Proteins involved in extracellular proteolysis
General information on the various proteins can be found at the MIME (Online Mendelian Inheritance in Man) site. Information on amino acid sequence, domain structure, referals to cDNA and gene sequences and 3D structures can be found at the Swissprot site.
Below information is given for the human protein. Between brackets Swissprot
access information is given for other species. A study (Julie et al.,2000) quantified mRNA levels for many extracellular proteases and extracellular matrix proteins in a rat carotid artery injury model. The primers used for quantitative RT-PCR are given in a supplement.
An overview of the various properties of the extracellular matrix is
given in "Molecular biology of the cell"
Protease precursors
Serine proteases
Plasminogen (PLG; MIME 173350; abbreviation: plg; EC 3.4.21.7; Swissprot P00747; Gene map locus and chromosome position 6q26)(bovine, dog, hedgehog, horse, lamprey, mouse, pig, rat, rhesus monkey, sheep). Precursor of plasmin, a trypsin.like enzyme, that efficiently degrades fibrin and most extracellular matrix proteins, except collagen and elastin. Contains five kringle domains and a serine protease domain. A plasminogen deficiency is linked to ligneous conjunctivitis.
Urokinase (PLAU; MIME191840; abbreviation: u-PA, synonym: urinary-type plasminogen activator; EC 3.4.21.73; Swissprot P00749, Gene map locus and chromosome position 10q24 )(bovine, baboon, chicken, mouse, pig, rat).
Free urokinase is an efficient activator of plasminogen, interaction of urokinase and plasminogen with cell surface receptors further increases efficacy of plasminogen activation. Contains a growth factor domain, a kringle domain and a serine protease domain.
Tissue-type plasminogen activator (PLAT; MIME 173370; abbreviation: t-PA; EC 3.4.21.68; Swissprot P00750; Gene map locus and chromosome position 8p12)(bovine, mouse, rat). Principal substrate is plasminogen, requires a cofactor such as fibrin, extracellular matric proteins or cell surface receptor to activate plasminogen efficiently. Contains a finger domain, a growth factor domain, two kringle domains and a serine protease domain. In endothelial cels, t-PA is stored in Weibel Palade bodies and is acutely released by treatment with thrombin or other secretagogues.
Vampire bat t-PA (DSPA), differs from t-PA in lacking one or more domains. DSPA alpha 1 and DSPA alpha 2 lack a kringle domain; DSPA beta lacks the finger domain and a kringle domain, while DSPA gamma lacks the finger domain, the growth factor domain and a kringle domain.
Plasma Prekallikrein (KLKB; MIME 229000; synonyms: Kininogenin, Fletcher Factor; EC 3.4.21.34, Swissprot P03952; Gene map locus 4q35)(mouse, rat). Plasma kallikrein can activate plasminogen, albeit more weakly than t-PA or u-PA, and convert pro-u-PA into active u-PA, in particular at the cell surface. A plasma kallikrein-dependent plasminogen cascade was shown to be required for adipocyte differentiation (Selvarajan et al.)
Prostate specific antigen (KLK3; MIME 176820; synonyms: Kallikrein 3, Seminin; EC 3.4.21.77, Swissprot P07288; Gene map locus 19q13).
May convert plasminogen into angiostatin-like fragments. PSA is member of the kallikrein gene family, consisting of 15 members all located on chromosome 19q13. Members of this family may play a role in controlling vital processes, like apoptosis, angiogenesis and tumor metastasis by cleavage of critical substrates such as growth factors, hormones or extracellular matrix (see: Yousef and Diamandis, 2002).
Membrane-type serine protease 1 (ST14; synonyms: MT-SP1, Matriptase; MIME: 606797; EC 3.4.21.-; Swissprot Q9Y5Y6 ; Gene map locus 11q24-q25). A cell membrane associated serine protease that can degrade the extracellular matrix. It may play a role in breast cancer invasion and metastasis. Exhibits trypsin-like activity as defined by cleavage of synthetic substrates with arg or lys as the p1 site.
