TIMP2

Summary

TIMP2 (TIMP metallopeptidase inhibitor 2, HGNC:11821) is a protein-coding gene on chromosome 17q25.3, encoding Metalloproteinase inhibitor 2 (P16035). Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor.

This gene is a member of the TIMP gene family. The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix. In addition to an inhibitory role against metalloproteinases, the encoded protein has a unique role among TIMP family members in its ability to directly suppress the proliferation of endothelial cells. As a result, the encoded protein may be critical to the maintenance of tissue homeostasis by suppressing the proliferation of quiescent tissues in response to angiogenic factors, and by inhibiting protease activity in tissues undergoing remodelling of the extracellular matrix.

Source: NCBI Gene 7077 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 34 total
• MANE Select transcript: NM_003255

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11821
Approved symbol	TIMP2
Name	TIMP metallopeptidase inhibitor 2
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	CSC-21K
Ensembl gene	ENSG00000035862
Ensembl biotype	protein_coding
OMIM	188825
Entrez	7077

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000262768, ENST00000536189, ENST00000585421, ENST00000586057, ENST00000586713, ENST00000592761, ENST00000706922, ENST00000706923, ENST00000970519

RefSeq mRNA: 1 — MANE Select: NM_003255 NM_003255

CCDS: CCDS11758

Canonical transcript exons

ENST00000262768 — 5 exons

Exon	Start	End
ENSE00001033832	78857522	78857646
ENSE00001319888	78924959	78925387
ENSE00002749550	78852977	78855864
ENSE00003642461	78873819	78873919
ENSE00003755534	78870898	78871006

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 319.5669 / max 16184.5792, expressed in 1746 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168513	313.9498	1746
208394	1.7417	934
168487	1.4533	727
168488	0.9627	527
168491	0.7539	365
168509	0.4472	102
168510	0.2284	77
168508	0.0299	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	99.85	gold quality
synovial joint	UBERON:0002217	99.83	gold quality
stromal cell of endometrium	CL:0002255	99.81	gold quality
tibia	UBERON:0000979	99.77	gold quality
urethra	UBERON:0000057	99.71	gold quality
descending thoracic aorta	UBERON:0002345	99.70	gold quality
trigeminal ganglion	UBERON:0001675	99.66	gold quality
ascending aorta	UBERON:0001496	99.65	gold quality
thoracic aorta	UBERON:0001515	99.65	gold quality
right coronary artery	UBERON:0001625	99.64	gold quality
aorta	UBERON:0000947	99.62	gold quality
visceral pleura	UBERON:0002401	99.61	gold quality
parietal pleura	UBERON:0002400	99.60	gold quality
popliteal artery	UBERON:0002250	99.59	gold quality
saphenous vein	UBERON:0007318	99.59	gold quality
tibial artery	UBERON:0007610	99.59	gold quality
skin of hip	UBERON:0001554	99.58	gold quality
left ovary	UBERON:0002119	99.58	gold quality
endocervix	UBERON:0000458	99.57	gold quality
artery	UBERON:0001637	99.57	gold quality
vein	UBERON:0001638	99.57	gold quality
vena cava	UBERON:0004087	99.53	gold quality
right ovary	UBERON:0002118	99.52	gold quality
gall bladder	UBERON:0002110	99.48	gold quality
body of uterus	UBERON:0009853	99.46	gold quality
coronary artery	UBERON:0001621	99.45	gold quality
mucosa of stomach	UBERON:0001199	99.44	gold quality
left coronary artery	UBERON:0001626	99.44	gold quality
mammary duct	UBERON:0001765	99.44	gold quality
nerve	UBERON:0001021	99.41	gold quality

Single-cell (SCXA)

