TISIDB

Summary
Symbol	MMP2
Name	matrix metallopeptidase 2
Aliases	TBE-1; CLG4; CLG4A; matrix metalloproteinase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); ......
Chromosomal Location	16q12.2
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	Isoform 1: Secreted, extracellular space, extracellular matrix. Membrane. Nucleus. Note=Colocalizes with integrin alphaV/beta3 at the membrane surface in angiogenic blood vessels and melanomas. Found in mitochondria, along microfibrils, and in nuclei of cardiomyocytes.; SUBCELLULAR LOCATION: Isoform 2: Cytoplasm. Mitochondrion.
Domain	PF00040 Fibronectin type II domain PF00045 Hemopexin PF00413 Matrixin PF01471 Putative peptidoglycan binding domain
Function	Ubiquitinous metalloproteinase that is involved in diverse functions such as remodeling of the vasculature, angiogenesis, tissue repair, tumor invasion, inflammation, and atherosclerotic plaque rupture. As well as degrading extracellular matrix proteins, can also act on several nonmatrix proteins such as big endothelial 1 and beta-type CGRP promoting vasoconstriction. Also cleaves KISS at a Gly-\|-Leu bond. Appears to have a role in myocardial cell death pathways. Contributes to myocardial oxidative stress by regulating the activity of GSK3beta. Cleaves GSK3beta in vitro. Involved in the formation of the fibrovascular tissues in association with MMP14.; FUNCTION: PEX, the C-terminal non-catalytic fragment of MMP2, posseses anti-angiogenic and anti-tumor properties and inhibits cell migration and cell adhesion to FGF2 and vitronectin. Ligand for integrinv/beta3 on the surface of blood vessels.; FUNCTION: Isoform 2: Mediates the proteolysis of CHUK/IKKA and initiates a primary innate immune response by inducing mitochondrial-nuclear stress signaling with activation of the pro-inflammatory NF-kappaB, NFAT and IRF transcriptional pathways.

> Gene Ontology [ TOP ]
Biological Process	GO:0001101 response to acid chemical GO:0001501 skeletal system development GO:0001503 ossification GO:0001525 angiogenesis GO:0001666 response to hypoxia GO:0001704 formation of primary germ layer GO:0001706 endoderm formation GO:0001955 blood vessel maturation GO:0001957 intramembranous ossification GO:0007369 gastrulation GO:0007492 endoderm development GO:0007565 female pregnancy GO:0007566 embryo implantation GO:0010171 body morphogenesis GO:0021700 developmental maturation GO:0022617 extracellular matrix disassembly GO:0030198 extracellular matrix organization GO:0030574 collagen catabolic process GO:0031349 positive regulation of defense response GO:0032963 collagen metabolic process GO:0033002 muscle cell proliferation GO:0035987 endodermal cell differentiation GO:0036072 direct ossification GO:0036293 response to decreased oxygen levels GO:0043062 extracellular structure organization GO:0043200 response to amino acid GO:0044236 multicellular organism metabolic process GO:0044243 multicellular organism catabolic process GO:0044259 multicellular organismal macromolecule metabolic process GO:0044706 multi-multicellular organism process GO:0045088 regulation of innate immune response GO:0045089 positive regulation of innate immune response GO:0048013 ephrin receptor signaling pathway GO:0048514 blood vessel morphogenesis GO:0048659 smooth muscle cell proliferation GO:0048660 regulation of smooth muscle cell proliferation GO:0048661 positive regulation of smooth muscle cell proliferation GO:0048705 skeletal system morphogenesis GO:0060323 head morphogenesis GO:0060324 face development GO:0060325 face morphogenesis GO:0060343 trabecula formation GO:0060346 bone trabecula formation GO:0061383 trabecula morphogenesis GO:0061430 bone trabecula morphogenesis GO:0070482 response to oxygen levels GO:0071229 cellular response to acid chemical GO:0071230 cellular response to amino acid stimulus GO:0071417 cellular response to organonitrogen compound GO:0071695 anatomical structure maturation GO:1904705 regulation of vascular smooth muscle cell proliferation GO:1904707 positive regulation of vascular smooth muscle cell proliferation GO:1990874 vascular smooth muscle cell proliferation
Molecular Function	GO:0004175 endopeptidase activity GO:0004222 metalloendopeptidase activity GO:0004252 serine-type endopeptidase activity GO:0008236 serine-type peptidase activity GO:0008237 metallopeptidase activity GO:0017171 serine hydrolase activity
Cellular Component	GO:0005578 proteinaceous extracellular matrix GO:0030016 myofibril GO:0030017 sarcomere GO:0043292 contractile fiber GO:0044449 contractile fiber part

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04670 Leukocyte transendothelial migration hsa04912 GnRH signaling pathway hsa04915 Estrogen signaling pathway
Reactome	R-HSA-1592389: Activation of Matrix Metalloproteinases R-HSA-422475: Axon guidance R-HSA-1442490: Collagen degradation R-HSA-1280215: Cytokine Signaling in Immune system R-HSA-1474228: Degradation of the extracellular matrix R-HSA-1266738: Developmental Biology R-HSA-2682334: EPH-Ephrin signaling R-HSA-3928665: EPH-ephrin mediated repulsion of cells R-HSA-1474244: Extracellular matrix organization R-HSA-168256: Immune System R-HSA-6785807: Interleukin-4 and 13 signaling R-HSA-5683057: MAPK family signaling cascades R-HSA-5687128: MAPK6/MAPK4 signaling R-HSA-392499: Metabolism of proteins R-HSA-381426: Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) R-HSA-162582: Signal Transduction R-HSA-449147: Signaling by Interleukins

