MMP2 (matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase).

Identity

Other names	CLG4 (Collagenase Type IV),
	CLG4A (Collagenase Type IV-A),
	TBE-1(as secreted by H-ras oncogene-transformed human bronchial epithelial cells),
	MMP-II.
Hugo	MMP2
Location	16q13-q21

DNA/RNA

Description	This gene can be found on chromosome 16 at location: 54,070,604-54,097,652
Transcription	The DNA sequence contains 13 exons and the transcript length: 3,069 bps translated to a 660 residues protein.

Protein

	Domain structure of the MMP2. Pre: signal sequence; Pro: propeptide with a free zinc-ligating thiol (SH) group; Zn: zinc-binding site; II: collagen-binding fibronectin type II inserts; H: hinge region; The hemopexin/vitronectin-like domain contains four repeats with the first and last linked by a disulfide bond.

Description	MMP2 is a Zn+2 dependent endopeptidase, synthesized and secreted in zymogen form. The nascent form of the protein shows an N-terminal signal sequence ("pre" domain) that directs the protein to the endoplasmic reticulum. The pre domain is followed by a propeptide-"pro" domain that maintains enzyme-latency until cleaved or disrupted, and a catalytic domain that contains the conserved zinc-binding region. A hemopexin/vitronectin-like domain is also seen, that is connected to the catalytic domain by a hinge or linker region. The hemopexin domain is involved in TIMP (Tissue Inhibitors of Metallo-Proteinases) binding, the binding of certain substrates, membrane activation, and some proteolytic activities. It also shows a series of three head-to-tail cysteine-rich repeats within its catalytic domain. These inserts resemble the collagen-binding type II repeats of fibronectin and are required to bind and cleave collagen and elastin. The regulation of MMP-2 activity occurs at many levels, of which regulation through TIMP-2 and its cell surface receptor, MT1-MMP (MMP14) is critically decisive. At higher levels of TIMP-2, MT1-MMP forms a ternary complex with MMP-2 through, leaving no free MT1-MMP receptors, thereby inhibiting the activation of pro-MMP-2 by MT1-MMP. But at lower levels of TIMP-2, due to availability of free MT1-MMP, MT1-MMP mediated activation of MMP-2 is observed. Further data also indicates that expression of TIMP-2, MMP-2 and MT1-MMP (MMP-14) is co-regulated transcriptionally, demonstrating an intricate network of regulation. Pro-MMP-2 activation is also seen by complex signaling induced by ECM proteins like osteopontin, various cytokines for example IL-8 in endothelial cells and other factors.
Expression	MMP2 is tightly regulated at the transcriptional and post-transcriptional levels.
Localisation	Peri/extracellular
Function	Primary function is degradation of proteins in the extracellular matrix. It proteolytically digests gelatin (denatured collagen), and types IV, V, VII, IX and X collagen. Physiologically, MMP-2 in coordination with other MMPs, play a role in normal tissue remodeling events such as embryonic development, angiogenesis, ovulation, mammary gland involution and wound healing. MMP2 is also involved in osteoblastic bone formation and/or inhibits osteoclastic bone resorption.
Homology	Homology in amino acid sequence is seen with the other members of Metalloproteinase family especially with MMP-9.

Mutations

Germinal

A G-to-A transition in codon 101 of exon 2 of MMP2 gene was detected in a Saudi family with idiopathic multicentric osteolysis. This mutation showed a replacement of an arginine by histidine (R101H) in the prodomain, a region highly conserved across species and other members of the MMP gene family that is involved in autoproteolytic activation of MMP2. In a case of Winchester Syndrome, a homozygous 1210G-A transition in exon 8 of the MMP2 gene, leads to glu-to-lys (E404K) substitution in the catalytic domain of the protein. The glutamic acid at codon 404 is believed to be essential for the peptidase activity of all metalloproteinases, as its carboxyl group catalyzes 2 proton transfers, helps stabilize the transition state, and triggers the release of the products.