Detected in 19 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-GEOD-81608	yes	500.17
E-MTAB-7052	yes	264.03
E-MTAB-8142	yes	92.84
E-MTAB-8410	yes	59.20
E-MTAB-10553	yes	42.85
E-MTAB-9221	yes	27.52
E-CURD-46	yes	19.49
E-HCAD-1	yes	18.08
E-MTAB-6678	yes	16.87
E-MTAB-10287	yes	16.47
E-CURD-112	yes	15.87
E-MTAB-9543	yes	15.43
E-HCAD-9	yes	14.71
E-ENAD-27	yes	13.04
E-HCAD-11	yes	9.19

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, DNMT3A, EGR1, ETV4, HIF1A, JUN, MYC, NR0B2, NR1H4, NR4A1, NR4A2, PTTG1, SMAD7, SP1, SP3, TFAP2A

miRNA regulators (miRDB)

135 targeting TIMP2, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795

Literature-anchored findings (GeneRIF, showing 40)

• The growth of the primary melanoma cell lines was stimulated by TIMP-1 and inhibited by TIMP-2. In contrast, the growth of the visceral metastatic melanoma cell line was stimulated by TIMP-2. (PMID:11606052)
• TIMP-2 may be involved in the pathogenesis of gestational trophoblastic disease (PMID:11912288)
• role in activating ras proteins (PMID:12147251)
• endometrium from women with endometriosis expressed higher levels of MMP-2 and MT1-MMP and lower levels of TIMP-2 than did endometrium from normal women (PMID:12372458)
• investigation of structural and functional differences between TIMP-4 and TIMP-2 by mutagenesis into C-terminal tails (PMID:12374789)
• This protein is present in normal and azoospermic human semen. (PMID:12406369)
• correlation between expression of MMP-2, TIMP-2 protein and the ratio of MMP-2/TIMP-2 and clinical-pathological parameters of patients with gallbladder carcinoma (PMID:12439941)
• TIMP2 expression is regulated by the ERK/MAPK pathway (PMID:12446683)
• Changes in plasma MMP-2 and TIMP-2 concentrations during cardiopulmonary bypass may play an important role in LV remodeling after cardiac surgery. (PMID:12470034)
• Progress curve analysis of MMP inhibition by TIMP-2 shows that it has lower reactivity with MMPs at less acidic conditions than TIMP-4. (PMID:12475252)
• The over-expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 may play a key role in invasion and lymph-node metastasis of in squamous carcinoma of the cervix. (PMID:12479097)
• TIMP-2 expression in breast cancer is related to survival. (PMID:12602913)
• TIMP-2 was significantly increased in CSF of Alzheimer’s disease and Huntington’s disease patients. (PMID:12614934)
• TIMP-2 mediated inhibition of angiogenesis is an MMP-independent mechanism. (PMID:12887919)
• TIMP-2 possesses two distinct types of anti-angiogenic activities which can be uncoupled from each other (PMID:12900406)
• TIMP-2 expression is markedly increased in clear cell carcinoma of the ovary, suggesting a role of TIMP-2 in its unique characteristics among ovarian cancers (PMID:12970394)
• palpable tumours demonstrated significantly more MMP-2 and significantly less MMP-9 expression than nonpalpable tumours (PMID:12970724)
• A bivariate analysis revealed a modest but significant genetic correlation between TIMP-1 and TIMP-2. (PMID:14517716)
• A gradual, time-dependent decline in TIMP-2 mRNA expression was observed in the presence of the synthetic androgen analogue R1881. (PMID:14598888)
• Our analysis of the entire coding region of TIMP-1, -2, and -3, which are the main inhibitors of metalloproteinase activity in the extracellular matrix, failed to show an association between genetic polymorphisms and an intracranial aneurysm (PMID:14605322)
• TIMP-2 stromal cell expression only was associated with adverse prognosis of urothelial bladder cancer patients. (PMID:14654538)
• effect of titanium, zirconia and alumina ceramics on activity and secretion in human osteoblasts (PMID:14661256)