Membrane-type serine protease 2 (TMPRSS4; synonyms: MT-SP2; MIME: 606797; EC 3.4.21.-; Swissprot Q9NRS4 ; Gene map locus 11q24-q25).
A type 2 membrane protein that may play a role in tumor progression, metastasis formation and tumor invasion. High levels in pancreatic, gastric, colorectal and ampullary cancer and weak expression in normal gastrointestinal and urogenital tract.
Transmembrane protease, serine 3 (TMPRSS3; synonyms: Tumor associated differentially-expressed gene-12 protein, TADG-12; MIME 605511; EC 3.4.21.-; Swissprot P57727; Gene map locus 21q22.3 )
Metalloproteinases
The MMPs can be divided in secreted MMPs and membrane bound MMPs.
All secreted MMPs contain a propeptide, a catalytic domain and (except MMP-7 and MMP-26) a hemopexin-like sequence. The active site of a secreted MMP is blocked by its propeptide. Proteolytic cleavage between the propeptide and catalytic domain results in propeptide release and MMP activation. The secreted MMPs have been divided in collagenases (MMPs 1, 8 and 13), gelatinases (MMPs 2 and 9), stromelysins (MMPs 3, 10 and 11) and matrilysins (MMP 7 and 26).
There are two types of membrane bound MMPs: transmembrane MMPs that have also a cytoplasmic domain (MMPs 14, 15, 16 and 21) and MMPs that are linked to the cell membrane by a GPI-anchor (MMP 17 and 25). All membrane-type MMPs have an arginine rich tetrapeptide linking the propeptide and the catalytic domain and can be activated by furin-type convertases.
Matrix metalloproteinase 1 (MMP-1; MIME 120353; synonyms: insterstitial collagenase, collagenase 1; EC 3.4.24.7; Swissprot P03956; Gene map locus 11q22-q23)(bovine, bull frog, horse, mouse, pig, rabbit, rat).
Matrix metalloproteinase 2 (MMP-2; MIME 120360; synonyms: gelatinase A, 72 kDa gelatinase; EC 3.4.24.24; Swissprot P08253; Gene map locus 16q13)(chicken, mouse, rabbit, rat).
Matrix metalloproteinase 3 (MMP-3; MIME 185250; synonym: stromelysin-1; EC 3.4.24.17; Swissprot P08254; Gene map locus 11q23)(horse, mouse, rabbit, rat).
Matrix metalloproteinase 7 (MMP-7; MIME 178990; synonym: matrilysin 1; EC 3.4.24.23; Swissprot P09237; Gene map locus 11q21-q22)(cat, mouse, rat).
Matrix metalloproteinase 8 (MMP-8; MIME 120355; synonyms: neutrophil collagenase, collagenase 2; EC 3.4.24.34, Swissprot P22894;Gene map locus 11q21-q22 )(mouse, rat).
Matrix metalloproteinase 9 (MMP 9; MIME 120361; synonyms: gelatinase B, 92 kDa gelatinase; EC 3.4.24.35; Swissprot P14780; Gene map locus 20q11.2-q13.1)(bovine, dog, mouse, rabbit, rat).
Matrix metalloproteinase 10 (MMP-10; MIME 185260; synonym: stromelysin-2; EC 3.4.24.22; Swissprot P09238; Gene map locus 11q22.3-q23)(mouse, rat).
Matrix metalloproteinase 11 (MMP-11; MIME 185261; synonym: stromelysin-3; EC 3.4.24.-; Swissprot P24347; Gene map locus 22q11.2 )(mouse, rat, xenopus).
Matrix metalloproteinase 12 (MMP-12; MIME 601046; synonym: macrophage metalloelastase, EC 3.4.24.65, Swissprot P39900; Gene map locus 11q22.2-q22.3)(mouse, rabbit, rat).
Matrix metalloproteinase 13 (MMP-13; MIME 600108; synonym: collagenase 3; EC 3.4.24.-; Swissprot P45452; Gene map locus 11q22.3)(bovine, horse , mouse, rabbit, rat, xenopus).
