TIMP1

Summary

TIMP1 (TIMP metallopeptidase inhibitor 1, HGNC:11820) is a protein-coding gene on chromosome Xp11.3, encoding Metalloproteinase inhibitor 1 (P01033). Metalloproteinase inhibitor that functions by forming one to one complexes with target metalloproteinases, such as collagenases, and irreversibly inactivates them by binding to their catalytic zinc cofactor. In precision oncology, TIMP1 Overexpression is associated with resistance to Paclitaxel in Breast Cancer (CIViC Level B); 1 further curated variant–drug associations are listed below.

This gene belongs to the TIMP gene family. The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases (MMPs), a group of peptidases involved in degradation of the extracellular matrix. In addition to its inhibitory role against most of the known MMPs, the encoded protein is able to promote cell proliferation in a wide range of cell types, and may also have an anti-apoptotic function. Transcription of this gene is highly inducible in response to many cytokines and hormones. In addition, the expression from some but not all inactive X chromosomes suggests that this gene inactivation is polymorphic in human females. This gene is located within intron 6 of the synapsin I gene and is transcribed in the opposite direction.

Source: NCBI Gene 7076 — RefSeq curated summary.

At a glance

• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• MANE Select transcript: NM_003254

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11820
Approved symbol	TIMP1
Name	TIMP metallopeptidase inhibitor 1
Location	Xp11.3
Locus type	gene with protein product
Status	Approved
Aliases	EPO
Ensembl gene	ENSG00000102265
Ensembl biotype	protein_coding
OMIM	305370
Entrez	7076

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

ENST00000218388, ENST00000377017, ENST00000441738, ENST00000445623, ENST00000456754, ENST00000905034, ENST00000905035, ENST00000905036, ENST00000951185, ENST00000951186

RefSeq mRNA: 1 — MANE Select: NM_003254 NM_003254

CCDS: CCDS14281

Canonical transcript exons

ENST00000218388 — 6 exons

Exon	Start	End
ENSE00001472498	47586521	47586789
ENSE00001472535	47582436	47582474
ENSE00001622276	47585543	47585667
ENSE00002299256	47585205	47585331
ENSE00003483372	47584936	47585015
ENSE00003657841	47583408	47583536

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 99.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1013.3858 / max 20467.4676, expressed in 1801 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196210	1011.5926	1801
196212	1.2840	511
196211	0.5092	281

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right coronary artery	UBERON:0001625	99.91	gold quality
left coronary artery	UBERON:0001626	99.85	gold quality
gall bladder	UBERON:0002110	99.85	gold quality
descending thoracic aorta	UBERON:0002345	99.85	gold quality
coronary artery	UBERON:0001621	99.84	gold quality
thoracic aorta	UBERON:0001515	99.81	gold quality
stromal cell of endometrium	CL:0002255	99.80	gold quality
ascending aorta	UBERON:0001496	99.80	gold quality
type B pancreatic cell	CL:0000169	99.73	gold quality
islet of Langerhans	UBERON:0000006	99.73	gold quality
pericardium	UBERON:0002407	99.73	gold quality
right adrenal gland	UBERON:0001233	99.71	gold quality
left adrenal gland	UBERON:0001234	99.70	gold quality
right ovary	UBERON:0002118	99.69	gold quality
left adrenal gland cortex	UBERON:0035825	99.69	gold quality
cartilage tissue	UBERON:0002418	99.66	gold quality
aorta	UBERON:0000947	99.64	gold quality
adrenal cortex	UBERON:0001235	99.64	gold quality
left ovary	UBERON:0002119	99.63	gold quality
right adrenal gland cortex	UBERON:0035827	99.62	gold quality
upper lobe of left lung	UBERON:0008952	99.60	gold quality
left uterine tube	UBERON:0001303	99.59	gold quality
upper lobe of lung	UBERON:0008948	99.58	gold quality
artery	UBERON:0001637	99.57	gold quality
adenohypophysis	UBERON:0002196	99.57	gold quality
decidua	UBERON:0002450	99.57	gold quality
endocervix	UBERON:0000458	99.55	gold quality
metanephros cortex	UBERON:0010533	99.55	gold quality
right atrium auricular region	UBERON:0006631	99.54	gold quality
tibial artery	UBERON:0007610	99.54	gold quality

Single-cell (SCXA)

Detected in 59 experiment(s), a significant marker in 50.