• Tissue from lateral and medial rectus muscles had different levels of expression of TIMP-1 and 2, MMP-2, and BMP-4, which may underlie different characteristics of these extraocular muscles and may influence wound healing after strabismus surgery. (PMID:14710472)
• TIMP-2 is hypermethylated in human cervical cancer (PMID:14712492)
• MMP-26 was colocalized with MMP-9, TIMP-2, and TIMP-4 in breast cancer cells. (PMID:14744773)
• TIMP-2 is shown to correlate with systemic symptoms in Hodgkin lymphoma (PMID:14962256)
• MMP and TIMP may be involved in the feto-neonatal development and may contribute to the pathogenesis of bronchopulmonary dysplasia and/or intraventricular hemorrhage in critically ill preterm neonates (PMID:14973177)
• MMP-2, TIMP-1 and TIMP-2 are downregulated in human orthotopic liver transplantation (PMID:14983226)
• hereditary neuralgic amyotrophy is not caused by point mutations of tissue inhibitor of metalloproteinase 2 (PMID:15052627)
• TIMP-2 correlated negatively with fractional shortening & positively with LV dimension. Changes in the release & activity of TIMP-2 may be associated with the mechanisms responsible for cardiac remodeling in patients with hypertrophic cardiomyopathy. (PMID:15056834)
• TIMP2 promotes growth of A549 lung cells, accompanied by increase in NF-kappaB activity and downregulation of IkappaBalpha and beta proteins and later increases in Bcl-3, IkappaB, and cyclin D1 proteins. (PMID:15147743)
• ERK 1/2- and p38 MAPK-modulated TIMP-2 expression regulates MT1-MMP activity and control TGF-beta1-induced pericellular collagenolysis (PMID:15247230)
• marked difference in MMPs and their inhibitors in the in vitro fertilized women and normally ovulating women (PMID:15248826)
• Plasma levels are increased in type 2 diabetic patients (PMID:15277439)
• analysis of the molecular basis of the inactivity of tissue inhibitor of metalloproteinase-2 against tumor necrosis factor-alpha-converting enzyme (PMID:15308656)
• data suggest that the MMP-2/TIMP2 system and an activated extrinsic coagulation pathway could cooperate in conditions of elevated SOX and could influence arterial remodeling resulting in the presence of CVD in haemodialysis patients (PMID:15351863)
• clearance of pro-matrix metalloproteinase (MMP)-2.tissue inhibitor of MMPs (TIMP-2) complex involves binding to the cell membrane and subsequent low density lipoprotein receptor-related protein (LRP)-dependent internalization and degradation (PMID:15489233)
• The expression of MMP-9, TIMP-1 and TIMP-2 was lower in the benign and low malignancy ovarian tumors compared with the malignant ones. (PMID:15557756)
• MMP-2 plays an essential role in tumor invasion and metastasis, while TIMP-2 is shown to strongly inhibit cancer invasion and metastasis. (PMID:15567754)
• This study found an up-regulation of TIMP-1, TIMP-2 and MMP-2 RNA in Duchenne Muscular Dystrophy muscle. (PMID:15616792)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	timp2a	ENSDARG00000061226
danio_rerio	timp2b	ENSDARG00000075261
mus_musculus	Timp2	ENSMUSG00000017466
rattus_norvegicus	Timp2	ENSRNOG00000089169
drosophila_melanogaster	Timp	FBGN0025879
caenorhabditis_elegans		WBGENE00019478

Paralogs (3): TIMP3 (ENSG00000100234), TIMP1 (ENSG00000102265), TIMP4 (ENSG00000157150)

Protein

Protein identifiers

Metalloproteinase inhibitor 2 — P16035 (reviewed: P16035)

Alternative names: CSC-21K, Tissue inhibitor of metalloproteinases 2

All UniProt accessions (5): A0A140VK57, P16035, A0A9L9PXQ8, A0A9L9PYH5, B4DFW2

UniProt curated annotations — full annotation on UniProt →

Function. Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor. Known to act on MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-13, MMP-14, MMP-15, MMP-16 and MMP-19.