Matrix metalloproteinase 14 (MMP-14; MIME 600754; synonyms: membrane-type matrix metalloproteinase 1, MT1-MMP; EC 3.4.24.-; Swissprot P50281; Gene map locus 14q11-q12)(mouse, pig, rabbit, rat).
Matrix metalloproteinase 15 (MMP-15; MIME 602261; synonyms: membrane-type matrix metalloproteinase 2, MT2-MMP; EC 3.4.24.-; Swissprot P51511; Gene map locus 16q13-q21)(mouse).
Matrix metalloproteinase 16 (MMP-16; MIME 602262; synonyms: membrane-type matrix metalloproteinase 3, MT-3-MMP; EC 3.4.24.-; Swissprot P51512; Gene map locus 8q21)(chicken, mouse, rat).
Matrix metalloproteinase 17 (MMP-17; MIME 602285; synonyms: membrane-type matrix metalloproteinase 4, MT-4-MMP; EC 3.4.24.-; Swissprot Q9ULZ9); Gene map locus 12q24.33)(mouse).
Matrix metalloproteinase 19 (MMP-19; MIME 601807; synonyms: MMP-18, RASI; EC 3.4.24.-; Swissprot Q99542; Gene map locus 12q14 )(mouse).
Matrix metalloproteinase 20 (MMP-20; MIME 604629; synonyms: enamel metalloproteinase, enamelysin; EC 3.4.24.-; Swissprot O60882 ; Gene map locus 11q22.3-q23)(bovine, mouse, pig).
Matrix metalloproteinase 21 (MMP-21; MIME 604871; synonyms: MMP-24, membrane-type matrix metalloproteinase 5, MT-MMP 5, EC 3.4.24.-, Swissprot Q9Y5R2; Gene map locus 20q11.2)(mouse).
Matrix metalloproteinase 23 (MMP-23; MIME 603321; EC 3.4.24.-; Swissprot Q9UBR9; Gene map locus 1p36.3)(mouse).There are two almost identical variants of MMP-23.
Matrix metalloproteinase 25 (MMP-25; synonyms: membrane-type matrix metalloproteinase 6, leukolysin, MT-MMP 6, EC 3.4.24.-, Swissprot Q9NPA2).
Matrix metalloproteinase 26 (MMP-26; MIME 605470; synonym: matrilysin-2, endometase; EC 3.4.24.-; Swissprot Q9NRE1; Gene map locus 11p15).
Matrix metalloproteinase 27 (MMP-27; EC 3.4.24.-; Swissprot Q9H306).
Matrix metalloproteinase 28 (MMP-28; epilysin; EC3.4.24.-, Swissprot Q9H239).
Aspartyl proteinases
Cathepsin D (CTSD; MIME 116840; EC 3.4.23.5, Swissprot P07339; Gene map locus 11p15.5)
CATHEPSIN D; CTSD)(bovine, chicken, mouse, pig, rat).
Heparanase (HPSE; MIME 604724; Swissprot Q9UL39; Gene map locus 4q21.3)(rat). This enzyme degrades the glycosaminoglycan part of the extracellular matrix and is required for the efficient degradation of the extracellular matrix. Furthermore, it can liberate heparansulfate binding growth factors. The protein has a putative C-terminal transmembrane domain. It requires proteolytic processing to be active.
A second heparanase-like proterin has been identified. Alternative splicing yields three different transcripts (Swissprot Q9HB37; Swissprot Q9HB38; Swissprot Q9HB39)
Inhibitors
Serpins
Antiplasmin (MIME 262850; synonyms: alpha2-antiplasmin, alpha2-plasmin inhibitor, Swissprot P08697; Gene map locus 17pter-p12)(bovine, mouse).
Plasminogen activator inhibitor type 1 (MIME 173360; abbreviation: PAI-1, Swissprot P05121; Gene map locus 7q21.3-q22)(bovine, mouse, mink, pig, rat).
Plasminogen activator inhibitor type 2 (MIME 173390; abbreviation:PAI-2, Swissprot P05120; Gene map locus 18q21.3)(mouse, rat).
