NP_001248395, NP_003806, NP_997074, NP_997077, NP_997078, NP_997079, NP_997080* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR001590	Peptidase_M12B	Domain
IPR001762	Disintegrin_dom	Domain
IPR002870	Peptidase_M12B_N	Domain
IPR006586	ADAM_Cys-rich	Domain
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR034027	Reprolysin_adamalysin	Domain
IPR036436	Disintegrin_dom_sf	Homologous_superfamily

Pfam: PF00200, PF01421, PF01562, PF08516

Enzyme classification (BRENDA):

• EC 3.4.24.B28 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

UniProt features (63 total): splice variant 14, disulfide bond 7, sequence conflict 6, compositionally biased region 5, glycosylation site 5, short sequence motif 4, binding site 4, sequence variant 3, domain 3, region of interest 2, modified residue 2, topological domain 2, signal peptide 1, propeptide 1, chain 1, active site 1, transmembrane region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13444-F1	73.35	0.31

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): 349

Ligand- & substrate-binding residues (4): 179 (in inhibited form); 348; 352; 358

Post-translational modifications (2): 715, 735

Disulfide bonds (7): 323–409, 365–393, 367–376, 480–500, 657–667, 661–673, 675–684

Glycosylation sites (5): 237, 389, 392, 606, 611

Mutagenesis-validated functional residues (1):

Position	Phenotype
484–485	reduces adam15-mediated t-cell aggregation.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-8941237	Invadopodia formation
R-HSA-1474244	Extracellular matrix organization

MSigDB gene sets: 265 (showing top): MORF_RAGE, BENPORATH_ES_WITH_H3K27ME3, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOCC_SECRETORY_GRANULE, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_GROWTH, GOCC_CELL_SURFACE, GOBP_REGENERATION, TGACCTY_ERR1_Q2, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, PRAMOONJAGO_SOX4_TARGETS_DN, PID_INTEGRIN_A9B1_PATHWAY

GO Biological Process (18): angiogenesis (GO:0001525), negative regulation of cell-matrix adhesion (GO:0001953), immune response to tumor cell (GO:0002418), proteolysis (GO:0006508), cell-matrix adhesion (GO:0007160), integrin-mediated signaling pathway (GO:0007229), male gonad development (GO:0008584), extracellular matrix disassembly (GO:0022617), negative regulation of cell growth (GO:0030308), negative regulation of cell migration (GO:0030336), collagen catabolic process (GO:0030574), tissue regeneration (GO:0042246), innate immune response (GO:0045087), cardiac epithelial to mesenchymal transition (GO:0060317), cellular response to phorbol 13-acetate 12-myristate (GO:1904628), response to hypobaric hypoxia (GO:1990910), cell adhesion (GO:0007155), negative regulation of receptor binding (GO:1900121)

GO Molecular Function (9): metalloendopeptidase activity (GO:0004222), integrin binding (GO:0005178), metallopeptidase activity (GO:0008237), SH3 domain binding (GO:0017124), immunoglobulin receptor binding (GO:0034987), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (13): acrosomal vesicle (GO:0001669), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), adherens junction (GO:0005912), cell surface (GO:0009986), motile cilium (GO:0031514), extracellular exosome (GO:0070062), cilium (GO:0005929), endomembrane system (GO:0012505), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Extracellular matrix organization	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
signaling receptor binding	3
immune response	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
regulation of cell-matrix adhesion	1
cell-matrix adhesion	1
negative regulation of cell-substrate adhesion	1
response to tumor cell	1
protein metabolic process	1
cell-substrate adhesion	1
cell surface receptor signaling pathway	1
gonad development	1
development of primary male sexual characteristics	1
cellular component disassembly	1
extracellular matrix organization	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
catabolic process	1
collagen metabolic process	1
regeneration	1
developmental growth	1
defense response to symbiont	1
epithelial to mesenchymal transition	1
heart morphogenesis	1
cellular response to lipid	1
cellular response to alcohol	1
cellular response to ketone	1
response to phorbol 13-acetate 12-myristate	1
response to hypoxia	1
cellular process	1
negative regulation of protein binding	1
regulation of receptor binding	1
endopeptidase activity	1
metallopeptidase activity	1