Subunit / interactions. Interacts (via the C-terminal) with MMP2 (via the C-terminal PEX domain); the interaction inhibits the MMP2 activity.

Subcellular location. Secreted.

Post-translational modifications. The activity of TIMP2 is dependent on the presence of disulfide bonds.

Induction. Down-regulated by TGFB1.

Similarity. Belongs to the protease inhibitor I35 (TIMP) family.

RefSeq proteins (1): NP_003246* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001134	Netrin_domain	Domain
IPR001820	TIMP	Family
IPR008993	TIMP-like_OB-fold	Homologous_superfamily
IPR027465	TIMP_C	Homologous_superfamily
IPR030490	TIMP_CS	Conserved_site

Pfam: PF00965

Enzyme classification (BRENDA):

• EC 3.4.24.22 — stromelysin 2 (BRENDA: 3 organisms, 37 substrates, 21 inhibitors, 2 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(7-METHOXYCOUMARIN-4-YL)ACETYL-ARG-PRO-LYS-PRO-V	0.023	1

UniProt features (48 total): strand 14, sequence conflict 10, helix 7, disulfide bond 6, site 3, region of interest 2, turn 2, signal peptide 1, chain 1, domain 1, binding site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1BR9	X-RAY DIFFRACTION	2.1
4ILW	X-RAY DIFFRACTION	2.1
1GXD	X-RAY DIFFRACTION	3.1
2TMP	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16035-F1	91.46	0.79

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 (3): 40 (involved in metalloproteinase-binding); 61 (involved in metalloproteinase-binding); 67 (involved in metalloproteinase-binding)

Ligand- & substrate-binding residues (1): 27

Disulfide bonds (6): 29–127, 39–152, 154–201, 159–164, 172–193, 27–98

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1592389	Activation of Matrix Metalloproteinases
R-HSA-6798695	Neutrophil degranulation
R-HSA-9839383	TGFBR3 PTM regulation

MSigDB gene sets: 465 (showing top): MODULE_52, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, REACTOME_INNATE_IMMUNE_SYSTEM, CHIBA_RESPONSE_TO_TSA_UP, GOBP_RESPONSE_TO_PEPTIDE, TGCACTT_MIR519C_MIR519B_MIR519A, GOCC_SECRETORY_GRANULE, GOBP_NEGATIVE_REGULATION_OF_HYDROLASE_ACTIVITY, GOZGIT_ESR1_TARGETS_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_128, SHAFFER_IRF4_TARGETS_IN_ACTIVATED_B_LYMPHOCYTE, MCBRYAN_PUBERTAL_TGFB1_TARGETS_UP, MEF2_02

GO Biological Process (4): response to hormone (GO:0009725), response to cytokine (GO:0034097), negative regulation of membrane protein ectodomain proteolysis (GO:0051045), negative regulation of metallopeptidase activity (GO:1905049)

GO Molecular Function (8): protease binding (GO:0002020), metalloendopeptidase inhibitor activity (GO:0008191), zinc ion binding (GO:0008270), peptidase inhibitor activity (GO:0030414), molecular function inhibitor activity (GO:0140678), enzyme inhibitor activity (GO:0004857), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), specific granule lumen (GO:0035580), tertiary granule lumen (GO:1904724), ficolin-1-rich granule lumen (GO:1904813), secretory granule lumen (GO:0034774)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Degradation of the extracellular matrix	1
Innate Immune System	1
Signaling by TGFBR3	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular organelle lumen	2
response to endogenous stimulus	1
response to chemical	1
response to peptide	1
membrane protein ectodomain proteolysis	1
negative regulation of protein catabolic process	1
negative regulation of proteolysis	1
regulation of membrane protein ectodomain proteolysis	1
metallopeptidase activity	1
negative regulation of peptidase activity	1
regulation of metallopeptidase activity	1
enzyme binding	1
metalloendopeptidase activity	1
endopeptidase inhibitor activity	1
transition metal ion binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
molecular function regulator activity	1
catalytic activity	1
enzyme regulator activity	1
molecular function inhibitor activity	1
binding	1
cation binding	1
cellular anatomical structure	1
external encapsulating structure	1
secretory granule lumen	1
specific granule	1
tertiary granule	1
ficolin-1-rich granule	1
secretory granule	1
cytoplasmic vesicle lumen	1