Experiment	Marker?	Max mean expression
E-HCAD-31	yes	18474.52
E-MTAB-8530	yes	17570.86
E-MTAB-8322	yes	17517.48
E-HCAD-1	yes	13523.76
E-HCAD-13	yes	11654.24
E-MTAB-9435	yes	9555.97
E-MTAB-8495	yes	9551.93
E-HCAD-15	yes	9412.06
E-GEOD-139324	yes	9313.26
E-HCAD-11	yes	8127.08
E-MTAB-10662	yes	7851.01
E-MTAB-6653	yes	7755.84
E-CURD-112	yes	6608.37
E-MTAB-8410	yes	6553.55
E-MTAB-6701	yes	5971.80

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ASCL1, ASH1L, ATF2, BARX2, EGR1, ETS1, ETV4, FOS, FOSB, FOSL2, GATA1, HIF1A, HR, JUN, JUND, NFATC1, NFKB1, NFKB, NFKBIA, NR0B2, NR1H4, NR3C1, PAX5, PPARD, RELA, RUNX1, RUNX2, RUNX3, SMAD2, SMAD3, SP1, SP3, SPI1, SPRY4, SSRP1, STAT1, STAT3, TCF3, TRPV4

miRNA regulators (miRDB)

5 targeting TIMP1, 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-6745	99.74	65.33	1321
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-1293	96.16	64.69	916
HSA-MIR-8071	95.69	64.93	484

