Reactome | MMP14:TIMP2 binds proMMP2

MMP14:TIMP2 binds proMMP2

Stable Identifier

R-HSA-1604350

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane, extracellular region

ReviewStatus

5/5

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The MMP14:TIMP2 complex can efficiently bind proMMP2. Physiological concentrations of TIMP2 enhance proMMP2 binding, but higher concentrations inhibit proMMP2 activation (Butler et al. 1998, Kinoshita et al. 1998), indicating that while MMP14:TIMP2 complexes bind proMMP2, local free MMP14 cleaves the TIMP-bound proMMP2 in the prodomain, leading to autoactivation between Asn109 Tyr110. In vivo the majority of MMP14 (MT1-MMP) is bound to TIMP2 and therefore functions as a receptor for proMMP2 (Nishida et al. 2008). Binding of TIMP-2 to proMMP2 occurs via interaction of the TIMP2 C domain (McQuibban et al. 2000) and the MMP2 hemopexin domain between hemopexin blades III and IV (Overall et al. 1999) in an interaction that is highly dependant upon the nature of the C-tail of the TIMP (Kai et al. 2002). TIMP-4 also binds the proMMP2 hemopexin domain (Bigg et al. 1997) to prevent activation by MMP14 (Bigg et al. 2001). An alternative cell surface localization mechanism exists that inhibits MMP2 activation: Cell surface Beta1 integrin binds native type I collagen, which in turn is bound by the fibronectin type II modules of MMP2 to prevent activation by MMP14 (Steffensen et al. 1998).

Literature References

PubMed ID	Title	Journal	Year
9632662	TIMP-2 promotes activation of progelatinase A by membrane-type 1 matrix metalloproteinase immobilized on agarose beads Okada, Y, Imai, K, Sato, H, Ohuchi, E, Okada, A, Seiki, M, Kinoshita, T	J Biol Chem	1998
9422744	The TIMP2 membrane type 1 metalloproteinase "receptor" regulates the concentration and efficient activation of progelatinase A. A kinetic study Schade van Westrum, S, Atkinson, SJ, Butler, GS, Butler, MJ, Crabbe, T, d'Ortho, MP, Clements, J, Tamura, T, Murphy, G, Will, H	J Biol Chem	1998