Protein interactions and networks

STRING

984 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAM15	SNX9	Q9Y5X1	977
ADAM15	SH3PXD2B	A1X283	889
ADAM15	SH3GL2	Q99962	748
ADAM15	GRB2	P29354	680
ADAM15	SRC	P12931	667
ADAM15	MAD2L2	Q9UI95	665
ADAM15	TIMP3	P35625	617
ADAM15	MAD2L1	Q13257	588
ADAM15	MMP14	P50281	588
ADAM15	REV3L	O60673	582
ADAM15	ITGAV	P06756	564
ADAM15	REV1	Q9UBZ9	541
ADAM15	ITGB5	P18084	541
ADAM15	SH3PXD2A	Q5TCZ1	537
ADAM15	NCK1	P16333	506

IntAct

109 interactions, top by confidence:

A	B	Type	Score
ADAM15	SRC	psi-mi:“MI:0407”(direct interaction)	0.750
ADAM15	SNX9	psi-mi:“MI:0407”(direct interaction)	0.750
ADAM15	SNX9	psi-mi:“MI:0915”(physical association)	0.750
SRC	ADAM15	psi-mi:“MI:0915”(physical association)	0.750
SNX9	ADAM15	psi-mi:“MI:0915”(physical association)	0.750
ADAM15	SRC	psi-mi:“MI:0915”(physical association)	0.750
ADAM15	SNX33	psi-mi:“MI:0407”(direct interaction)	0.710
ADAM15	SH3PXD2A	psi-mi:“MI:0407”(direct interaction)	0.710
ADAM15	NPHP1	psi-mi:“MI:0407”(direct interaction)	0.710
ADAM15	HCK	psi-mi:“MI:0407”(direct interaction)	0.710
ADAM15	GRB2	psi-mi:“MI:0407”(direct interaction)	0.710
ADAM15	HCK	psi-mi:“MI:0915”(physical association)	0.710
ADAM15	SNX33	psi-mi:“MI:0915”(physical association)	0.710
NPHP1	ADAM15	psi-mi:“MI:0915”(physical association)	0.710
SH3PXD2A	ADAM15	psi-mi:“MI:0915”(physical association)	0.710
GRB2	ADAM15	psi-mi:“MI:0915”(physical association)	0.710
ADAM15	GRB2	psi-mi:“MI:0915”(physical association)	0.710
ADAM15	SH3PXD2A	psi-mi:“MI:0915”(physical association)	0.710
ADAM15	NPHP1	psi-mi:“MI:0915”(physical association)	0.710
Itga5	ITGB3	psi-mi:“MI:0915”(physical association)	0.700
ADAM15	LCK	psi-mi:“MI:0407”(direct interaction)	0.670

BioGRID (102): ADAM15 (Two-hybrid), ADAM15 (Two-hybrid), RBPMS (Two-hybrid), NUP62 (Two-hybrid), BANP (Two-hybrid), TRIP13 (Two-hybrid), ADAM15 (Affinity Capture-MS), ADAM15 (Affinity Capture-RNA), ADAM15 (Affinity Capture-MS), ADAM15 (Affinity Capture-MS), ADAM15 (Affinity Capture-MS), ADAM15 (Two-hybrid), ADAM15 (Two-hybrid), SNX33 (Two-hybrid), ADAM15 (Two-hybrid)

ESM2 similar proteins: A0EQL2, A2AJ76, A2AJA7, A6H8M9, A8T650, A8T682, A8T688, A8T6A6, D3ZLH5, F1QVU0, O08628, O75173, O88839, P04278, P08514, P08689, P0DV84, P15196, P20701, P29376, P32970, P38570, P60882, P80012, P97497, P97793, Q13444, Q15113, Q5RFQ8, Q5TM20, Q61398, Q63191, Q6UXC1, Q7Z304, Q7Z442, Q7Z7M0, Q8BNJ2, Q8CG85, Q8K1S7, Q8NBP7

Diamond homologs: A0A0B4U9L8, A0A6B7FMR5, A2CJE2, A2CJE3, A2CJE4, A3R0T9, A4PBQ9, A8QL48, A8QL49, A8QL59, B8K1W0, C0LZJ5, C5H5D1, C5H5D2, C5H5D3, C5H5D4, C5H5D5, C5H5D6, C9E1R8, C9E1S0, D3TTC1, D3TTC2, D5LMJ3, D6PXE8, D8VNS0, F8RKV9, F8RKW0, F8RKW1, F8S108, G5EFD5, J3S829, J3S830, J3SDW6, J3SDW8, O35227, O35674, O42138, O43184, O77780, O88839