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)
• All patient groups had higher urinary TIMP-1 concentrations than healthy volunteers. (PMID:11705862)
• 17beta-estradiol had no influence on production in MG-63 cells or human osteoblast cultures (PMID:11762702)
• inhibition of apoptosis of activated hepatic stellar cells mediated via effects on matrix metalloproteinase inhibition (PMID:11796725)
• The role of TIMPs and MMPs in the pathogenesis of atopic dermatitis was studied by evaluating serum levels of TIMP-1 and MMP-3 in AD and controls. TIMP-1 was significantly higher in AD during exacerbation than in nonatopic subjects, but MMP-3 was not. (PMID:11876751)
• Variability of X chromosome inactivation: effect on levels of TIMP1 RNA and role of DNA methylation. (PMID:11935340)
• TIMP-1 expression was increased notably in partially sclerotic glomeruli, and most prominently expressed in tubulointerstitium, mainly in tubular epithelial cells, interstitial cells, and vascular endothelial cells. (PMID:11940298)
• elevation of serum and urine levels in patients with kidney diseases (PMID:12032189)
• TIMP-1 was intensively detected in both stromal and epithelial cells in the menstrual period but the expression decreased in other stages of the menstrual cycle. (PMID:12034345)
• Regulation of TIMP-1 phenotypic expression in Epstein–Barr virus-immortalized B lymphocytes. (PMID:12063180)
• role in activating ras proteins (PMID:12147251)
• enhancement of TIMP-1 is associated with suppression of prostate neoplasm invasiveness caused by staurosporine treatment (PMID:12150976)
• polymorphisms and cerebrospinal fluid levels of this protein in sporadic Alzheimer’s disease (PMID:12218659)
• MMP-9 level and TIMP-1 levels increased after birth but are not linked to bronchopulmonary dysplasia outcome; low MMP-2 level at birth is associated with the development of BPD (PMID:12376362)
• This protein is present in normal and azoospermic human semen. (PMID:12406369)
• the association between the positive expression of TIMP-1 and the invasiveness and metastasis was negative. (PMID:12452001)
• Progress curve analysis of MMP inhibition by TIMP-1 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 in squamous carcinoma of the cervix. (PMID:12479097)
• TIMP-1 expression is regulated by IL-10 and IL-10 receptor signaling in primary human prostate tumor cell lines. (PMID:12496489)
• TIMP1 may have a role in the pathogenesis of papillary thyroid carcinoma (PMID:12538453)
• association between TIMP-1 and the process of renal scarring in pyelonephritis (PMID:12612199)
• Levels of TIMP-1 were significantly elevated in cerebrospinal fluid samples from all disease groups: Parkinson’s, amyotrophic lateral sclerosis, and Huntington’s and Alzheimer’s disease. (PMID:12614934)
• Significantly lower expression of tissue inhibitor of matrix metalloproteinase-1 was found in follicular fluid of female patients with polycystic ovary syndrome compared with normally ovulating patients (PMID:12620441)
• TIMP-1 protein levels were significantly elevated among Kawasaki disease patients, compared to those of febrile and afebrile controls (PMID:12626459)
• N-TIMP-1 interaction with the catalytic domain of MMP-3 investigation by titration calorimetry and 15N NMR (PMID:12634064)
• expression and regulation by intestinal myofibroblasts in inflammatory bowel disease (PMID:12651627)
• TIMP-1 has a role in inhibiting tumor growth by angiogenesis suppression (PMID:12704667)
• The interaction between MMP-9 and TIMP-1 in the processes of gastric tumor invasion and metastasis is that MMP-9 mainly promotes tumor invasion and metastasis and TIMP-1 inhibits functions of MMP-9. (PMID:12717827)
• IL-10 receptor signaling of TIMP-1 expression is regulated by tyrosine phosphorylation of a novel gene (IL-10E1) in human prostate cells (PMID:12771930)
• multiple roles of MMP-9 and TIMP-1 in progress of inflammation and tissue damage and/or in repair, depending on clinical stages of SLE (PMID:12791318)
• STAT1 and STAT3 may, at least in part, mediate angiotensin II-induced TIMP-1 mRNA expression in human renal proximal tubular epithelial cells, implicating a role of the STAT signaling pathway in pathogenesis of renal tubulointerstitial fibrosis. (PMID:12846741)
• study suggested that, in fibroblasts that were derived from the continent woman, tissue inhibitor of metalloproteinase 1 protein production increases with increasing estrogen levels and that, in stress incontinent fibroblasts, no similar increase occurs (PMID:12861139)
• threonine 98 is critical in initiating MT1-MMP binding and complex stabilization (PMID:12869573)
• Patients with deteriorating heart failure have increased expression of TIMP1 and MMP1 mRNA. Correlation with pro-inflammatory cytokines suggests common pathways of regulation and potential activation by IL-6 and IL1-beta. (PMID:12873541)
• anti-apoptotic effects of TIMP-1 in human breast epithelial cells through TIMP-1-specific signal transduction pathways (PMID:12904305)
• Imbalanced ratio of TIMP-1:MMP-9 may not only play a role in the pathogenesis of COPD, but also relate to FEV(1.0)% of prediction and RV/TLC%. (PMID:12921631)
• In diseased brain the ability of astrocytes to counteract the destructive effects of MMP through expression of TIMP-1 is diminished by chronic activation. Our studies reveal new opportunities for therapeutics in HIV-associated dementia (PMID:12951656)
• Palpable tumours (T2, T3) expressed significantly more MMP-2 and significantly less MMP-9 than T1c tumours (PMID:12970724)
• A bivariate analysis revealed a strong and highly significant correlation between TIMP-1 and TGF-beta1, which was due to common genetic and environmental sources. (PMID:14517716)
• 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)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Timp1	ENSMUSG00000001131
rattus_norvegicus	Timp1	ENSRNOG00000010208

Paralogs (3): TIMP2 (ENSG00000035862), TIMP3 (ENSG00000100234), TIMP4 (ENSG00000157150)

Protein

Protein identifiers

Metalloproteinase inhibitor 1 — P01033 (reviewed: P01033)

