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Matrix Metalloproteinase 2 Releases Active Soluble Ectodomain Of Proc. Natl. Acad. Sci. USA Vol. 93, pp. 7069-7074, July 1996 Cell Biology Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1 (fibroblast growth factor receptor cleavage/fibroblast growth factor receptor crosslinking/gelatinase A) EHUD LEVI*t, RAFAEL FRIDMANtt, HUA-QUAN MIAO*, YONG-SHENG MA§, AVNER YAYON§, AND ISRAEL VLODAVSKY*¶ *Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem 91120, Israel; tDepartment of Pathology, Wayne State University School of Medicine, Detroit, MI 48201; and §Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel Communicated by Leo Sachs, Weizmann Institute of Science, Rehovot, Israel, April 5, 1996 (received for review February 25, 1996) ABSTRACT Recent studies have demonstrated the exis- The 72-kDa [matrix metalloproteinase type 2 (MMP2)] and tence ofa soluble fibroblast growth factor (FGF) receptor type the 92-kDa (MMP9) gelatinases are two members of a large 1 (FGFR1) extracellular domain in the circulation and in family of zinc-dependent endopeptidases, the matrix metal- vascular basement membranes. However, the process of loproteinases (MMP), known to cleave ECM proteins in FGFR1 ectodomain release from the plasma membrane is not normal and pathological conditions (12-16). Like other mem- known. Here we report that the 72-kDa gelatinase A (matrix bers of the MMP family, the gelatinases are secreted in a latent metalloproteinase type 2, MMP2) can hydrolyze the Val368- form, requiring activation for proteolytic activity, and are Met369 peptide bond of the FGFR1 ectodomain, eight amino inhibited by the tissue inhibitors of metalloproteinases acids upstream of the transmembrane domain, thus releasing (TIMPs; refs. 12-14). Recent studies demonstrated that latent the entire extracellular domain. Similar results were obtained proMMP2 is activated by a novel subgroup of MMPs, the regardless of whether FGF was first bound to the receptor or membrane-type MMPs, which are bound to the plasma mem- not. The action of MMP2 abolished binding of FGF to an brane of normal and tumor cells by a unique transmembrane immobilized recombinant FGFR1 ectodomain fusion protein domain (17, 18). The localization of active MMP2 and mem- and to Chinese hamster ovary cells overexpressing FGFR1. brane-type MMPs on the cell surface may play a role in the The released recombinant FGFR1 ectodomain was able to degradation of ECM components in areas of cell-matrix bind FGF after MMP2 cleavage, suggesting that the cleaved interactions. It is conceivable that nonmatrix cell surface soluble receptor maintained its FGF binding capacity. The proteins, including cell surface receptors, may also be the activity of MMP2 could not be reproduced by the 92-kDa target of membrane-bound MMPs. It has been recently shown gelatinase B (MMP9) and was inhibited by tissue inhibitor of that MMP2 can hydrolyze ,B-amyloid isolated from brains of metalloproteinase type 2. These studies demonstrate that Alzheimer disease patients (19, 20), and galectin-3, a cell FGFR1 may be a specific target for MMP2 on the cell surface, surface lectin involved in cell-cell and cell-matrix interactions yielding a soluble FGF receptor that may modulate the in tumor cell metastasis (21). mitogenic and angiogenic activities of FGF. The biological activity of FGF may be regulated by several mechanisms, including binding to high and low affinity recep- The fibroblast growth factors (FGFs) constitute a family of tors on the cell surface (1-3), release of FGF from ECM by nine structurally related polypeptides characterized by high heparanase (22, 23), and as recently proposed, release of the affinity to heparin. The FGFs participate in a wide array of entire ectodomain of the FGFR into the circulation and ECM biological activities, including the induction of cellular prolif- (24, 25). A soluble truncated FGFR1 was recently detected in eration, tissue regeneration, neurite outgrowth, angiogenesis, the basement membrane of retinal vascular endothelial cells by and embryonic mesoderm induction (1-3). This gene family use of an antibody raised against the extracellular domain of includes the prototypes acidic FGF (aFGF) and basic FGF FGFR1 (25). The mechanism by which FGFR may be released (bFGF) that, unlike most other polypeptide growth factors, are from the cell surface was not elucidated, but it may involve the primarily cell associated proteins, consistent with a lack of a action of a protease acting on the cell surface and cleaving the conventional signal sequence for secretion (1-3). FGFs elicit extracellular domain of the high affinity receptor. In our study, their biological responses by binding to cell surface tyrosine we examined the ability of the gelatinases to hydrolyze murine kinase receptors. Four distinct but highly related FGF recep- FGFR1 and FGFR2 ectodomains. Here we demonstrate that tors (FGFRs) have been identified (4-6). The prototype human recombinant MMP2, but not