Implicated in

Entity	Elevated expression of MMP-2, along with MMP-9 is usually seen in invasive and highly tumorigenic cancers such as colorectal tumors, gastric carcinoma, pancreatic carcinoma, breast cancer, oral cancer, melanoma, malignant gliomas, Chondrosarcoma, gastrointestinal adenocarcinoma. Levels are also increased in malignant astrocytomas, carcinomatous meningitis, and brain metastases.
Oncogenesis	MMPs promote tumor progression and metastasis in invasive cancers by degradation of the ECM (ExtraCellular Matrix), which consists of two main components: Basement membranes and interstitial connective tissue. Though ECM comprises of many proteins (laminin-5, proteoglycans, entactin, osteonectin) collagen IV is the major element. MMP-2 & MMP-9 efficiently degrade collagen IV and laminin-5 thereby, assisting the metastatic cancerous cells to pass through the basement membrane. The degradation of ECM not only assists migration of metastatic cancerous cells, but also allows enhanced tumor growth by providing necessary space. Further, it is noteworthy that the ratio of active to latent form of MMP-2 increased with tumor progression in invasive cancers. MMP-2, with its family members also promotes angiogenesis (a critical process required for tumor cell survival) by degrading the vascular basement membrane and the interstitium.
Note	Arthritis, Autosomal recessive osteolysis disorder, Coronary Artery disease, pulmonary-emphysema and diabetic retinopathy.

External links

	Nomenclature
Hugo	MMP2
GDB	MMP2
Entrez_Gene	MMP2  4313  matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase)
	Cards
Atlas	MMP2ID41396ch16q13
GeneCards	MMP2
Ensembl	MMP2 [Search_View]   ENSG00000087245 [Gene_View]
Genatlas	MMP2
GeneLynx	MMP2
eGenome	MMP2
euGene	4313
	Genomic and cartography
GoldenPath	MMP2  -     chr16:54070589-54098103 +  16q13-q21   [Description]    (hg18-Mar_2006)
Ensembl	MMP2 - 16q13-q21 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	MMP2
	Gene and transcription
Genbank	AL542407 [ ENTREZ ]
Genbank	AL832088 [ ENTREZ ]
Genbank	BC002576 [ ENTREZ ]
Genbank	BQ004983 [ ENTREZ ]
Genbank	CR598192 [ ENTREZ ]
RefSeq	NM_004530 [ SRS ]    NM_004530 [ ENTREZ ]
RefSeq	AC_000059 [ SRS ]    AC_000059 [ ENTREZ ]
RefSeq	NC_000016 [ SRS ]    NC_000016 [ ENTREZ ]
RefSeq	NT_010498 [ SRS ]    NT_010498 [ ENTREZ ]
RefSeq	NW_926462 [ SRS ]    NW_926462 [ ENTREZ ]
AceView	MMP2 AceView - NCBI
Unigene	Hs.513617 [ SRS ]    Hs.513617 [ NCBI ]     HS513617 [ spliceNest ]
Fast-db	8807 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P08253 [ SRS]    P08253 [ EXPASY ]     P08253 [ INTERPRO ]
Prosite	PS00546 CYSTEINE_SWITCH [ SRS ]    PS00546 CYSTEINE_SWITCH [ Expasy ]
Prosite	PS00023 FN2_1 [ SRS ]    PS00023 FN2_1 [ Expasy ]
Prosite	PS51092 FN2_2 [ SRS ]    PS51092 FN2_2 [ Expasy ]
Prosite	PS00024 HEMOPEXIN [ SRS ]    PS00024 HEMOPEXIN [ Expasy ]
Prosite	PS00142 ZINC_PROTEASE [ SRS ]    PS00142 ZINC_PROTEASE [ Expasy ]
Interpro	IPR000562 FN_type2_col_bd [ SRS ]    IPR000562 FN_type2_col_bd [ EBI ]
Interpro	IPR000585 Hemopexin [ SRS ]    IPR000585 Hemopexin [ EBI ]