Alternative names: Erythroid-potentiating activity, Fibroblast collagenase inhibitor, Tissue inhibitor of metalloproteinases 1

All UniProt accessions (6): P01033, H0Y789, Q5H9A7, Q5H9B4, Q5H9B5, Q6FGX5

UniProt curated annotations — full annotation on UniProt →

Function. Metalloproteinase inhibitor that functions by forming one to one complexes with target metalloproteinases, such as collagenases, and irreversibly inactivates them by binding to their catalytic zinc cofactor. Acts on MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13 and MMP16. Does not act on MMP14. Also functions as a growth factor that regulates cell differentiation, migration and cell death and activates cellular signaling cascades via CD63 and ITGB1. Plays a role in integrin signaling. Mediates erythropoiesis in vitro; but, unlike IL3, it is species-specific, stimulating the growth and differentiation of only human and murine erythroid progenitors.

Subunit / interactions. Interacts with MMP1, MMP3, MMP10 and MMP13, but has only very low affinity for MMP14. Interacts with CD63; identified in a complex with CD63 and ITGB1.

Subcellular location. Secreted.

Tissue specificity. Detected in rheumatoid synovial fluid (at protein level).

Post-translational modifications. The activity of TIMP1 is dependent on the presence of disulfide bonds. N-glycosylated.

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

RefSeq proteins (1): NP_003245* (*=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 (50 total): strand 14, helix 8, disulfide bond 6, mutagenesis site 5, turn 3, region of interest 3, glycosylation site 2, sequence conflict 2, site 2, signal peptide 1, chain 1, domain 1, binding site 1, modified residue 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
3V96	X-RAY DIFFRACTION	1.9
9SOP	X-RAY DIFFRACTION	1.95
9SOS	X-RAY DIFFRACTION	2
3MA2	X-RAY DIFFRACTION	2.05
9SOQ	X-RAY DIFFRACTION	2.3
7S7L	X-RAY DIFFRACTION	2.34
6MAV	X-RAY DIFFRACTION	2.37
2J0T	X-RAY DIFFRACTION	2.54
6N9D	X-RAY DIFFRACTION	2.67
1UEA	X-RAY DIFFRACTION	2.8
7S7M	X-RAY DIFFRACTION	3
1D2B	SOLUTION NMR
1OO9	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01033-F1	90.09	0.75

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 (2): 57 (involved in metalloproteinase-binding); 158 (involved in metalloproteinase-binding)

Ligand- & substrate-binding residues (1): 24

Post-translational modifications (1): 178

Disulfide bonds (6): 24–93, 26–122, 36–147, 150–197, 155–160, 168–189

Glycosylation sites (2): 53, 101

Mutagenesis-validated functional residues (5):

Position	Phenotype
25	reduced interaction with metalloproteinase.
25	normal interaction with metalloproteinase.
30	nearly abolishes metalloproteinase inhibition.
32	nearly abolishes metalloproteinase inhibition.
121	decreases protein flexibility and increases affinity for mmp14.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-1592389	Activation of Matrix Metalloproteinases
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-6783783	Interleukin-10 signaling
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-9839383	TGFBR3 PTM regulation

MSigDB gene sets: 728 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_NK_CELL_VS_CD11B_DC_DN, MODULE_172, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_HEMOGLOBIN_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, MCLACHLAN_DENTAL_CARIES_UP, GOBP_MYELOID_CELL_HOMEOSTASIS, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_RESPONSE_TO_ELECTRICAL_STIMULUS, HARRIS_HYPOXIA

GO Biological Process (17): connective tissue replacement involved in inflammatory response wound healing (GO:0002248), positive regulation of cell population proliferation (GO:0008284), response to hormone (GO:0009725), negative regulation of endopeptidase activity (GO:0010951), response to cytokine (GO:0034097), negative regulation of apoptotic process (GO:0043066), negative regulation of catalytic activity (GO:0043086), response to peptide hormone (GO:0043434), negative regulation of membrane protein ectodomain proteolysis (GO:0051045), cartilage development (GO:0051216), cellular response to UV-A (GO:0071492), negative regulation of trophoblast cell migration (GO:1901164), cellular response to peptide (GO:1901653), negative regulation of metallopeptidase activity (GO:1905049), cellular response to acetaldehyde (GO:1905641), regulation of integrin-mediated signaling pathway (GO:2001044), signal transduction (GO:0007165)