Protein interactions and networks

STRING

2460 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TIMP2	MMP2	P08253	999
TIMP2	MMP14	P50281	999
TIMP2	MMP9	P14780	998
TIMP2	MMP3	P08254	959
TIMP2	MMP7	P09237	932
TIMP2	HPX	P02790	932
TIMP2	MMP1	P03956	921
TIMP2	IGFBP7	Q16270	862
TIMP2	MMP8	P22894	831
TIMP2	MMP13	P45452	821
TIMP2	MMP10	P09238	791
TIMP2	IL6	P05231	789
TIMP2	TGFB1	P01137	777
TIMP2	TIMP3	P35625	770
TIMP2	MMP16	P51512	768

IntAct

45 interactions, top by confidence:

A	B	Type	Score
TIMP2	MMP2	psi-mi:“MI:0407”(direct interaction)	0.690
TIMP2	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
MMP14	TIMP2	psi-mi:“MI:0914”(association)	0.560
MMP14	TIMP2	psi-mi:“MI:0915”(physical association)	0.560
TIMP2	ZMYM6	psi-mi:“MI:0914”(association)	0.530
UBE3A	HERC2	psi-mi:“MI:0914”(association)	0.500
TIMP2	FECH	psi-mi:“MI:0915”(physical association)	0.500
UBE3A	IGLC7	psi-mi:“MI:0914”(association)	0.350
UBE3A	TXNL1	psi-mi:“MI:0914”(association)	0.350
MMP2	COL2A1	psi-mi:“MI:0914”(association)	0.350
MMP14	TMEM120B	psi-mi:“MI:0914”(association)	0.350
MMP2	PLOD3	psi-mi:“MI:0914”(association)	0.350
LY86	TMEM131L	psi-mi:“MI:0914”(association)	0.350
PTPRN	KCNK1	psi-mi:“MI:0914”(association)	0.350
ELSPBP1	QSOX1	psi-mi:“MI:0914”(association)	0.350
PRG2	QSOX1	psi-mi:“MI:0914”(association)	0.350
WNT10A	MANBA	psi-mi:“MI:0914”(association)	0.350
WNT3A	MANBA	psi-mi:“MI:0914”(association)	0.350
SLURP1	MAN2B1	psi-mi:“MI:0914”(association)	0.350
LYPD6B	ZNF195	psi-mi:“MI:0914”(association)	0.350
TIMP2	RANBP1	psi-mi:“MI:0915”(physical association)	0.000
TIMP2	PSMA6	psi-mi:“MI:0915”(physical association)	0.000
TIMP2	PGRMC1	psi-mi:“MI:0915”(physical association)	0.000
TIMP2	PSAT1	psi-mi:“MI:0915”(physical association)	0.000
TIMP2	NUDC	psi-mi:“MI:0915”(physical association)	0.000
TIMP2	NPEPPS	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (301): TIMP3 (Affinity Capture-MS), FECH (Affinity Capture-MS), ZMYM6 (Affinity Capture-MS), Pcsk5 (Affinity Capture-Western), FECH (Affinity Capture-MS), TIMP3 (Affinity Capture-MS), ZMYM6 (Affinity Capture-MS), TIMP2 (Affinity Capture-MS), TIMP2 (Affinity Capture-RNA), TIMP2 (Reconstituted Complex), TIMP2 (Affinity Capture-RNA), SNCG (Affinity Capture-MS), PSMA7 (Affinity Capture-MS), ITGB1 (Reconstituted Complex), ITGA5 (Reconstituted Complex)

