Three small integrin‐binding ligand N‐linked glycoproteins (SIBLINGs) bind and activate specific matrix metalloproteinases

Abstract

Matrix metalloproteinases (MMPs) are critical for development, wound healing, and for the progression of cancer. It is generally accepted that MMPs are secreted in a latent form (proMMP) and are activated only upon removal of their inhibitory propeptides. This report shows that three members of the SIBLING (Small, Integrin-Binding LIgand, N-linked Glycoprotein) family can specifically bind (Kd approximately equal nM) and activate three different MMPs. Binding of SIBLING to their corresponding proMMPs is associated with structural changes as indicated by quenching of intrinsic tryptophan fluorescence, increased susceptibility to plasmin cleavage, and decreased inhibition by specific natural and synthetic inhibitors. Activation includes both making the proMMPs enzymatically active and the reactivation of the TIMP (tissue inhibitors of MMP) inhibited MMPs. Bone sialoprotein specifically binds proMMP-2 and active MMP-2, while osteopontin binds proMMP-3 and active MMP-3, and dentin matrix protein-1 binds proMMP-9 and active MMP-9. Both pro and active MMP-SIBLING complexes are disrupted by the abundant serum protein, complement Factor H, thereby probably limiting SIBLING-mediated activation to regions immediately adjacent to sites of secretion in vivo. These data suggest that the SIBLING family offers an alternative method of controlling the activity of at least three MMPs.

Role of matrix metalloproteinases in dental caries, pulp and periapical inflammation: An overview

“…19 Moreover, phosphorylated proteins released by bacterial acids from the collagen scaffold interact with TIMP-inhibited MMPs within the carious lesion and reactivate them, enhancing the degradation process. 22 TIMPs as per current studies consist of four members -TIMP-1, -2, -3 and -4. They form complexes with the active forms of MMPs and under certain circumstances with their latent forms as well.…”

Gelatinase-mediated migration and invasion of cancer cells

“…Bone sialoprotein specifically binds MMP-2, while osteopontin binds MMP-3, and dentin matrix protein-1 binds MMP-9. Interestingly, binding of the SIBLINGS to the MMPs activates the proenzymes and reduces their susceptibility to the MMP-inhibitors (Fedarko et al, 2004).…”

Characterization of a rat model with site‐specific bone metastasis induced by MDA‐MB‐231 breast cancer cells and its application to the effects of an antibody against bone sialoprotein

“…27,28 Lately, Fedarko and colleges reported about another specific interaction partner of BSP, the matrix metalloproteinase MMP-2, which is activated after its binding to the sialoprotein. 29 Matrix metalloproteinases are a class of hydrolytic enzymes supposed to be important in tumor development and metastasis. 30 Taken together, these findings as well as our results support the hypothesis that BSP has the potential to act as an adapter molecule in the pathogenesis of bone metastasis.…”