GO Molecular Function (9): protease binding (GO:0002020), cytokine activity (GO:0005125), growth factor activity (GO:0008083), metalloendopeptidase inhibitor activity (GO:0008191), zinc ion binding (GO:0008270), peptidase inhibitor activity (GO:0030414), enzyme inhibitor activity (GO:0004857), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (9): extracellular region (GO:0005576), basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), extracellular matrix (GO:0031012), platelet alpha granule lumen (GO:0031093), extracellular exosome (GO:0070062), collagen trimer (GO:0005581), secretory granule lumen (GO:0034774)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by Interleukins	2
Response to elevated platelet cytosolic Ca2+	1
Degradation of the extracellular matrix	1
Metabolism of proteins	1
Post-translational protein modification	1
Signaling by TGFBR3	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of peptidase activity	2
response to peptide	2
catalytic activity	2
receptor ligand activity	2
wound healing involved in inflammatory response	1
connective tissue replacement	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
response to endogenous stimulus	1
response to chemical	1
endopeptidase activity	1
regulation of endopeptidase activity	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
negative regulation of molecular function	1
regulation of catalytic activity	1
response to hormone	1
response to nitrogen compound	1
response to oxygen-containing compound	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
skeletal system development	1
animal organ development	1
connective tissue development	1
cellular response to UV	1
response to UV-A	1
negative regulation of cell migration	1
negative regulation of multicellular organismal process	1
trophoblast cell migration	1
regulation of trophoblast cell migration	1
negative regulation of reproductive process	1
cellular response to chemical stimulus	1
metallopeptidase activity	1
regulation of metallopeptidase activity	1
cellular response to aldehyde	1
response to acetaldehyde	1

Protein interactions and networks

STRING

3384 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TIMP1	MMP9	P14780	999
TIMP1	MMP3	P08254	998
TIMP1	MMP14	P50281	996
TIMP1	MMP2	P08253	994
TIMP1	CD63	P08962	990
TIMP1	MMP1	P03956	985
TIMP1	FN1	P02751	914
TIMP1	MMP7	P09237	912
TIMP1	CD44	P16070	907
TIMP1	MMP12	P39900	907
TIMP1	IL6	P05231	888
TIMP1	MMP13	P45452	864
TIMP1	MMP10	P09238	839
TIMP1	COL1A1	P02452	817
TIMP1	ICAM1	P05362	811

IntAct

57 interactions, top by confidence:

A	B	Type	Score
TIMP1	CD63	psi-mi:“MI:0915”(physical association)	0.690
CD63	TIMP1	psi-mi:“MI:0915”(physical association)	0.690
TIMP1	CD63	psi-mi:“MI:0403”(colocalization)	0.690
TIMP1	CD63	psi-mi:“MI:0914”(association)	0.690
TIMP1	CD63	psi-mi:“MI:0407”(direct interaction)	0.690
MMP9	TIMP1	psi-mi:“MI:0914”(association)	0.640
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
TIMP1	MMP9	psi-mi:“MI:2364”(proximity)	0.640
CD82	TIMP1	psi-mi:“MI:0407”(direct interaction)	0.600
TIMP1	CD82	psi-mi:“MI:0914”(association)	0.600
TIMP1	CD82	psi-mi:“MI:0407”(direct interaction)	0.600
CD82	TIMP1	psi-mi:“MI:0403”(colocalization)	0.600
TIMP1	CD82	psi-mi:“MI:0403”(colocalization)	0.600
IGFBP1	SUSD5	psi-mi:“MI:0914”(association)	0.530
MMP10	TIMP1	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
COL5A1	TIMP1	psi-mi:“MI:0915”(physical association)	0.510
TIMP1	TIMP1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (58): Pcsk5 (Affinity Capture-Western), TIMP1 (Affinity Capture-MS), TIMP1 (Affinity Capture-MS), TIMP1 (Affinity Capture-MS), TIMP1 (Affinity Capture-MS), TIMP1 (Reconstituted Complex), CD63 (Affinity Capture-Western), TIMP1 (Affinity Capture-Western), RECQL5 (Two-hybrid), ECH1 (Two-hybrid), EEF1B2 (Two-hybrid), MMP14 (Affinity Capture-Luminescence), MMP3 (Co-crystal Structure), MMP1 (Reconstituted Complex), TIMP1 (Affinity Capture-Western)

