Here is some more on MMP's

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I'm reproducitng this from Horst Ibelgauft's webpage.

Matrix metalloproteinases

( abbr. MMP ). These enzymes, known collectively also asmatrixins ,

are zinc-dependent endopeptidases that function extracellularly at

neutral pH. For full activity these enzymes also require extrinsic

calcium ions. proteases contain a conserved catalytic domain which is

characterized by three histidine residues complexing a zinc atom to

form the active site.

These proteases constitute a large and growing protein family which

are highly related in terms of structure and enzymatic properties.

The individual proteins are now given the designation MMP followed by

a number (see also individual entries: MMP-1 , MMP-2 , MMP-3 , MMP-

7 , MMP-8 , MMP-9 , MMP-10 , MMP-11 , MMP-12 , MMP-13 , MMP-14 , MMP-

15 , MMP-16 , MMP-17 , MMP-18 , MMP-19 , MMP-20 , MMP-21 , MMP-22 ,

MMP-23 , MMP-24 , MMP-25 , MMP-26 ).

Some MMPs have been found to exist also as membrane-bound proteins.

They are referred to asmembrane-type MMPs ( abbr. MT-MMP ; MT1-MMP

(new name: MMP-14 ), MT2-MMP (new name: MMP-15 ), MT3-MMP (new name:

MMP-16 ), MT4-MMP (new name: MMP-17 ), MT5-MMP ), MT-6-MMP. Their

location at the surface of cells implies that these enzymes could

play a role in the modulation of cell-matrix interactions.

Historically, individual members were named after what was thought to

be the major substrate, or by the cellular source. This gave rise to

names such as collagenases which degrade interstitial collagens

(types I, II and III), type IV collagenases and gelatinases which

degrade basement membrane collagen type 4 and gelatins (denatured

collagens), and stromelysins which degrade a broad range of

substrates including proteoglycans , laminin, gelatins and

fibronectin . It is known now that most of these enzymes cleave

multiple substrates, including the inactive polypeptide proforms

(zymogen ) of other family members. These enzymes also cleave non-

matrix proteins such as myelin basic protein and alpha-1-antitrypsin.

Since the activities of MMPs are potentially dangerous in a cellular

environment their expression is controlled tightly at the

transcriptional and/or post-translational level.

MMPs are usually not expressed constitutively (see also: Gene

expression ). The expression of MMP genes can be modified by a

variety of physiologic and pharmacologic signals, including cytokines

and growth factors , bacterial endotoxin, phorbol esters ,

phagocytosable material, and hormones. These factors can act directly

through positive or negative regulatory elements in the promoter

regions of MMP genes (see also: Gene expression ) or influence

expression of MMP genes indirectly. Despite their sometimes high

sequence homology MMPs exhibit differences in cellular synthesis and

inducibility by cytokines and growth factors .

All MMPs are synthesized as fairly large preproenzymes. Most of them

are secreted from the cells as proenzymes ( promatrixins ). These

proenzymes require activation before becoming fully active and this

involves regulated proteolysis causing the loss of the propeptide.

The regulatory propeptide sequence contains a free cysteine residue

which has the ability of bvindingf to zinc. This interaction

maintains latency of the enzymes, which become active once the

propeptide is removed from the catalytic domain of the protein. MMP

activation can be achieved by autoactivation and by a variety of

other proteases, including furin, urokinase, and plasmin, and various

other members of the MMP family.

The activation of these proenzymes is one of the critical steps that

leads to extracellular matrix breakdown. In vitro the enzyme proforms

can be activated by a variety of proteinases, including plasmin,

trypsin, kallikrein, neutrophil elastase, cathepsin G . They are

activated also by a number of organomercury compounds (for example 4-

aminophenylmercuric acetate). In vivo activation occurs mainly in the

pericellular environment. Many MMPs have been shown to undergo cross-

activation by other MMPs. Some of the membrane-bound enzymes have

been found also to be capable of activating secreted enzyme forms. In

addition, they appear to recruit the activated enzymes to the cell

membrane (see, for example: MMP-14 ; see also: fetuins). The

activation of inactive proforms of matrix endopeptidases among each

other can lead to cascades of activation and this programmed

expression plays a significant role in normal and pathological

processes.

At the post-translational level the extracellular activities of these

enzymes are governed not only by proteolytic cleavage, but also by

complexation with naturally occuring protein inhibitors. Tissue

inhibitors of metalloproteinases , ( TIMP-1 , TIMP-2 , TIMP-3 , TIMP-

4 ) are related proteins that can form complexes with all known MMPs.

Some proenzyme forms (MMP-2 and MMP-9 ) are found in complex with

such tissue inhibitors (designatedproMMP-2/TIMP-2 andproMMP-9/TIMP-

1 , respectively). Some of the matrix metalloproteinases can be

activated by other enzymes also when they are complexed with their

inhibitors. Another natural inhibitor of several serum proteases is

Alpha-2-Macroglobulin .

MMPs have been linked with a wide array of biological activities and

play important roles during organ development and pathological

processes. Collectively MMPs are key enzymes for the metabolism of

extracellular matrix proteins, including fibrillar and non-fibrillar

collagens, fibronectin , laminin and basement membrane or

interstitial stroma glycoproteins. Due to their activities these

enzymes are considered to be important therapeutic targets for the

treatment of various diseases where tissue degradation is part of the

pathology, such as cancer and arthritis.

Under physiological conditions MMPs are involved in extracellular

degradation and breakdown of matrix proteins during normal tissue

remodelling processes such as wound healing , pregnancy, and

angiogenesis . MMPs are believed to facilitate cellular migration

across basement membranes. The release of these enzymes by various

cell types has been implicated in the pathogenesis of many diseases

and diverse invasive processes, including tissue distruction during

inflammatory reactions, and diseases such as arthritis,

periodontitis, glomerulonephritis, atherosclerosis, tissue

ulceration, cancer, and multiple sclerosis. It has been found that

tissue destruction in disease processes often correlates with an

imbalance of MMPs over their protein inhibitors, TIMPs.

Cytokines , growth factors , and hormones have been found to regulate

expression of MMPs and their inhibitors, TIMPs, in a complex manner.

Some of these proteolytic enzymes have been found also to participate

directly in reactions governed by cytokines in that they are engaged

in cytokine activation. For example, MMP-2 , MMP-3 , and MMP-9 have

been found to be capable of activating the precursor of IL1-beta , a

function generally ascribed to one of the enzymes known as caspases

(Caspase-1 , IL1-beta Convertase ). In addition, these enzymes also

inactivate the mature cytokine with different efficiencies. MMPs thus

may be involved in the regulation of IL1-beta activities at sites of

chronic or acute inflammation .

date of last revision: 01/07/1999

References: Borkakoti N Matrix metalloproteases: variations on a

theme. Progress in Biophysics and Molecular Biology 70(1): 73-94

(1998); Giambernardi TA et al Overview of matrix metalloproteinase

expression in cultured human cells. Matrix Biology 16(8): 483-496

(1998); Nagase H Activation mechanisms of matrix metalloproteinases.

Biol. Chem. 378(3-4): 151-160 (1997)