ESM2 similar proteins: A0A8M9PFP2, A1L2K1, A4IGL3, A4IH88, A8WFR0, B0S5G3, F1LW30, L7VG99, O42146, O73746, O75339, O93449, O97591, P12032, P15203, P16035, P16176, P16368, P20614, P23667, P25785, P26652, P30120, P30121, P30970, P35625, P39876, P48032, P61269, P79121, Q01H84, Q09199, Q28GB8, Q3KTM2, Q5PXZ9, Q60453, Q66K08, Q6DDG2, Q6UXZ4, Q7ZV46

Diamond homologs: O02722, O42146, O73746, O77717, O97563, O97591, P01033, P12032, P16035, P16368, P20414, P20614, P25785, P26652, P30120, P30121, P35624, P35625, P39876, P48032, P49061, P50122, P61269, P79121, P81546, P81556, Q5PXZ9, Q5RC60, Q60453, Q95KL9, Q99727, Q9JHB3, Q9TRZ7, Q9TTY1, Q9TUL9, Q9W6B4, Q9WUC6, O97590, Q21265

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PTTG1	“down-regulates quantity”	TIMP2
DNMT3A	“down-regulates quantity by repression”	TIMP2	“transcriptional regulation”
TIMP2	“up-regulates quantity”	LRP2	binding
TIMP2	down-regulates	Angiogenesis

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1577 predictions. Top by Δscore:

Variant	Effect	Δscore
17:78855862:GATC:G	acceptor_loss	1.0000
17:78855863:ATCT:A	acceptor_loss	1.0000
17:78855865:C:CC	acceptor_gain	1.0000
17:78855876:C:CT	acceptor_gain	1.0000
17:78857518:TTA:T	donor_loss	1.0000
17:78857519:TACCT:T	donor_loss	1.0000
17:78857520:ACCT:A	donor_loss	1.0000
17:78857642:CTTTC:C	acceptor_gain	1.0000
17:78857643:TTTC:T	acceptor_gain	1.0000
17:78857644:TTC:T	acceptor_gain	1.0000
17:78857645:TC:T	acceptor_gain	1.0000
17:78857646:CC:C	acceptor_gain	1.0000
17:78857647:C:CC	acceptor_gain	1.0000
17:78857647:CT:C	acceptor_loss	1.0000
17:78870894:ACAC:A	donor_loss	1.0000
17:78870897:C:CG	donor_loss	1.0000
17:78871003:ACAT:A	acceptor_gain	1.0000
17:78871004:CAT:C	acceptor_gain	1.0000
17:78871004:CATC:C	acceptor_gain	1.0000
17:78871005:AT:A	acceptor_gain	1.0000
17:78871007:C:CC	acceptor_gain	1.0000
17:78871007:C:T	acceptor_loss	1.0000
17:78871008:T:C	acceptor_loss	1.0000
17:78873816:TACC:T	donor_loss	1.0000
17:78873817:A:AT	donor_loss	1.0000
17:78873818:C:CT	donor_loss	1.0000
17:78873915:GATCA:G	acceptor_gain	1.0000
17:78873916:ATCA:A	acceptor_gain	1.0000
17:78873917:TCA:T	acceptor_gain	1.0000
17:78873918:CA:C	acceptor_gain	1.0000