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
HCK	up-regulates	ADAM15	phosphorylation
HCK	unknown	ADAM15	phosphorylation
LCK	up-regulates	ADAM15	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 81 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	7	63.8×	2e-09
Regulation of KIT signaling	6	63.3×	3e-08
Regulation of signaling by CBL	6	52.3×	8e-08
Co-inhibition by CTLA4	5	45.5×	2e-06
Signaling by CSF1 (M-CSF) in myeloid cells	7	42.5×	2e-08
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	6	37.6×	5e-07
Signaling by SCF-KIT	8	34.8×	7e-09
Co-stimulation by CD28	5	33.4×	9e-06

GO biological processes:

GO term	Partners	Fold	FDR
Fc-gamma receptor signaling pathway involved in phagocytosis	6	55.4×	4e-07
leukocyte migration	5	41.1×	2e-05
negative regulation of inflammatory response to antigenic stimulus	5	39.6×	2e-05
B cell receptor signaling pathway	7	37.0×	4e-07
ephrin receptor signaling pathway	7	31.7×	6e-07
peptidyl-tyrosine phosphorylation	5	27.7×	1e-04
T cell costimulation	5	24.6×	1e-04
substrate adhesion-dependent cell spreading	5	22.6×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	129
Likely benign	16
Benign	2

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
151159	GRCh38/hg38 1q21.3-23.1(chr1:154566501-157624084)x3	Pathogenic
3063199	GRCh37/hg19 1q21.3-23.1(chr1:154302443-156868186)x1	Pathogenic
4682506	GRCh37/hg19 1q21.3-22(chr1:154822196-156304685)x3	Pathogenic
60040	GRCh38/hg38 1q21.3-22(chr1:154575689-155292901)x1	Pathogenic

SpliceAI

3287 predictions. Top by Δscore:

Variant	Effect	Δscore
1:155053906:ACAG:A	acceptor_gain	1.0000
1:155053907:CAGGG:C	acceptor_gain	1.0000
1:155053908:AG:A	acceptor_gain	1.0000
1:155053908:AGGGA:A	acceptor_gain	1.0000
1:155053909:GG:G	acceptor_gain	1.0000
1:155053909:GGGA:G	acceptor_gain	1.0000
1:155053909:GGGAG:G	acceptor_gain	1.0000
1:155053985:TTTGG:T	donor_loss	1.0000
1:155053988:GGTG:G	donor_loss	1.0000
1:155053989:G:GG	donor_gain	1.0000
1:155053990:T:A	donor_loss	1.0000
1:155053991:G:GT	donor_loss	1.0000
1:155054312:A:AG	acceptor_gain	1.0000
1:155054312:AGAG:A	acceptor_gain	1.0000
1:155054313:G:GG	acceptor_gain	1.0000
1:155054313:GA:G	acceptor_gain	1.0000
1:155054313:GAGG:G	acceptor_gain	1.0000
1:155054313:GAGGC:G	acceptor_gain	1.0000
1:155054502:GCCGG:G	donor_gain	1.0000
1:155054503:CCGGG:C	donor_loss	1.0000
1:155054505:GG:G	donor_gain	1.0000
1:155054506:GG:G	donor_gain	1.0000
1:155054506:GGTG:G	donor_loss	1.0000
1:155054507:G:GA	donor_loss	1.0000
1:155054512:G:GT	donor_gain	1.0000
1:155055785:A:AG	acceptor_gain	1.0000
1:155055786:G:GG	acceptor_gain	1.0000
1:155055786:GTA:G	acceptor_gain	1.0000
1:155055786:GTAGA:G	acceptor_gain	1.0000
1:155055929:CA:C	acceptor_loss	1.0000