Interpro	IPR001818 Pept_M10A_M12B [ SRS ]    IPR001818 Pept_M10A_M12B [ EBI ]
Interpro	IPR006025 Pept_M_Zn_BS [ SRS ]    IPR006025 Pept_M_Zn_BS [ EBI ]
Interpro	IPR006026 Peptidase_M [ SRS ]    IPR006026 Peptidase_M [ EBI ]
Interpro	IPR002477 Peptidoglycan-bd-like [ SRS ]    IPR002477 Peptidoglycan-bd-like [ EBI ]
CluSTr	P08253
Pfam	PF00040 fn2 [ SRS ]    PF00040 fn2 [ Sanger ]    pfam00040 [ NCBI-CDD ]
Pfam	PF00045 Hemopexin [ SRS ]    PF00045 Hemopexin [ Sanger ]    pfam00045 [ NCBI-CDD ]
Pfam	PF00413 Peptidase_M10 [ SRS ]    PF00413 Peptidase_M10 [ Sanger ]    pfam00413 [ NCBI-CDD ]
Pfam	PF01471 PG_binding_1 [ SRS ]    PF01471 PG_binding_1 [ Sanger ]    pfam01471 [ NCBI-CDD ]
Smart	SM00059 FN2 [EMBL]
Smart	SM00120 HX [EMBL]
Smart	SM00235 ZnMc [EMBL]
Prodom	PD000995 FN_Type_II[INRA-Toulouse]
Prodom	P08253 MMP2_HUMAN [ Domain structure ]   P08253 MMP2_HUMAN  [ sequences sharing at least 1 domain ]
Blocks	P08253
PDB	1CK7 [ SRS ]    1CK7 [ PdbSum ],   1CK7 [ IMB ]   1CK7 [ RSDB ]
PDB	1CXW [ SRS ]    1CXW [ PdbSum ],   1CXW [ IMB ]   1CXW [ RSDB ]
PDB	1EAK [ SRS ]    1EAK [ PdbSum ],   1EAK [ IMB ]   1EAK [ RSDB ]
PDB	1GEN [ SRS ]    1GEN [ PdbSum ],   1GEN [ IMB ]   1GEN [ RSDB ]
PDB	1GXD [ SRS ]    1GXD [ PdbSum ],   1GXD [ IMB ]   1GXD [ RSDB ]
PDB	1HOV [ SRS ]    1HOV [ PdbSum ],   1HOV [ IMB ]   1HOV [ RSDB ]
PDB	1J7M [ SRS ]    1J7M [ PdbSum ],   1J7M [ IMB ]   1J7M [ RSDB ]
PDB	1KS0 [ SRS ]    1KS0 [ PdbSum ],   1KS0 [ IMB ]   1KS0 [ RSDB ]
PDB	1QIB [ SRS ]    1QIB [ PdbSum ],   1QIB [ IMB ]   1QIB [ RSDB ]
PDB	1RTG [ SRS ]    1RTG [ PdbSum ],   1RTG [ IMB ]   1RTG [ RSDB ]
HPRD	00386
	Protein Interaction databases
DIP	P08253
IntAct	P08253
	Polymorphism : SNP, mutations, diseases
OMIM	120360;277950;605156    [ map ]
GENECLINICS	120360;277950;605156
SNP	MMP2 [dbSNP-NCBI]
SNP	NM_004530 [SNP-NCI]
SNP	MMP2 [GeneSNPs - Utah]  MMP2] [HGBASE - SRS]
HAPMAP	MMP2 [HAPMAP]
COSMIC	MMP2 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	MMP2
	General knowledge
Family Browser	MMP2 [UCSC Family Browser]
SOURCE	NM_004530
SMD	Hs.513617
SAGE	Hs.513617
Enzyme	3.4.24.24 [ Enzyme-SRS ]   3.4.24.24 [ Brenda-SRS ]   3.4.24.24 [ KEGG ]   3.4.24.24 [ WIT ]
GO	blood vessel maturation [Amigo]  blood vessel maturation
GO	gelatinase A activity [Amigo]  gelatinase A activity
GO	calcium ion binding [Amigo]  calcium ion binding
GO	protein binding [Amigo]  protein binding
GO	extracellular region [Amigo]  extracellular region
GO	proteinaceous extracellular matrix [Amigo]  proteinaceous extracellular matrix
GO	extracellular space [Amigo]  extracellular space
GO	plasma membrane [Amigo]  plasma membrane
GO	proteolysis [Amigo]  proteolysis
GO	metabolic process [Amigo]  metabolic process
GO	zinc ion binding [Amigo]  zinc ion binding
GO	sarcomere [Amigo]  sarcomere
GO	collagen catabolic process [Amigo]  collagen catabolic process
BIOCARTA	Inhibition of Matrix Metalloproteinases    [Genes]
KEGG	Leukocyte transendothelial migration
KEGG	GnRH signaling pathway
PubGene	MMP2
TreeFam	MMP2
CTD	4313 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	MMP2 Related clones (RZPD - Berlin)
	PubMed
PubMed	375 Pubmed reference(s) in LocusLink