MMP9, cleaves a recom- FGFR contains three IgG-like domains in its extracellular binant FGFR1 fusion protein, releasing the entire ectodomain. portion, a single transmembrane domain, and a tyrosine kinase MMP2 hydrolysis was achieved with both free and FGF- domain that is split into two segments by a short interkinase occupied receptor. The MMP2-hydrolyzed ectodomain re- region (5). In addition to the four distinct FGFRs, an alter- We MMP2 native splicing mechanism gives rise to multiple forms of tained its ability to bind FGF. also show that FGFR type 1 (FGR1), FGFR2, and FGFR3 (4-9). In addition treatment of cells overexpressing FGFR1 markedly reduces to interacting with their high affinity receptors, FGFs also interact with lower affinity binding sites identified as heparan Abbreviations: FGF, fibroblast growth factor; FGFR, FGF receptor; aFGF, acidic FGF; bFGF, basic FGF; FGFR1, FGF receptor type 1; sulfate proteoglycans and found on the surface of cells and in ECM, extracellular matrix; MMP, matrix metalloproteinase; MMP2, the extracellular matrix (ECM; refs. 1-3). Cells that naturally MMP type 2; TIMP2, tissue inhibitor of metalloproteinase type 2; do not express heparan sulfate proteoglycans but overexpress proMMP, latent MMP; AP, alkaline phosphatase; APMA, p- high affinity receptors for FGFs fail to respond mitogenically aminophenylmercuric acetate. FRAP, FGFR1 ectodomain-AP fusion to aFGF or bFGF, unless heparin is added (10, 11). protein; BAP, mouse Bek ectodomain-AP fusion protein; DSS, disuccinimidylsuberate; CHO, Chinese hamster ovary. tThe first two authors contributed equally to this work. The publication costs of this article were defrayed in part by page charge ITo whom reprint requests should be addressed at: Department of payment. This article must therefore be hereby marked "advertisement" in Oncology, Hadassah Hospital, P.O. Box 12000, Jerusalem 91120, accordance with 18 U.S.C. §1734 solely to indicate this fact. Israel. 7069 Downloaded by guest on September 24, 2021 7070 Cell Biology: Levi et al. Proc. Natl. Acad. Sci. USA 93 (1996) binding of FGF. The results suggest a novel mechanism of FGF Treatment of Immobilized FGFR-AP Fusion Protein with regulation modulated by the action of MMP2. MMPs Followed by 125I-bFGF Binding and Crosslinking. Ninety-six-well plates. FGFR-AP fusion protein [FRAP or mouse Bek ectodomain-AP fusion protein (BAP)] immobi- MATERIALS AND METHODS lized onto 96-well plates was incubated (37°C, 5 h, except when Materials. Sodium heparin from porcine intestinal mucosa stated otherwise) with recombinant proMMP2 or proMMP9 was obtained from Hepar (Franklin, OH). Recombinant hu- (3 ,ug/ml, except when stated otherwise) in the presence or man bFGF, kindly provided by Takeda (Osaka), and aFGF (a absence of 1 mM APMA, 10 mM EDTA, or recombinant gift of G. Neufeld, Technion, Haifa, Israel) were iodinated by TIMP2 (1:1 molar ratio of MMP/TIMP2). The wells were then chloramine T as described (26). The specific activity was washed three times and incubated (2 h, 22°C) with 5 ng/ml -1.7 x 105 cpm/ng of 1251-bFGF and -0.4 x 105 cpm/ng of iodinated aFGF or bFGF in the absence and presence of 0.1 125I-aFGF, and the labeled preparations were kept for up to 3 ,tg/ml or 0.02 Ag/ml heparin, respectively. The wells were weeks at -70°C. 1251-Na was purchased from Amersham. washed once with binding medium followed by one wash with Mouse anti-human placental alkaline phosphatase (AP) mAbs Hepes buffer, pH 7.4, containing 0.5 M NaCl (aFGF) or 2 M coupled to agarose were purchased from Sigma. Rabbit anti- NaCl (bFGF), and a final wash with binding buffer. The bound Bek polyclonal antiserum was generated by injecting glutathi- 1251-FGF was released with 2 M NaCl in 20 mM sodium one S-transferase fused with the ectodomain region of mouse acetate, pH 4.5, and counted in a y counter. Bek (9). Sepharose beads. The immobilized FGFR-AP (FRAP or Expression and Purification of Recombinant MMPs and BAP) was equilibrated with MMP reaction buffer (50 mM TIMPs. Human recombinant proMMP2, proMMP9, and Tris-HCl, pH 7.2/5 mM CaCl2/0.02% sodium azide/1 mM TIMP type 2 (TIMP2) were all expressed in HeLa cells using APMA) and incubated (5 h, 37°C) with 3 p,g/ml recombinant a recombinant vaccinia virus expression system (Vac/T7) as proMMP2 in a final volume of 80 ,lI. The beads were washed described (27, 28). proMMP2 and proMMP9 were purified by and suspended in 80 Al of MMP reaction buffer. EDTA (10 gelatin-affinity chromatography from the media (Opti-MEM mM) was then added to both the supernatant and the pellet to I, GIBCO/BRL) of HeLa cells coinfected with the appropri- inhibit the enzyme activity before bFGF binding and crosslink- ate recombinant viruses as described (27, 28). TIMP2 was ing. The supernatant containing the released FGFR1 ectodo- purified by affinity chromatography using an mAb (CA-101) main and the pellet containing the FRAP fragment remaining against human TIMP2, as described (27, 28).
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