ESM2 similar proteins: A1A5X5, A1L2K1, A4D0V7, O02722, O42146, O54715, O97563, O97591, P01033, P01186, P10600, P12032, P15203, P16035, P16047, P17125, P20414, P20614, P24591, P25785, P30120, P30121, P35455, P35624, P40682, P49061, P50122, P55104, P81546, P81556, Q07258, Q13219, Q15904, Q5Q0T9, Q5RC60, Q5RJL6, Q641Q3, Q6Q484, Q7ZV46, Q8C1Q4

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

3 interactions.

A	Effect	B	Mechanism
SPRY4	“up-regulates quantity by expression”	TIMP1	“transcriptional regulation”
TIMP1	“down-regulates activity”	MMP9	binding
TIMP1	down-regulates	Angiogenesis

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

1259 predictions. Top by Δscore:

Variant	Effect	Δscore
7:100720989:GCACG:G	donor_gain	1.0000
7:100720992:CGGTG:C	donor_loss	1.0000
7:100720994:G:GG	donor_gain	1.0000
7:100720994:GTGA:G	donor_loss	1.0000
7:100720995:T:A	donor_loss	1.0000
7:100721556:A:AG	acceptor_gain	1.0000
7:100721557:G:GG	acceptor_gain	1.0000
7:100721557:GA:G	acceptor_gain	1.0000
7:100721557:GAAT:G	acceptor_gain	1.0000
7:100721701:ACGGT:A	donor_loss	1.0000
7:100721702:CGGT:C	donor_loss	1.0000
7:100721705:T:G	donor_loss	1.0000
7:100722841:CAG:C	donor_gain	1.0000
7:100722842:AG:A	donor_gain	1.0000
7:100722843:GG:G	donor_gain	1.0000
7:100722843:GGTG:G	donor_loss	1.0000
7:100722844:G:GG	donor_gain	1.0000
7:100722844:GT:G	donor_loss	1.0000
7:100722845:T:G	donor_loss	1.0000
7:100722972:T:TA	acceptor_gain	1.0000
7:100722973:GGCA:G	acceptor_loss	1.0000
7:100722976:A:AG	acceptor_gain	1.0000
7:100722976:AGAAG:A	acceptor_gain	1.0000
7:100722977:G:GA	acceptor_gain	1.0000
7:100722977:GAA:G	acceptor_gain	1.0000
7:100722977:GAAGG:G	acceptor_gain	1.0000
X:47582471:AGAGG:A	donor_loss	1.0000
X:47582472:GAG:G	donor_gain	1.0000
X:47582472:GAGGT:G	donor_loss	1.0000
X:47584931:T:TA	acceptor_gain	1.0000