Plasminogen activator inhibitor type 3 (MIME 601841; synonyms: PAI-3, protein C inhibitor, Swissprot P05154; Gene map locus 14q32.1)(mouse).
Protease nexin 1 (MIME 177010; abbreviation: PN-1; synonym: glia derived nexin, Swissprot P07093; Gene map locus 2q33-q35)(mouse, rat).
Neuroserpin (MIME 602445; synonym: protease inhibitor 12, Swissprot Q99574; Gene map locus 3q26)(chicken, mouse).
Maspin (MIME 154790; Protease inhibitor 5, Swissprot P36952; Gene map locus 18q21.3)(mouse, rat).
Protease inhibitor 14 (MIME 605587; abbreviation: PI14; Protein sequence; Gene map locus 3q26.1-q26.2).
Kallistatin , an inhibitor of angiogensis and tumor growth (MIME 147935; synonyms: kallikrein inhibitor, protease inhibitor 4, SerpinA4, PI4, KST, Swissprot P29622; Gene map locus 14q31-q32.1)(mouse, rat)
Kunitz type serine proteinase inhibitors
Bikunin (MIME 176870; synonyms Alpha-1-microglobulin, Inter-alpha-trypsin inhibitor light chain, Swissprot P02760; Gene map locus 9q32-q33)(bovine, mouse, pig, rat). Bikunin is the light chain of inter-alpha-trypsin inhibitor. It contains two Kunitz tyxpe inhibitor domains. It is present in plasma and urine and inhibits trypsin, plasmin, and leukocyte elastase.
HGF activator inhibitor type 1 (MIME 605123; synonyms HAI-1 MT-SP1, SPINT-1, Swissprot O43278)(mouse). The inhibitor contains a transmembrane domain and two Kunitz-type inhibitor domains.
HGF activator inhibitor type 2 (MIME 605124 http://www.ncbi.nlm.nih.gov:80/entrez/dispomim.cgi?id=605124 ; synonyms HAI-2; MT-SP2; placental bikunin; SPINT-2; Swissprot O43291; Gene map locus 19q13.1)(mouse). The inhibitor contains a transmembrane domain and two Kunitz-type inhibitor domains.
Tissue factor pathway inhibitor, type 2. (MIME 600033; abbreviation: TFPI-2; synonym: placental protein 5; Swissprot P48307; Gene map locus 7q22)(mouse).
TFPI-2 has three Kunitz type inhibitor domains. It efficiently inhibits
plasmin (Ki = 3 nM), MMP-1 (Ki = 58 nM), MMP-13 (Ki = 32 nM) and to a
lesser extent
MMP-2 and MMP-9 Ki's ~2 µM). The inhibitor binds to the extracellular
matrix and may modulate, positively or negatively, the invasive and metastatic
properties of tumor cells.
TIMPS
Tissue inhibitor of metalloproteinases-1 (MIME 305370; abbreviation: TIMP-1; Swissprot P01033; Gene map locus Xp11.3-p11.23)(bovine, baboon, dog, horse, mouse, pig, rabbit, rat, sheep).
Tissue inhibitor of metalloproteinases-2 (MIME 188825; abbreviation: TIMP-2; Swissprot P16035; Gene map locus 17q25).(bovine, chicken, chinese hamster, dog, guinea pig, horse, mouse, rabbit, rat).
Tissue inhibitor of metalloproteinases-3(MIME 188826; abbreviation: TIMP-3; Swissprot P35625; Gene map locus 22q12.1-q13.2)(bovine, chicken, mouse, rabbit, rat, xenopus).
Tissue inhibitor of metalloproteinases-4 (MIME 601915; abbreviation: TIMP-4; Swissprot Q99727)(bovine, rat).
General proteinase inhibitor
Alpha-2-Macroglobulin (MIME 103950; abbreviation: A2M; Swissprot P01023; Gene map locus 12p13.3-p12.3)(mouse, rat).