> KEGG and Reactome Pathway

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KEGG

hsa04670 Leukocyte transendothelial migration
hsa04912 GnRH signaling pathway
hsa04915 Estrogen signaling pathway

Reactome

R-HSA-1592389: Activation of Matrix Metalloproteinases
R-HSA-422475: Axon guidance
R-HSA-1442490: Collagen degradation
R-HSA-1280215: Cytokine Signaling in Immune system
R-HSA-1474228: Degradation of the extracellular matrix
R-HSA-1266738: Developmental Biology
R-HSA-2682334: EPH-Ephrin signaling
R-HSA-3928665: EPH-ephrin mediated repulsion of cells
R-HSA-1474244: Extracellular matrix organization
R-HSA-168256: Immune System
R-HSA-6785807: Interleukin-4 and 13 signaling
R-HSA-5683057: MAPK family signaling cascades
R-HSA-5687128: MAPK6/MAPK4 signaling
R-HSA-392499: Metabolism of proteins
R-HSA-381426: Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-162582: Signal Transduction
R-HSA-449147: Signaling by Interleukins

Summary
Symbol	MMP2
Name	matrix metallopeptidase 2
Aliases	TBE-1; CLG4; CLG4A; matrix metalloproteinase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); ......
Chromosomal Location	16q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between MMP2 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

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Literatures describing the relation between MMP2 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
29683683	melanoma	Promote immunity (T cell function); increase the efficacy of immunotherapy	To achieve this, an amphiphilic peptide, consisting of a functional 3-diethylaminopropyl isothiocyanate (DEAP) molecule, a peptide substrate of matrix metalloproteinase-2 (MMP-2), and DPPA-1, was synthesized and coassembled with NLG919.
16891318	Glioblastoma	Promote immunity	Yet again, MP inhibition by the broad spectrum inhibitors GM 6001 or MMP inhibitor III selectively enhanced the expression of MICA and ULBP2 on the surface of LNT- 229 cells but not of other NKG2DL (Fig. 4A). For MICA, this effect was significantly more prominent on control than on TGF-b1/2 siRNA cells. Thus, escape from NKG2D-mediated immune surveillance of malignant gliomas in vivo may be promoted by the inhibition of MICA and ULBP2 expression via an autocrine TGF-beta loop and by MP-dependent shedding from the cell surface.

Summary
Symbol	MMP2
Name	matrix metallopeptidase 2
Aliases	TBE-1; CLG4; CLG4A; matrix metalloproteinase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); ......
Chromosomal Location	16q12.2
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 MMP2 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	MMP2
Name	matrix metallopeptidase 2
Aliases	TBE-1; CLG4; CLG4A; matrix metalloproteinase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); ......
Chromosomal Location	16q12.2
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 MMP2 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	-1.786	0.00256
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-1.924	0.503
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-1.675	0.401
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.558	0.333
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.822	0.779
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.226	0.951
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	-0.667	0.326
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	-1.163	0.576
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.357	0.89
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.93	0.659
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	2.727	0.347
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.311	0.151

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of MMP2 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	7.1	0	7.1	0.452
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	10	0	10	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	11.1	1.4	9.7	0.0589
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	11.1	1.7	9.4	0.0895
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	11.8	-11.8	0.193
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	16.7	-16.7	0.429
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	9.1	-9.1	0.458
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	11.1	0	11.1	0.36
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	25	0	25	0.364
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	7.9	0	7.9	0.26
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	9.1	0	9.1	0.519
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	6.2	0	6.2	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	7.7	-7.7	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	8.3	-8.3	1

Summary
Symbol	MMP2
Name	matrix metallopeptidase 2
Aliases	TBE-1; CLG4; CLG4A; matrix metalloproteinase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); ......
Chromosomal Location	16q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of MMP2. 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	MMP2
Name	matrix metallopeptidase 2
Aliases	TBE-1; CLG4; CLG4A; matrix metalloproteinase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); ......
Chromosomal Location	16q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of MMP2. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by MMP2. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	MMP2
Name	matrix metallopeptidase 2
Aliases	TBE-1; CLG4; CLG4A; matrix metalloproteinase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); ......
Chromosomal Location	16q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of MMP2. 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	MMP2
Name	matrix metallopeptidase 2
Aliases	TBE-1; CLG4; CLG4A; matrix metalloproteinase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); ......
Chromosomal Location	16q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of MMP2 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	MMP2
Name	matrix metallopeptidase 2
Aliases	TBE-1; CLG4; CLG4A; matrix metalloproteinase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); ......
Chromosomal Location	16q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between MMP2 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	MMP2
Name	matrix metallopeptidase 2
Aliases	TBE-1; CLG4; CLG4A; matrix metalloproteinase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase); ......
Chromosomal Location	16q12.2
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting MMP2 collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting MMP2.

ID	Name	Drug Type	Targets	#Targets
DB00786	Marimastat	Small Molecule	MMP1, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP1 ......	23
DB01197	Captopril	Small Molecule	ACE, BDKRB1, LTA4H, MMP2, MMP9	5
DB01630	SC-74020	Small Molecule	MMP2	1
DB04866	Halofuginone	Small Molecule	COL1A1, MMP2	2
DB05387	AE-941	Small Molecule	MMP12, MMP2, MMP9	3

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