AlphaMissense

1348 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:47586664:G:C	W199C	0.998
X:47586664:G:T	W199C	0.998
X:47586569:T:A	C168S	0.996
X:47586570:G:C	C168S	0.996
X:47586577:G:C	W170C	0.996
X:47586577:G:T	W170C	0.996
X:47585598:G:C	W128C	0.994
X:47585598:G:T	W128C	0.994
X:47586571:C:G	C168W	0.992
X:47586632:T:A	C189S	0.992
X:47586633:G:C	C189S	0.992
X:47586662:T:A	W199R	0.991
X:47586662:T:C	W199R	0.991
X:47584951:T:G	F46C	0.990
X:47585280:T:A	C93S	0.990
X:47585281:G:C	C93S	0.990
X:47586532:T:G	C155W	0.989
X:47586569:T:C	C168R	0.989
X:47586632:T:C	C189R	0.989
X:47586634:C:G	C189W	0.989
X:47586656:T:A	C197S	0.989
X:47586657:G:C	C197S	0.989
X:47584945:C:A	A44D	0.988
X:47585323:T:C	L107P	0.988
X:47585662:T:A	C150S	0.988
X:47585663:G:C	C150S	0.988
X:47586570:G:A	C168Y	0.988
X:47586633:G:A	C189Y	0.988
X:47583521:T:A	C36S	0.987
X:47583522:G:C	C36S	0.987

dbSNP variants (sampled 300 via entrez): RS1000082751 (X:47586417 C>G), RS1001077846 (X:47583197 CAAT>C), RS1001096299 (X:47581904 C>T), RS1001206339 (X:47585416 G>A), RS1002150296 (X:47583793 T>G), RS1002212163 (X:47582058 G>A), RS1002347720 (X:47581389 C>A,T), RS1003105671 (X:47586207 C>G), RS1004203680 (X:47580896 T>C), RS1005003282 (X:47584181 C>A), RS1005595003 (X:47580718 C>A), RS1005663832 (X:47583322 G>A,C,T), RS1007316568 (X:47587076 G>A), RS1010495379 (X:47584117 A>G), RS1011508902 (X:47586256 A>C)

Disease associations

OMIM: gene MIM:305370 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
TIMP1 Overexpression	Paclitaxel	Breast Cancer	Resistance	CIViC B	EID927
TIMP1 Overexpression	Fulvestrant	Breast Cancer	Resistance	CIViC D	EID901

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1617640	EPO		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, affects methylation, increases expression	9
Tobacco Smoke Pollution	decreases expression, increases expression, increases secretion, affects expression	9
Estradiol	affects cotreatment, increases expression, decreases expression	6
Aflatoxin B1	affects expression, increases expression, increases methylation	6
Arsenic Trioxide	decreases expression, decreases reaction, increases expression, increases reaction	4
Dronabinol	decreases reaction, increases expression, affects cotreatment, increases response to substance	4
Cyclosporine	increases expression	4
Particulate Matter	decreases expression, increases abundance, increases secretion	4
thymoquinone	decreases reaction, increases expression	3
bisphenol A	affects expression, increases expression, affects cotreatment, decreases expression	3
methanandamide	decreases reaction, increases expression, affects cotreatment, increases response to substance	3
Air Pollutants	decreases expression, increases abundance, affects cotreatment, increases expression	3
Ascorbic Acid	affects cotreatment, increases expression, affects expression	3
Cannabidiol	affects cotreatment, increases expression, decreases reaction	3
Nickel	increases expression	3
Phenytoin	increases expression	3
Quercetin	increases expression, increases reaction, decreases expression	3
Tetradecanoylphorbol Acetate	increases reaction, decreases reaction, increases expression	3
Tretinoin	affects cotreatment, increases expression	3
Oleic Acid	affects cotreatment, increases expression, affects expression, decreases reaction	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
SB 203580	decreases reaction, increases expression	2
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases expression, decreases reaction, increases expression	2
U 0126	affects expression, decreases reaction, increases expression	2
(+)-JQ1 compound	decreases reaction, increases expression, decreases expression	2
Aerosols	increases expression	2
Vehicle Emissions	increases secretion, affects cotreatment, increases expression, increases abundance	2
Cadmium	decreases expression, increases expression	2
Chromium	increases expression, decreases reaction	2
Cisplatin	affects cotreatment, increases expression	2

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C3KM	N/Tert-1 TIMP1	Telomerase immortalized cell line	Male
CVCL_TS38	HAP1 TIMP1 (-) 1	Cancer cell line	Male
CVCL_XU26	HAP1 TIMP1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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