MATRIX METALLOPROTEINASE-2 RELEASES ACTIVE SOLUBLE ECTODOMAIN OF FIBROBLAST GROWTH-FACTOR RECEPTOR-1

Recent studies have demonstrated the existence of a soluble fibroblast growth factor (FGF) receptor type 1 (FGFR1) extracellular domain in t he circulation and in vascular basement membranes. However, the proces s of FGFR1 ectodomain release from the plasma membrane is not known. H ere we report that the 72-kDa gelatinase A (matrix metalloproteinase t ype 2, MMP2) can hydrolyze the Val(368)-Met(369) peptide bond of the F GFR1 ectodomain, eight amino acids upstream of the transmembrane domai n, thus releasing the entire extracellular domain. Similar results wer e obtained regardless of whether FGF was first bound to the receptor o r not. The action of MMP2 abolished binding of FGF to an immobilized r ecombinant FGFR1 ectodomain fusion protein and to Chinese hamster ovar y cells overexpressing FGFR1. The released recombinant FGFR1 ectodomai n was able to bind FGF after MMP2 cleavage, suggesting that the cleave d soluble receptor maintained its FGF binding capacity. The activity o f MMP2 could not be reproduced by the 92-kDa gelatinase B (MMP9) and w as inhibited by tissue inhibitor of metalloproteinase type 2. These st udies demonstrate that FGFR1 may be a specific target for MMP2, on the cell surface, yielding a soluble FGF receptor that may modulate the m itogenic and angiogenic activities of FGF.