Type IV collagen α1-chain noncollagenous domain blocks MMP-2 activation both in-vitro and in-vivo

alpha 1(IV)NC1 inhibits angiogenesis by regulating MAPK activation, this biological function was partly attributed alpha 1(IV)NC1 binding to alpha 1 beta 1-integrin. However, its potent antiangiogenic activity and the molecular targets of alpha 1(IV has not been investigated. In the present study, the regulation of MMP-2 activation by alpha 1(IV)NC1 was evaluated. alpha 1 beta 1-integrin which is required for inhibition of angiogenesis is not playing a role in cellular invasion and inhibition of MMP-2 activation by alpha 1(IV)NC1. We found that alpha 1(IV)NC1 binds the CBD of MMP-2 and forming a stable complex that prevents activation of MMP-2. The antiangiogenic activity of alpha 1(IV)NC1 is mediated, in part, by this binding activity. In addition, up-regulation of TIMP-2 by alpha 1(IV)NC1 led to saturation of MT1-MMP binding sites, which in turn led to inhibition of MMP-2 activation. In-vivo studies using alpha 1-integrin null-mice treated with higher doses of alpha 1(IV)NC1 showed integrin independent inhibition of tumor growth and active-MMP-2, without affecting MMP-9, MMP-7 and angiostatin.