AlphaMissense

1459 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:78855721:C:A	W203C	1.000
17:78855721:C:G	W203C	1.000
17:78855723:A:G	W203R	1.000
17:78855723:A:T	W203R	1.000
17:78855751:G:C	C193W	1.000
17:78855752:C:A	C193F	1.000
17:78855752:C:G	C193S	1.000
17:78855752:C:T	C193Y	1.000
17:78855753:A:G	C193R	1.000
17:78855753:A:T	C193S	1.000
17:78855808:C:A	W174C	1.000
17:78855808:C:G	W174C	1.000
17:78855810:A:G	W174R	1.000
17:78855810:A:T	W174R	1.000
17:78855814:G:C	C172W	1.000
17:78855815:C:G	C172S	1.000
17:78855816:A:G	C172R	1.000
17:78855816:A:T	C172S	1.000
17:78857588:C:A	W133C	1.000
17:78857588:C:G	W133C	1.000
17:78857607:C:G	C127S	1.000
17:78857607:C:T	C127Y	1.000
17:78857608:A:G	C127R	1.000
17:78857608:A:T	C127S	1.000
17:78870945:C:G	C98S	1.000
17:78870945:C:T	C98Y	1.000
17:78870946:A:G	C98R	1.000
17:78870946:A:T	C98S	1.000
17:78855727:A:C	C201W	0.999
17:78855728:C:A	C201F	0.999

dbSNP variants (sampled 300 via entrez): RS1000001586 (17:78918553 T>C,G), RS1000021645 (17:78903335 A>G), RS1000052083 (17:78926947 C>T), RS1000056290 (17:78924200 G>A,T), RS1000058962 (17:78923218 G>A), RS1000102814 (17:78913897 A>G), RS1000112915 (17:78923766 A>C), RS1000127584 (17:78865913 T>C,G), RS1000172760 (17:78899154 G>C), RS1000225238 (17:78896407 G>A), RS1000286333 (17:78900950 C>G,T), RS1000287843 (17:78886764 A>G), RS1000353000 (17:78918825 C>G), RS1000376597 (17:78873146 C>T), RS1000384917 (17:78894819 GA>G,GAA)

Disease associations

OMIM: gene MIM:188825 | disease phenotypes: MIM:600669

GenCC curated gene-disease

Mondo (1): idiopathic generalized epilepsy (MONDO:0005579)

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001144_9	Dupuytren’s disease	6.000000e-07
GCST001762_54	Obesity-related traits	8.000000e-06
GCST002126_15	Periodontitis (CDC/AAP)	2.000000e-06
GCST003815_1	Late-onset Alzheimer’s disease	1.000000e-06
GCST006585_2442	Blood protein levels	3.000000e-29
GCST006979_257	Heel bone mineral density	4.000000e-15

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004229	Dupuytren Contracture
EFO:1001870	late-onset Alzheimers disease
EFO:0009270	heel bone mineral density

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562694	Epilepsy, Idiopathic Generalized (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	7
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, increases methylation	7
Benzo(a)pyrene	affects expression, increases expression, increases methylation	5
Cyclosporine	affects expression, decreases expression, increases expression, affects cotreatment	5
Estradiol	decreases expression, decreases reaction, affects cotreatment, increases expression	4
Particulate Matter	affects expression, affects cotreatment, decreases reaction, increases expression, decreases expression (+1 more)	4
Arsenic Trioxide	decreases expression	3
Air Pollutants	affects cotreatment, decreases reaction, decreases expression, increases abundance, affects expression	3
Arsenic	affects expression, affects methylation, affects reaction	3
Tetrachlorodibenzodioxin	decreases expression, increases expression	3
methylmercuric chloride	increases expression	2
bisphenol A	decreases reaction, increases expression, decreases expression	2
methylparaben	decreases activity, increases expression	2
sodium arsenite	increases expression	2
cobaltous chloride	decreases expression	2
(+)-JQ1 compound	increases expression, decreases expression	2
Aspirin	decreases expression, increases expression	2
Cadmium	decreases expression	2
Glucose	affects cotreatment, decreases expression, increases expression, decreases reaction	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Quercetin	increases expression	2
Selenium	decreases expression, decreases reaction	2
Tretinoin	decreases expression, increases expression	2
Aflatoxin B1	affects expression, increases methylation	2
aristolochic acid I	increases expression	1
ferric oxide	increases expression	1
bisphenol F	increases expression	1
HET0016	decreases reaction, increases expression	1
perfluorotetradecanoic acid	increases expression	1
cinobufagin	increases expression	1

