Membrane-Type 1 Matrix Metalloproteinase Downregulates Fibroblast Growth Factor-2 Binding to the Cell Surface and Intracellular Signaling.
Membrane-Type 1 Matrix Metalloproteinase Downregulates Fibroblast Growth Factor-2 Binding to the Cell Surface and Intracellular Signaling.
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DOI：
10.1002/jcp.24717
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发表时间：
2015-02
影响因子：
5.6
通讯作者：
Mignatti, Paolo
中科院分区：
文献类型：
--
作者：
Tassone, Evelyne;Valacca, Cristina;Mignatti, Paolo
1 型膜基质金属蛋白酶（MT1-MMP、MMP-14）是一种具有胞外催化结构域和短胞质尾的跨膜蛋白酶，可降解胞外基质成分，并通过与胞外、胞内和跨膜蛋白的蛋白水解和非蛋白水解相互作用来控制多种细胞功能。在这里，我们表明，在肿瘤细胞中，MT1-MMP 通过减少以高和低亲和力结合到细胞表面的 FGF-2 量，下调成纤维细胞生长因子 2 (FGF-2) 信号传导。与缺乏 MT1-MMP 的细胞相比，FGF-2 在 MT1-MMP 表达细胞中诱导的 ERK1/2 MAP 激酶激活较弱。这种效应在表达蛋白水解无活性 MT1-MMP 的细胞中被消除，但在表达缺乏血红素样或细胞质结构域的 MT1-MMP 突变体的细胞中持续存在，表明 FGF-2 信号传导被 MT1-MMP 蛋白水解活性下调。 MT1-MMP 表达导致 FGFR-1 和 -4 下调，以及细胞表面相关 FGF-2 量减少。此外，MT1-MMP 强烈减少以低亲和力结合到细胞表面的 FGF-2 的量。由于 FGF-2 与低亲和力结合位点的结合是与其高亲和力受体结合的先决条件，因此下调与细胞表面的低亲和力结合会导致 FGF-2 信号传导减弱。与这一结论一致，FGF-2在体外诱导肿瘤细胞迁移和侵袭的作用在缺乏MT1-MMP的细胞中比在表达MT1-MMP的细胞中更强。因此，MT1-MMP 通过蛋白水解机制控制 FGF-2 信号传导，从而降低细胞对 FGF-2 的生物反应。
Membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14), a transmembrane proteinase with an extracellular catalytic domain and a short cytoplasmic tail, degrades extracellular matrix components and controls diverse cell functions through proteolytic and non-proteolytic interactions with extracellular, intracellular and transmembrane proteins. Here we show that in tumor cells MT1-MMP downregulates fibroblast growth factor-2 (FGF-2) signaling by reducing the amount of FGF-2 bound to the cell surface with high and low affinity. FGF-2 induces weaker activation of ERK1/2 MAP kinase in MT1-MMP expressing cells than in cells devoid of MT1-MMP. This effect is abolished in cells that express proteolytically inactive MT1-MMP but persists in cells expressing MT1-MMP mutants devoid of hemopexin-like or cytoplasmic domain, showing that FGF-2 signaling is downregulated by MT1-MMP proteolytic activity. MT1-MMP expression results in downregulation of FGFR-1 and -4, and in decreased amount of cell surface-associated FGF-2. In addition, MT1-MMP strongly reduces the amount of FGF-2 bound to the cell surface with low affinity. Because FGF-2 association with low-affinity binding sites is a prerequisite for binding to its high-affinity receptors, downregulation of low-affinity binding to the cell surface results in decreased FGF-2 signaling. Consistent with this conclusion, FGF-2 induction of tumor cell migration and invasion in vitro is stronger in cells devoid of MT1-MMP than in MT1-MMP expressing cells. Thus, MT1-MMP controls FGF-2 signaling by a proteolytic mechanism that decreases the cell’s biological response to FGF-2.
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影响因子：
3.7
作者：
Bax DA;Little SE;Gaspar N;Perryman L;Marshall L;Viana-Pereira M;Jones TA;Williams RD;Grigoriadis A;Vassal G;Workman P;Sheer D;Reis RM;Pearson AD;Hargrave D;Jones C
通讯作者：
Jones C
DOI：
10.1038/nrm3528
发表时间：
2013-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Endo, K;Takino, T;Sato, H
通讯作者：
Sato, H
DOI：
10.1073/pnas.86.11.3978
发表时间：
1989-06-01
影响因子：
11.1
作者：
FLORKIEWICZ, RZ;SOMMER, A
通讯作者：
SOMMER, A
影响因子：
11.5
作者：
Katayama, A;Bandoh, N;Harabuchi, Y
通讯作者：
Harabuchi, Y