Other inhibitors
RECK (Abbreviation of "Reversion-inducing cysteine-rich protein with Kazal motifs"; MIME 605227; Swissprot O95980; Gene map locus 9p13-p12)(mouse ). Contains three Kazal.like protease inhibitor domains and is attached to the cell mebrane via a GPI-anchor. It inhibits MMP-9, as well as MMP-2 and MMP-14 (MT1-MMP).
Thrombin-activatable fibrinolysis inhibitor (MIME 603101; abbreviation: TAFI; synonym: procarboxypeptidase B, Swiss-Prot P15086; Gene map locus 13q14.11).
Apolipoprotein(a) (MIME 152200; Swissprot P08519; Gene map locus 6q27).
Histidine-rich glycoprotein (MIME 142640; synonym: Histidine-proline rich glycoprotein Swissprot P04196; Gene map locus 3q27)(bovine, rabbit).
Tetranectin (MIME 187520; synonym: Plasminogen-kringle 4 binding protein, Swissprot P05452; Gene map locus 3p22-p21.3)(mouse)
Receptors
Urokinase receptor (MIME 173391; abbreviation: u-PAR; synonym: CD87, Swissprot Q03405; Gene map locus 19q13)(bovine, mouse, rat). Binds u-PA and accelerates plasminogen activation at the cell surface. Is also required for the LRP mediated clearance of u-PA. An alternative spliced variant has been described for mouse and rat u-PAR; the variant may encode a secreted truncated form of u-PAR.
Annexin II (MIME 151740;), (synonyms: Lipocortin 2, Calpactin I heavy chain, Chromobindin 8, Placental anticoagulant protein IV, Swissprot P07355; Gene map locus 15q21-q22)(bovine, chicken, mouse, pig, rat, xenopus).
May exist as a monomer, or binding with p11, a cellular ligand of annexinII, may lead the formation of a hetero dimer or hetero tetramer . Binds t-PA and plasminogen and accelerates plasminogen activbation by t-PA at the cell surface. Also binds cathepsin D which can activate pro-urokinase.
Low-density lipoprotein receptor-related protein 1 (MIME 107770; abbreviation: LRP-1; synonyms: alpha-2-macroglobulin receptor, CD91, Swissprot Q07954; Gene map locus 12q13.1-q13.3)(C.elegans, chicken, mouse). A multiligand clearance receptor, that mediates the clearance of free t-PA and of complexes of t-PA and u-PA with PAI-1. May require a co-receptor for efficient cleranace, e.g. u-PAR for clearance of u-PA/PAI-1 complexes. A homologous receptor LRP1B was shown to be inactivated in many non-small cell lung cancer cell lines
Low-density lipoprotein receptor-related protein 2 (MIME 600073; abbreviation: LRP-2; synonyms: megalin, Glycoprotein-330, gp-330 Swissprot P98164; Gene map locus 2q24-q31)(rat). A multiligand clearance receptor, that mediates the clearance of free t-PA and of complexes of t-PA and u-PA with PAI-1.
Very low-density lipoprotein receptor (MIME 192977; abbreviation: VLDL-R; synonym: VLDL Receptor,, Swissprot P98155; Gene map locus 9p24 )(chicken, mouse, rabbit, rat). A multiligand clearance receptor, that mediates the clearance of free t-PA and of complexes of t-PA and u-PA with PAI-1.
Alpha Enolase (MIME: 172430; synonym: 2-phospho-d-glycerate hydro-lyase, phosphopyruvate hydratase, non- neural enolase, EC 4.2.1.11, Swissprot P06733; Gene map locus 1pter-p36.13)(bovine, chicken, mouse, rat). Alpha enolase binds plasminogen and thereby facilitates plasminogen activation at the cell surface.
Alpha-2-macroglobulin receptor-associated protein (MIME 104225; abbreviation: RAP; synonym: low density lipoprotein receptor-related protein-associated protein 1, RAP, Swissprot P30533; Gene map locus 4p16.3)(mouse, rat).
RAP is a general inhibitor of ligand clearance mediated by LRP-1, LRP-2 and the VLDL-R.mouse