The low density lipoprotein receptor-related protein modulates levels of matrix metalloproteinase 9 (MMP-9) by mediating its cellular catabolism.
Members of the matrix metalloproteinase (MMP) family of enzymes participate in matrix remodeling and share a number of structural and functional features. The activity of this family of proteinases is carefully regulated at the level of zymogen activation and by a family of specific inhibitors termed tissue inhibitors of metalloproteinases (TIMP). It is now becoming clear that levels of certain MMPs are modulated by their association with cellular receptors that mediate their rapid internalization and degradation. In the current investigation we report that the amount of MMP-9 in conditioned cell culture medium is significantly increased when mouse embryonic fibroblasts are grown in the presence of the 39-kDa receptor-associated protein (RAP), an antagonist of ligand binding to low density lipoprotein receptor-related protein (LRP). In vitro assays reveal that the MMP-9.TIMP-1 complex binds to LRP with high affinity and that the binding determinant for LRP appears to reside on MMP-9. Cell lines expressing LRP mediate the internalization of 125I-labeled MMP-9.TIMP-1 complexes, whereas cell lines genetically deficient in LRP show a diminished capacity to mediate the cellular catabolism of MMP-9.TIMP-1 complexes. The results demonstrate that LRP is a functional receptor for MMP-9 and suggest a major role for LRP in modulating remodeling of the extracellular matrix by regulating extracellular proteinase activity.
Hahn-Dantona
E
E
Department of Vascular Biology, Holland Laboratory, American Red Cross, Rockville, Maryland 20855, USA.
Ruiz
J F
JF
Bornstein
P
P
Strickland
D K
DK
D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004797:Enzyme-Linked Immunosorbent Assay; D026541:Heymann Nephritis Antigenic Complex; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D011485:Protein Binding
D017077:Culture Media, Conditioned; D026541:Heymann Nephritis Antigenic Complex; D008562:Membrane Glycoproteins; D020780:Matrix Metalloproteinase 9