Cellosaurus cell lines

8 cell lines: 5 cancer cell line, 2 transformed cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C7DQ	Abcam A-549 TIMP2 KO	Cancer cell line	Male
CVCL_C7EE	Abcam HCT 116 TIMP2 KO	Cancer cell line	Male
CVCL_C7ES	Abcam THP-1 TIMP2 KO	Cancer cell line	Male
CVCL_E8D7	CHO-S TIMP-2-EK-6XHis	Spontaneously immortalized cell line	Female
CVCL_E8D8	HEK-293-F coTIMP-2-6XHis	Transformed cell line	Female
CVCL_E8D9	HEK-293-F TIMP-2-EK-6XHis	Transformed cell line	Female
CVCL_TS39	HAP1 TIMP2 (-) 1	Cancer cell line	Male
CVCL_XU27	HAP1 TIMP2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03590197	PHASE4	COMPLETED	Effect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Epilepsy
NCT03940326	PHASE4	COMPLETED	Levetiracetam Versus Valproate in Idiopathic Generalized Tonic-clonic Seizures
NCT00150735	PHASE3	COMPLETED	Monotherapy With Levetiracetam in Newly Diagnosed Patients Suffering From Epilepsy
NCT00150748	PHASE3	COMPLETED	Long Term Follow up Treatment With Levetiracetam in Subjects of 4 Years and Older With Generalized Epilepsy
NCT03678753	PHASE3	COMPLETED	Randomized, Double-Blind Study to Evaluate Efficacy and Safety of Cenobamate Adjunctive Therapy in PGTC Seizures
NCT05147571	PHASE3	ACTIVE_NOT_RECRUITING	RNS System NAUTILUS Study
NCT06908356	PHASE2	RECRUITING	An Open Label Trial to Evaluate the Efficacy and Safety of PRAX-628 in Adults With Focal Onset or Tonic-Clonic Seizures
NCT06425159	PHASE2/PHASE3	TERMINATED	A Study to Determine if BHV-7000 is Effective and Safe in Adults With Idiopathic Generalized Epilepsy With Generalized Tonic-clonic Seizures
NCT00001325	Not specified	COMPLETED	Metabolic Abnormalities in Children With Epilepsy
NCT00916903	Not specified	TERMINATED	Genetic Disease Gene Identification
NCT01311440	Not specified	COMPLETED	Modified Atkins Diet Treatment for Adults With Drug-resistant Epilepsy
NCT01432821	Not specified	COMPLETED	Blinking and Yawning in Epilepsy: The Role of Dopamine
NCT03368469	Not specified	WITHDRAWN	Transcranial Direct Current Stimulation (tDCS) in Children and Adolescents With Epilepsy and Depression
NCT03457961	Not specified	UNKNOWN	Post-market Study of AMPA Receptor Antagonists for Epilepsy Patients in Hong Kong
NCT03955432	Not specified	TERMINATED	Long-term Cardiac Monitoring in Epilepsy
NCT04252846	Not specified	COMPLETED	A Study to Investigate Dosage, Effectiveness, and Safety of Perampanel When Used as First Add-on Therapy in Participants >=12 Years With Partial Onset Seizures With or Without Secondary Generalization or With Primary Generalized Tonic-Clonic Seizures Associated With Idiopathic Generalized Epilepsy
NCT04965571	Not specified	COMPLETED	Clinical Features and Outcome of Wilson’s Disease With Generalized Epilepsy in Chinese Patients
NCT05374928	Not specified	ACTIVE_NOT_RECRUITING	Human Epilepsy Project 3
NCT05530109	Not specified	TERMINATED	Study of Attentional Disorders in Patients Suffering From Idiopathic Generalized Epilepsy.
NCT06388174	Not specified	RECRUITING	Idiopathic Generalized Epilepsy Syndromes
NCT06797791	Not specified	COMPLETED	Assessment of Multifocal Continuous Theta Burst Transcranial Magnetic Stimulation (cTBS) Effects in Generalized Epilepsy Patients.