Three small integrin binding ligand N-linked glycoproteins (SIBLINGs) bind and activate specific matrix metalloproteinases.
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.
Fedarko
Neal S
NS
Division of Geriatrics, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ndarko@jhmi.edu
Jain
Alka
A
Karadag
Abdullah
A
Fisher
Larry W
LW
D017242:Complement Factor H / Q000494:pharmacology; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D058574:Integrin-Binding Sialoprotein; D016023:Integrins / Q000378:metabolism; D008024:Ligands; D046911:Macromolecular Substances; D020782:Matrix Metalloproteinases / Q000302:isolation & purification / Q000378:metabolism*; D008954:Models, Biological; D053495:Osteopontin; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism; D012795:Sialoglycoproteins / Q000302:isolation & purification / Q000378:metabolism
C493495:CFH protein, human; C513309:DMP1 protein, human; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C546871:IBSP protein, human; C546873:Ibsp protein, rat; D058574:Integrin-Binding Sialoprotein; D016023:Integrins; D008024:Ligands; D046911:Macromolecular Substances; D010750:Phosphoproteins; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; D017242:Complement Factor H; D020782:Matrix Metalloproteinases