The membrane-anchored metalloproteinase regulator RECK stabilizes focal adhesions and anterior-posterior polarity in fibroblasts
The membrane-anchored metalloproteinase regulator RECK stabilizes focal adhesions and anterior-posterior polarity in fibroblasts
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DOI：
10.1038/onc.2008.486
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发表时间：
2009-03-01
期刊：
影响因子：
8
通讯作者：
Noda, M.
中科院分区：
文献类型：
--
作者：
Morioka, Y.;Monypenny, J.;Noda, M.
越来越多的证据表明，具有Kazal基序的逆转诱导富含半胱氨酸的蛋白(RECK)是一种膜锚定的基质金属蛋白酶调节因子，在哺乳动物的发育和肿瘤抑制中起着至关重要的作用。然而，它在单细胞水平上的作用机制在很大程度上仍不清楚。在小鼠成纤维细胞中，RECK大量分布在核周、膜皱纹和细胞表面。缺乏RECK的细胞表现为扩散减少，前后(AP)极性模糊，迁移速度加快，定向持续性降低；这些特征也存在于转化的成纤维细胞和低表达的纤维肉瘤细胞中。RECK缺陷的细胞不能形成离散的局灶性粘连，GTP结合的rac1和CDc42水平增加，去酪氨酸微管蛋白水平显著降低，这是稳定微管的标志。RECK缺乏的细胞还表现出明胶溶解活性升高和纤维连接蛋白纤维减少。当细胞被纤维连接蛋白包裹的底物上时，RECK缺陷细胞的表型受到很大程度的抑制。这些发现表明，RECK调节细胞周围细胞外基质的降解，从而允许细胞形成适当的细胞-底物黏附，并在迁移过程中保持AP的极性；这一机制在恶性细胞中受到损害。
Accumulating evidence indicates that Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a membrane-anchored matrix metalloproteinase regulator, plays crucial roles in mammalian development and tumor suppression. Its mechanisms of action at the single cell level, however, remain largely unknown. In mouse fibroblasts, RECK is abundant around the perinuclear region, membrane ruffles and cell surface. Cells lacking Reck show decreased spreading, ambiguous anterior-posterior (AP) polarity, and increased speed and decreased directional persistence in migration; these characteristics are also found in transformed fibroblasts and fibrosarcoma cells with low RECK expression. RECK-deficient cells fail to form discrete focal adhesions, have increased levels of GTP-bound Rac1 and Cdc42, and a marked decrease in the level of detyrosinated tubulin, a hallmark of stabilized microtubules. RECK-deficient cells also show elevated gelatinolytic activity and decreased fibronectin fibrils. The phenotype of RECK-deficient cells is largely suppressed when the cells are plated on fibronectin-coated substrates. These findings suggest that RECK regulates pericellular extracellular matrix degradation, thereby allowing the cells to form proper cell-substrate adhesions and to maintain AP polarity during migration; this mechanism is compromised in malignant cells.