Matrix metalloproteinase 9 (MMP-9)-dependent processing of ?ig-h3 protein regulates cell migration, invasion, and adhesion.
Cell migration is critically involved in inflammation, cancer, and development. In this study, transforming growth factor-?-induced protein (?ig-h3) was identified as a substrate of matrix metalloproteinase-9 (MMP-9) by site-directed mutagenesis. ?ig-h3 has two cleavage sites with the consensus sequence Pro-Xaa-Xaa-Hy-(Ser/Thr) (Hy is a hydrophobic amino acid) (PGSFT beginning at amino ... acid 135 and PPMGT beginning at amino acid 501). Using recombinant human ?ig-h3 and MMP-9, ?ig-h3 from ?ig-h3-transfected HEK293F cells, and MMP-9 from MMP-9-transfected HEK293F cells, human macrophages, and neutrophils, we found that MMP-9 proteolytically cleaves ?ig-h3. Cleavage leads to the loss of its adhesive property and its release from extracellular matrix proteins, collagen IV, and fibronectin. Spheroids formed by increased cell-cell interactions were observed in ?ig-h3-transfected HEK293F cells but not in vehicle-transfected HEK293F cells. In human glioma U87MG cells, MMP-9 constitutive overexpression resulted in endogenous ?ig-h3 cleavage. ?ig-h3 cleavage by MMP-9 led to increased cell invasion, and ?ig-h3 knockdown also resulted in increased cell invasion. The ?ig-h3 fragment cleaved by MMP-9 could bind to the surface of macrophages, and it may play a role as a peptide chemoattractant by inducing macrophage migration via focal adhesion kinase/Src-mediated signal activation. Thus, intact ?ig-h3 is responsible for cell migration inhibition, cell-cell contact, and cell-extracellular matrix interaction. Experimental evidence indicates that MMP-9-cleaved ?ig-h3 plays a role in MMP-9-mediated tumor cell and macrophage migration.
Mesh Terms:
Cell Adhesion, Cell Membrane, Cell Movement, Chemotaxis, Extracellular Matrix, Extracellular Matrix Proteins, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Interleukin-1beta, Macrophages, Matrix Metalloproteinase 9, Mutagenesis, Site-Directed, Neoplasm Invasiveness, Phosphorylation, Signal Transduction, Transforming Growth Factor beta, U937 Cells
Cell Adhesion, Cell Membrane, Cell Movement, Chemotaxis, Extracellular Matrix, Extracellular Matrix Proteins, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Interleukin-1beta, Macrophages, Matrix Metalloproteinase 9, Mutagenesis, Site-Directed, Neoplasm Invasiveness, Phosphorylation, Signal Transduction, Transforming Growth Factor beta, U937 Cells
J Biol Chem
Date: Nov. 09, 2012
PubMed ID: 23019342
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