Levi E, Fridman R, Miao H Q, Ma Y S, Yayon A, Vlodavsky I
Department of Oncology, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7069-74. doi: 10.1073/pnas.93.14.7069.
Recent studies have demonstrated the existence of a soluble fibroblast growth factor (FGF) receptor type 1 (FGFR1) extracellular domain in the circulation and in vascular basement membranes. However, the process of FGFR1 ectodomain release from the plasma membrane is not known. Here we report that the 72-kDa gelatinase A (matrix metalloproteinase type 2, MMP2) can hydrolyze the Val368-Met369 peptide bond of the FGFR1 ectodomain, eight amino acids upstream of the transmembrane domain, thus releasing the entire extracellular domain. Similar results were obtained regardless of whether FGF was first bound to the receptor or not. The action of MMP2 abolished binding of FGF to an immobilized recombinant FGFR1 ectodomain fusion protein and to Chinese hamster ovary cells overexpressing FGFR1 The released recombinant FGFR1 ectodomain was able to bind FGF after MMP2 cleavage, suggesting that the cleaved soluble receptor maintained its FGF binding capacity. The activity of MMP2 could not be reproduced by the 92-kDa gelatinase B (MMP9) and was inhibited by tissue inhibitor of metalloproteinase type 2. These studies demonstrate that FGFR1 may be a specific target for MMP2 on the cell surface, yielding a soluble FGF receptor that may modulate the mitogenic and angiogenic activities of FGF.
最近的研究表明，在循环系统和血管基底膜中存在可溶性成纤维细胞生长因子（FGF）受体1型（FGFR1）的细胞外结构域。然而，FGFR1胞外结构域从质膜释放的过程尚不清楚。在此我们报告，72 kDa的明胶酶A（基质金属蛋白酶2型，MMP2）能够水解FGFR1胞外结构域跨膜结构域上游八个氨基酸处的Val368 - Met369肽键，从而释放整个细胞外结构域。无论FGF是否首先与受体结合，均得到类似结果。MMP2的作用消除了FGF与固定化重组FGFR1胞外结构域融合蛋白以及与过表达FGFR1的中国仓鼠卵巢细胞的结合。经MMP2切割后释放的重组FGFR1胞外结构域能够结合FGF，这表明切割后的可溶性受体保持了其FGF结合能力。92 kDa的明胶酶B（MMP9）不能重现MMP2的活性，且MMP2的活性受到金属蛋白酶组织抑制剂2型的抑制。这些研究表明，FGFR1可能是细胞表面MMP2的特异性靶点，产生一种可调节FGF促有丝分裂和血管生成活性的可溶性FGF受体。