Bibliography

An interactive computer graphics study of thermolysin-catalyzed peptide cleavage and inhibition by N-carboxymethyl dipeptides.

Hangauer DG, Monzingo AF, Matthews BW

Biochemistry. 1984 ; 23 (24) : 5730-5741.

PMID 6525336

Activity of type IV collagenases in benign and malignant breast disease.

Davies B, Miles DW, Happerfield LC, Naylor MS, Bobrow LG, Rubens RD, Balkwill FR

British journal of cancer. 1993 ; 67 (5) : 1126-1131.

PMID 8494711

Structure of human pro-matrix metalloproteinase-2: activation mechanism revealed.

Morgunova E, Tuuttila A, Bergmann U, Isupov M, Lindqvist Y, Schneider G, Tryggvason K

Science (New York, N.Y.). 1999 ; 284 (5420) : 1667-1670.

PMID 10356396

Matrix metalloproteinases in angiogenesis: a moving target for therapeutic intervention.

Stetler-Stevenson WG

The Journal of clinical investigation. 1999 ; 103 (9) : 1237-1241.

PMID 10225966

Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis.

Zeng ZS, Cohen AM, Guillem JG

Carcinogenesis. 1999 ; 20 (5) : 749-755.

PMID 10334190

Active synovial matrix metalloproteinase-2 is associated with radiographic erosions in patients with early synovitis.

Goldbach-Mansky R, Lee JM, Hoxworth JM, Smith D 2nd, Duray P, Schumacher RH Jr, Yarboro CH, Klippel J, Kleiner D, El-Gabalawy HS

Arthritis research. 2000 ; 2 (2) : 145-153.

PMID 11062605

Matrix Metalloproteinases and TIMPs.

Woessner JF, Nagase H

New York. : page Ox.

The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis.

John A, Tuszynski G

Pathology oncology research : POR. 2001 ; 7 (1) : 14-23.

PMID 11349215

Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.

Martignetti JA, Aqeel AA, Sewairi WA, Boumah CE, Kambouris M, Mayouf SA, Sheth KV, Eid WA, Dowling O, Harris J, Glucksman MJ, Bahabri S, Meyer BF, Desnick RJ

Nature genetics. 2001 ; 28 (3) : 261-265.

PMID 11431697

Osteopontin stimulates tumor growth and activation of promatrix metalloproteinase-2 through nuclear factor-kappa B-mediated induction of membrane type 1 matrix metalloproteinase in murine melanoma cells.

Philip S, Bulbule A, Kundu GC

The Journal of biological chemistry. 2001 ; 276 (48) : 44926-44935.

PMID 11564733

Don't mess with the matrix.

Vu TH

Nature genetics. 2001 ; 28 (3) : 202-203.

PMID 11431682

Matrix metalloproteinases in arthritic disease.

Murphy G, Knˆ§uper V, Atkinson S, Butler G, English W, Hutton M, Stracke J, Clark I

Arthritis research. 2002 ; 4 Suppl 3 : S39-S49.

PMID 12110122

Matrix metalloproteinases and their role in pancreatic cancer: a review of preclinical studies and clinical trials.

Bloomston M, Zervos EE, Rosemurgy AS 2nd

Annals of surgical oncology. 2002 ; 9 (7) : 668-674.

PMID 12167581

Matrix metalloproteinases as novel disease markers in Takayasu arteritis.

Matsuyama A, Sakai N, Ishigami M, Hiraoka H, Kashine S, Hirata A, Nakamura T, Yamashita S, Matsuzawa Y

Circulation. 2003 ; 108 (12) : 1469-1473.

PMID 12952836

Production and activation of matrix metalloproteinase-2 in proliferative diabetic retinopathy.

Noda K, Ishida S, Inoue M, Obata K, Oguchi Y, Okada Y, Ikeda E

Investigative ophthalmology & visual science. 2003 ; 44 (5) : 2163-2170.

PMID 12714657

Osteopontin induces nuclear factor kappa B-mediated promatrix metalloproteinase-2 activation through I kappa B alpha /IKK signaling pathways, and curcumin (diferulolylmethane) down-regulates these pathways.

Philip S, Kundu GC

The Journal of biological chemistry. 2003 ; 278 (16) : 14487-14497.

PMID 12473670

Matrix metalloproteinase-2: mechanism and regulation of NF-kappaB-mediated activation and its role in cell motility and ECM-invasion.

Philip S, Bulbule A, Kundu GC

Glycoconjugate journal. 2004 ; 21 (8-9) : 429-441.

PMID 15750784

Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis.

Li A, Varney ML, Valasek J, Godfrey M, Dave BJ, Singh RK

Angiogenesis. 2005 ; 8 (1) : 63-71.

PMID 16132619

Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2.

Zankl A, Bonafˆ© L, Calcaterra V, Di Rocco M, Superti-Furga A

Clinical genetics. 2005 ; 67 (3) : 261-266.

PMID 15691365

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Contributor(s)

Written	10-2005	Gopal Chandra Kundu, Pralhad Deepak Patil
		CSIR-JRF,c/o Dr. G. C. Kundu, National Center for Cell Science, NCCS Complex, Ganeshkhind, Pune(Maharastra)-411007, India

Citation

This paper should be referenced as such :

Kundu GC, Patil DP . MMP2 (matrix metallopeptidase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase).. Atlas Genet Cytogenet Oncol Haematol. October 2005 . URL : http://AtlasGeneticsOncology.org/Genes/MMP2ID41396ch16q13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Wed Jul 2 08:25:03 2008