TISIDB

Summary
Symbol	TIMP3
Name	TIMP metallopeptidase inhibitor 3
Aliases	tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory); HSMRK222; K222; K222T ......
Chromosomal Location	22q12.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Secreted, extracellular space, extracellular matrix.
Domain	PF00965 Tissue inhibitor of metalloproteinase
Function	Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor. May form part of a tissue-specific acute response to remodeling stimuli. Known to act on MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, MMP-14 and MMP-15.

> Gene Ontology [ TOP ]
Biological Process	GO:0001933 negative regulation of protein phosphorylation GO:0002576 platelet degranulation GO:0006509 membrane protein ectodomain proteolysis GO:0006887 exocytosis GO:0007601 visual perception GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors GO:0009894 regulation of catabolic process GO:0009895 negative regulation of catabolic process GO:0010466 negative regulation of peptidase activity GO:0010951 negative regulation of endopeptidase activity GO:0031329 regulation of cellular catabolic process GO:0031330 negative regulation of cellular catabolic process GO:0033619 membrane protein proteolysis GO:0036462 TRAIL-activated apoptotic signaling pathway GO:0042176 regulation of protein catabolic process GO:0042177 negative regulation of protein catabolic process GO:0042326 negative regulation of phosphorylation GO:0043409 negative regulation of MAPK cascade GO:0045055 regulated exocytosis GO:0045861 negative regulation of proteolysis GO:0050953 sensory perception of light stimulus GO:0051043 regulation of membrane protein ectodomain proteolysis GO:0051045 negative regulation of membrane protein ectodomain proteolysis GO:0051346 negative regulation of hydrolase activity GO:0052547 regulation of peptidase activity GO:0052548 regulation of endopeptidase activity GO:0070371 ERK1 and ERK2 cascade GO:0070372 regulation of ERK1 and ERK2 cascade GO:0070373 negative regulation of ERK1 and ERK2 cascade GO:0097191 extrinsic apoptotic signaling pathway GO:1902041 regulation of extrinsic apoptotic signaling pathway via death domain receptors GO:1902043 positive regulation of extrinsic apoptotic signaling pathway via death domain receptors GO:1902532 negative regulation of intracellular signal transduction GO:1903121 regulation of TRAIL-activated apoptotic signaling pathway GO:1903984 positive regulation of TRAIL-activated apoptotic signaling pathway GO:1904683 regulation of metalloendopeptidase activity GO:1904684 negative regulation of metalloendopeptidase activity GO:1905048 regulation of metallopeptidase activity GO:1905049 negative regulation of metallopeptidase activity GO:2001233 regulation of apoptotic signaling pathway GO:2001235 positive regulation of apoptotic signaling pathway GO:2001236 regulation of extrinsic apoptotic signaling pathway GO:2001238 positive regulation of extrinsic apoptotic signaling pathway
Molecular Function	GO:0002020 protease binding GO:0004857 enzyme inhibitor activity GO:0004866 endopeptidase inhibitor activity GO:0008191 metalloendopeptidase inhibitor activity GO:0030414 peptidase inhibitor activity GO:0061134 peptidase regulator activity GO:0061135 endopeptidase regulator activity
Cellular Component	GO:0005578 proteinaceous extracellular matrix GO:0005604 basement membrane GO:0030141 secretory granule GO:0031089 platelet dense granule lumen GO:0031983 vesicle lumen GO:0034774 secretory granule lumen GO:0042827 platelet dense granule GO:0044420 extracellular matrix component GO:0060205 cytoplasmic membrane-bounded vesicle lumen GO:0099503 secretory vesicle

> KEGG and Reactome Pathway [ TOP ]
KEGG	-
Reactome	R-HSA-109582: Hemostasis R-HSA-76002: Platelet activation, signaling and aggregation R-HSA-114608: Platelet degranulation R-HSA-76005: Response to elevated platelet cytosolic Ca2+

Summary
Symbol	TIMP3
Name	TIMP metallopeptidase inhibitor 3
Aliases	tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory); HSMRK222; K222; K222T ......
Chromosomal Location	22q12.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between TIMP3 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining [ TOP ]
There is no record.

Summary
Symbol	TIMP3
Name	TIMP metallopeptidase inhibitor 3
Aliases	tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory); HSMRK222; K222; K222T ......
Chromosomal Location	22q12.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of TIMP3 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	TIMP3
Name	TIMP metallopeptidase inhibitor 3
Aliases	tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory); HSMRK222; K222; K222T ......
Chromosomal Location	22q12.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of TIMP3 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	-1.339	0.0053
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-1.526	0.62
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-1.203	0.598
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.36	0.445
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.378	0.879
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.34	0.912
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	-0.154	0.798
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-0.278	0.909
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.055	0.984
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	1.139	0.623
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	2.894	0.352
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.31	0.0782

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of TIMP3 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	5.9	-5.9	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	7.1	-7.1	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	0	0	1
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	0	0	1
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	5.9	-5.9	0.447
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	9.1	-9.1	0.458
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	0	0	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	0	0	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	0	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	1

Summary
Symbol	TIMP3
Name	TIMP metallopeptidase inhibitor 3
Aliases	tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory); HSMRK222; K222; K222T ......
Chromosomal Location	22q12.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of TIMP3. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	TIMP3
Name	TIMP metallopeptidase inhibitor 3
Aliases	tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory); HSMRK222; K222; K222T ......
Chromosomal Location	22q12.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of TIMP3. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by TIMP3. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	TIMP3
Name	TIMP metallopeptidase inhibitor 3
Aliases	tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory); HSMRK222; K222; K222T ......
Chromosomal Location	22q12.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of TIMP3. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	TIMP3
Name	TIMP metallopeptidase inhibitor 3
Aliases	tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory); HSMRK222; K222; K222T ......
Chromosomal Location	22q12.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of TIMP3 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	TIMP3
Name	TIMP metallopeptidase inhibitor 3
Aliases	tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory); HSMRK222; K222; K222T ......
Chromosomal Location	22q12.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between TIMP3 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	TIMP3
Name	TIMP metallopeptidase inhibitor 3
Aliases	tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory); HSMRK222; K222; K222T ......
Chromosomal Location	22q12.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting TIMP3 collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting TIMP3.

ID	Name	Drug Type	Targets	#Targets
DB05383	Pimagedine	Small Molecule	AKR1B1, NOS2, TIMP3	3

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