UniProt functional annotation for P08253



	UniProt functional annotation for P08253

UniProt code: P08253.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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.

Catalytic activity: Reaction=Cleavage of gelatin type I and collagen types IV, V, VII, X. Cleaves the collagen-like sequence Pro-Gln-Gly-|-Ile-Ala-Gly-Gln.; EC=3.4.24.24; Evidence={ECO:0000305|PubMed:11179305, ECO:0000305|PubMed:11431697, ECO:0000305|PubMed:12147339, ECO:0000305|PubMed:2834383};

Cofactor: Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000269|PubMed:10356396, ECO:0000269|PubMed:12147339, ECO:0000269|PubMed:21813640, ECO:0000269|PubMed:8549817}; Note=Binds 4 Ca(2+) ions per subunit. {ECO:0000269|PubMed:10356396, ECO:0000269|PubMed:21813640, ECO:0000269|PubMed:8549817};

Cofactor: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:10356396, ECO:0000269|PubMed:12032297, ECO:0000269|PubMed:12147339, ECO:0000269|PubMed:21813640}; Note=Binds 2 Zn(2+) ions per subunit. {ECO:0000269|PubMed:10356396, ECO:0000269|PubMed:12032297, ECO:0000269|PubMed:21813640};

Activity regulation: Inhibited by histatin-3 1/24 (histatin-5). {ECO:0000269|PubMed:11179305}.

Subunit: Interacts (via the C-terminal hemopexin-like domains- containing region) with the integrin alpha-V/beta-3; the interaction promotes vascular invasion in angiogenic vessels and melamoma cells. Interacts (via the C-terminal PEX domain) with TIMP2 (via the C- terminal); the interaction inhibits the degradation activity. Interacts with GSK3B. {ECO:0000269|PubMed:11320090, ECO:0000269|PubMed:11710594, ECO:0000269|PubMed:11751392, ECO:0000269|PubMed:11928808, ECO:0000269|PubMed:12032297, ECO:0000269|PubMed:12147339, ECO:0000269|PubMed:1655733, ECO:0000269|PubMed:19493954}.

Subcellular location: [Isoform 1]: Secreted, extracellular space, extracellular matrix {ECO:0000305|PubMed:2834383}. 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.

Tissue specificity: Produced by normal skin fibroblasts. PEX is expressed in a number of tumors including gliomas, breast and prostate. {ECO:0000269|PubMed:11751392}.

Induction: Aspirin appears to inhibit expression. {ECO:0000269|PubMed:18971601}.

Domain: The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation- peptide release activates the enzyme.

Ptm: Phosphorylation on multiple sites modulates enzymatic activity. Phosphorylated by PKC in vitro. {ECO:0000269|PubMed:17435175}.

Ptm: The propeptide is processed by MMP14 (MT-MMP1) and MMP16 (MT- MMP3). Autocatalytic cleavage in the C-terminal produces the anti- angiogenic peptide, PEX. This processing appears to be facilitated by binding integrinv/beta3. {ECO:0000269|PubMed:12879005, ECO:0000269|PubMed:9119036}.

Disease: Multicentric osteolysis, nodulosis, and arthropathy (MONA) [MIM:259600]: An autosomal recessive syndrome characterized by severe multicentric osteolysis with predominant involvement of the hands and feet. Additional features include coarse face, corneal opacities, patches of thickened, hyperpigmented skin, hypertrichosis and gum hypertrophy. {ECO:0000269|PubMed:11431697, ECO:0000269|PubMed:15691365, ECO:0000269|PubMed:16542393}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: [Isoform 2]: Induced by oxidative stress. {ECO:0000305}.

Similarity: Belongs to the peptidase M10A family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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.


Catalytic activity:		Reaction=Cleavage of gelatin type I and collagen types IV, V, VII, X. Cleaves the collagen-like sequence Pro-Gln-Gly-\|-Ile-Ala-Gly-Gln.; EC=3.4.24.24; Evidence={ECO:0000305\|PubMed:11179305, ECO:0000305\|PubMed:11431697, ECO:0000305\|PubMed:12147339, ECO:0000305\|PubMed:2834383};
Cofactor:		Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000269\|PubMed:10356396, ECO:0000269\|PubMed:12147339, ECO:0000269\|PubMed:21813640, ECO:0000269\|PubMed:8549817}; Note=Binds 4 Ca(2+) ions per subunit. {ECO:0000269\|PubMed:10356396, ECO:0000269\|PubMed:21813640, ECO:0000269\|PubMed:8549817};
Cofactor:		Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269\|PubMed:10356396, ECO:0000269\|PubMed:12032297, ECO:0000269\|PubMed:12147339, ECO:0000269\|PubMed:21813640}; Note=Binds 2 Zn(2+) ions per subunit. {ECO:0000269\|PubMed:10356396, ECO:0000269\|PubMed:12032297, ECO:0000269\|PubMed:21813640};
Activity regulation:		Inhibited by histatin-3 1/24 (histatin-5). {ECO:0000269\|PubMed:11179305}.
Subunit:		Interacts (via the C-terminal hemopexin-like domains- containing region) with the integrin alpha-V/beta-3; the interaction promotes vascular invasion in angiogenic vessels and melamoma cells. Interacts (via the C-terminal PEX domain) with TIMP2 (via the C- terminal); the interaction inhibits the degradation activity. Interacts with GSK3B. {ECO:0000269\|PubMed:11320090, ECO:0000269\|PubMed:11710594, ECO:0000269\|PubMed:11751392, ECO:0000269\|PubMed:11928808, ECO:0000269\|PubMed:12032297, ECO:0000269\|PubMed:12147339, ECO:0000269\|PubMed:1655733, ECO:0000269\|PubMed:19493954}.
Subcellular location:		[Isoform 1]: Secreted, extracellular space, extracellular matrix {ECO:0000305\|PubMed:2834383}. 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.
Tissue specificity:		Produced by normal skin fibroblasts. PEX is expressed in a number of tumors including gliomas, breast and prostate. {ECO:0000269\|PubMed:11751392}.
Induction:		Aspirin appears to inhibit expression. {ECO:0000269\|PubMed:18971601}.
Domain:		The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation- peptide release activates the enzyme.
Ptm:		Phosphorylation on multiple sites modulates enzymatic activity. Phosphorylated by PKC in vitro. {ECO:0000269\|PubMed:17435175}.
Ptm:		The propeptide is processed by MMP14 (MT-MMP1) and MMP16 (MT- MMP3). Autocatalytic cleavage in the C-terminal produces the anti- angiogenic peptide, PEX. This processing appears to be facilitated by binding integrinv/beta3. {ECO:0000269\|PubMed:12879005, ECO:0000269\|PubMed:9119036}.
Disease:		Multicentric osteolysis, nodulosis, and arthropathy (MONA) [MIM:259600]: An autosomal recessive syndrome characterized by severe multicentric osteolysis with predominant involvement of the hands and feet. Additional features include coarse face, corneal opacities, patches of thickened, hyperpigmented skin, hypertrichosis and gum hypertrophy. {ECO:0000269\|PubMed:11431697, ECO:0000269\|PubMed:15691365, ECO:0000269\|PubMed:16542393}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		[Isoform 2]: Induced by oxidative stress. {ECO:0000305}.
Similarity:		Belongs to the peptidase M10A family. {ECO:0000305}.