AlphaMissense

5536 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:155057208:T:G	F390C	0.996
1:155057207:T:C	F390L	0.991
1:155057209:C:A	F390L	0.991
1:155057209:C:G	F390L	0.991
1:155058025:T:A	C531S	0.990
1:155058026:G:C	C531S	0.990
1:155058271:T:A	C583S	0.990
1:155058272:G:C	C583S	0.990
1:155056130:G:C	W265C	0.989
1:155056130:G:T	W265C	0.989
1:155056993:C:A	A347D	0.989
1:155057210:A:C	S391R	0.989
1:155057212:C:A	S391R	0.989
1:155057212:C:G	S391R	0.989
1:155057219:A:C	S394R	0.989
1:155057221:C:A	S394R	0.989
1:155057221:C:G	S394R	0.989
1:155057211:G:T	S391I	0.988
1:155056186:T:C	F284S	0.987
1:155056196:G:C	W287C	0.987
1:155056196:G:T	W287C	0.987
1:155058256:T:A	C578S	0.987
1:155058257:G:C	C578S	0.987
1:155057208:T:C	F390S	0.986
1:155056992:G:C	A347P	0.985
1:155058728:T:A	C646S	0.985
1:155058729:G:C	C646S	0.985
1:155056128:T:A	W265R	0.983
1:155056128:T:C	W265R	0.983
1:155057087:G:A	M378I	0.983

dbSNP variants (sampled 300 via entrez): RS1000321813 (1:155054090 C>T), RS1000322784 (1:155053786 A>G), RS1001443235 (1:155058692 C>T), RS1001729797 (1:155052507 C>G), RS1002171075 (1:155052501 C>T), RS1002270398 (1:155059099 G>A), RS1002372229 (1:155057638 A>T), RS1002834178 (1:155055303 G>A), RS1003116715 (1:155055523 G>A,C), RS1003236682 (1:155050312 C>G), RS1003397907 (1:155061341 A>C,G), RS1003870859 (1:155060970 A>AGCCCT), RS1004177491 (1:155049684 T>G), RS1004396517 (1:155055106 A>G), RS1004408830 (1:155050345 G>A,C)

Disease associations

OMIM: gene MIM:605548 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST001942_19	Prostate cancer	2.000000e-08
GCST003989_36	Chin dimples	5.000000e-11
GCST004863_43	Mosquito bite size	6.000000e-06
GCST007294_124	Body fat distribution (trunk fat ratio)	8.000000e-35
GCST007294_3	Body fat distribution (trunk fat ratio)	6.000000e-21
GCST007294_50	Body fat distribution (trunk fat ratio)	1.000000e-15
GCST007295_17	Body fat distribution (leg fat ratio)	3.000000e-13
GCST007295_37	Body fat distribution (leg fat ratio)	7.000000e-17
GCST007295_72	Body fat distribution (leg fat ratio)	1.000000e-28
GCST007325_36	General risk tolerance (MTAG)	4.000000e-08
GCST007400_18	Systemic lupus erythematosus	8.000000e-07
GCST008103_81	Bipolar disorder	1.000000e-06
GCST010696_19	Cortical thickness (min-P)	2.000000e-10
GCST010697_10	Cortical surface area (min-P)	3.000000e-10
GCST010698_59	Subcortical volume (min-P)	9.000000e-10
GCST010699_20	Brain morphology (min-P)	7.000000e-10
GCST010700_5	Cortical thickness (MOSTest)	8.000000e-17
GCST010701_66	Cortical surface area (MOSTest)	1.000000e-09
GCST010702_43	Subcortical volume (MOSTest)	3.000000e-10
GCST010703_253	Brain morphology (MOSTest)	4.000000e-14
GCST011122_29	Walking pace	3.000000e-08
GCST90002382_12	Eosinophil percentage of white cells	1.000000e-10
GCST90020028_627	Hip circumference adjusted for BMI	4.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0008378	mosquito bite reaction size measurement
EFO:0004341	body fat distribution
EFO:0008579	risk-taking behaviour
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0007991	eosinophil percentage of leukocytes
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2331050 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — M12: Astacin/Adamalysin

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation, affects expression	3
sodium arsenite	increases abundance, increases expression	2
Acetaminophen	decreases expression, increases expression	2
Particulate Matter	increases expression, decreases expression, affects cotreatment, increases abundance	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	affects cotreatment, decreases expression	1
beta-lapachone	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
monomethylarsonous acid	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
Temozolomide	increases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Air Pollutants	increases oxidation, affects cotreatment, increases abundance	1
Arsenic	increases abundance, increases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases expression	1
Carmustine	decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Dieldrin	decreases expression	1
Doxorubicin	affects expression	1
Estradiol	increases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2342412	Binding	Inhibition of ADAM15 (unknown origin)-integrin alphaVbeta3 interaction in human K562 cells pretreated at 200 uM for 30 mins to immobilized sPLA2 before adding cells by phosphatase assay	Identification of inhibitors against interaction between pro-inflammatory sPLA2-IIA protein and integrin αvβ3. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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