The Matrix Metalloproteinase (MMP) and Tissue Inhibitor of Metalloproteinase (TIMP) Genes: Transcriptional and Posttranscriptional Regulation, Signal

互联网2014-02-13

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Developmental and homeostatic remodeling of the extracellular matrix (ECM) is a highly regulated process orchestrated by a family of zinc-containing, calcium-dependent neutral proteases known as the matrix metallo-proteinases (MMP). This family of enzymes, which now contains twenty members, can collectively degrade all structural proteins of the ECM including interstitial collagens (I, II, III, and V), basement membrane collagens (IV), fibronectin, laminin, proteoglycan, and elastin (Table 1 ). The enzymatic activity of MMP family members is controlled by a group of inhibitor proteins known as the Tissue Inhibitors of Metalloproteinases (TIMPs), which consist of four family members (Table 2 ). Whereas all four TIMPs can inhibit all MMPs in vitro, preferential TIMP-MMP interactions and tissue-restricted TIMP expression suggest that each TIMP has a specific function (Table 2 ).

Table 1 The Matrix Metalloproteinases (MMPs)

MMP family member	Common names	Substrates	Selected references
MMP-1	Collagenase-1	Collagens I, II, III, VI, X, gelatins, aggrecan, entactin	*(154–158)*
MMP-2	72 kDa Gelatinase, Gelatinase A	Gelatins, collagens I,IV, V, VII, X, XI, fibronectin, laminin, aggrecan, elastin, large tenascin C, vitronectin, β-amyloid protein precursor	*(157–159)*
MMP-3	Stromelysin-1	Aggrecan, gelatins, fibronectin, laminin, collagen III, IV, IX, X, large tenascin C, vitronectin	*(28,157,158,160,161)*
MMP-7	Matrilysin, Pump	Aggrecan, fibronectin, laminin, collagen IV, elastin, entactin, small tenascin C, vitronectin	*(157,158,162,163)*
MMP-8	Collagenase-2, Neutrophil Collagenase	Collagens I, II, III, aggrecan	*(157,158,164)*
MMP-9	92 kDa Gelatinase, Gelatinase B	Gelatins, collagens IV, V, XIV, aggrecan, elastin, entactin, vitronectin	*(157,158,165,166)*
MMP-10	Stromelysin-2	Aggrecan, fibronectin, laminin, collagen IV	*(157,158,167)*
MMP-11	Stromelysin-3	Fibronectin, laminin, collagen IV, aggrecan, gelatins	*(141,158)*
MMP-12	Metalloelastase	Elastin	*(147,158)*
MMP-13	Collagenase-3	Collagens I, II, III	*(88,89,124,158,168,169)*
MMP-14	Membrane-type-1 -MMP	Collagens I, II, III, fibronectin, laminin, vitronectin, proteoglycan, ProMMP-2, ProMMP-13	*(158,170)*
MMP-15	Membrane-type-2-MMP	Not known	*(158,171)*
MMP-16	Membrane-type-3-MMP	ProMMP-2	*(158,172)*
MMP-17	Membrane-type-4-MMP	Not known	*(158,173)*
MMP-18	Collagenase-4,Xenopus Collagenase	Collagen I	*(158,174,175)*
MMP-19		Not Known	*(158,176,177)*
MMP-20	Enamelysin	Amelogenin (The major tooth enamel matrix protein)	*(178)*

Table 2 Tissue Inhibitors of Metalloproteinases (TIMPs)

Family	Reported functions	Selected References
TIMP-1	Inhibition of all known MMP family members. Associates with proMMP-9. Inhibits angiogenesis. Erythroid-potentiating actvity.	*(179–181)*
TIMP-2	Inhibitions all known MMP family members. Associates with MT1-MMP and MMP-2 at cell surface and regulates MMP-2 activation.	*(181–184)*
TIMP-3	Inhibition of all known MMP family members. Extracellular matrix-associated. Mutation associated with Sorsby's fundus dystrophy.	*(55,181,185–188)*
TIMP-4	Inhibition of all known MMP family members. Restricted expression suggests tissue specific TIMP function.	*(181,189,190)*