MMP14:TIMP2:proMMP2 MMP14:TIMP2:MMP2 intermediate form Initial activation of proMMP2 by MMP14 Authored: Jupe, S, 2011-09-09 EC Number: 3.4.21 Edited: Jupe, S, 2012-02-21 MMP2 is activated by the MT-MMPs MMP14 (Sato et al. 1994), MMP15 (Butler et al. 1997) and MMP16 (Takino et al. 1995). MMP14 (MT1-MMP) initially cleaves the Asn66-Leu67 bond of MMP2, followed by autocleavage of the Asn109-Tyr110 bond (Strongin et al. 1993, Atkinson et al. 1995). Residue numbering here refers to the UniProt canonical sequence.<br><br>MMP2 processing by MMP14 or MMP16 is very inefficient unless the MT-MMP has pre-bound TIMP2, which in turn binds MMP2. Physiological concentrations of TIMP2 enhance MMP2 binding, but higher concentrations inhibit proMMP2 activation (Butler et al. 1998, Kinoshita et al. 1998), indicating that MT-MMP:TIMP2 complexes bind MMP2, but local free MT-MMP subsequently cleaves the TIMP-bound proMMP2. In vivo the majority of MMP14 is bound to TIMP2 and functions as a receptor for proMMP2 (Nishida et al. 2008). In contrast, activation of proMMP2 by MMP15 occurs in a TIMP independent manner, with TIMP2 inhibiting activation at all concentrations (Morrison et al. 2001). Native type I collagen binds to the hemopexin C domain of MMP14, and following clustering of the enzyme together enhances proMMP2 activation (Tam et al. 2002). However, proMMP2 also binds the cell via cell surface Beta1 integrin, which binds native type I collagen which in turn is bound by the fibronectin type II modules of MMP2, preventing activation by MMP14 (Steffensen et al. 1998). ConA is the only known stimulator of cells to induce proMMP2 activation by MMP14 (Overall & Sodek 1990). Pubmed11584019 Pubmed12145314 Pubmed18974156 Pubmed2174435 Pubmed7559440 Pubmed8015608 Pubmed8314771 Pubmed8530478 Pubmed9119036 Pubmed9422744 Pubmed9632662 Pubmed9685420 Reactome Database ID Release 431604360 Reactome, http://www.reactome.org ReactomeREACT_118593 Reviewed: Butler, GS, 2012-02-28 Reviewed: Overall, CM, 2012-02-28