Activation of ARF6 by ARNO stimulates epithelial cell migration through downstream activation of both Rac1 and phospholipase D.
Activation of ARF6 by ARNO stimulates epithelial cell migration through downstream activation of both Rac1 and phospholipase D.
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DOI：
10.1083/jcb.200104019
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发表时间：
2001-08-06
期刊：
影响因子：
--
通讯作者：
Casanova JE
中科院分区：
文献类型：
--
作者：
Santy LC;Casanova JE
上皮细胞的迁移对于组织形态发生、伤口愈合和上皮肿瘤的转移是必不可少的。在这里，我们表明，ARNO，鸟嘌呤核苷酸交换因子ADP-核糖基化因子（ARF）GTP酶，诱导Madin-Darby犬肾上皮细胞发展广泛的板状伪足，从邻近的细胞分离，并表现出迁移行为的显着增加。这种转变需要ARNO催化活性，我们表明，导致增强内源性ARF 6的激活，但不是ARF 1，使用一种新的下拉测定。我们进一步证明，ARNO的表达导致内源性Rac 1的激活增加，并且Rac激活是ARNO诱导的细胞运动所必需的。最后，ARNO诱导的ARF 6活化也导致磷脂酶D（PLD）活化增加，抑制PLD活性也抑制运动性。然而，抑制PLD并不能阻止Rac的激活。总之，这些数据表明，ARF 6激活刺激两种不同的信号通路，一种导致Rac激活，另一种导致膜磷脂组成的变化，并且这两种通路都是细胞运动所必需的。
Migration of epithelial cells is essential for tissue morphogenesis, wound healing, and metastasis of epithelial tumors. Here we show that ARNO, a guanine nucleotide exchange factor for ADP-ribosylation factor (ARF) GTPases, induces Madin-Darby canine kidney epithelial cells to develop broad lamellipodia, to separate from neighboring cells, and to exhibit a dramatic increase in migratory behavior. This transition requires ARNO catalytic activity, which we show leads to enhanced activation of endogenous ARF6, but not ARF1, using a novel pulldown assay. We further demonstrate that expression of ARNO leads to increased activation of endogenous Rac1, and that Rac activation is required for ARNO-induced cell motility. Finally, ARNO-induced activation of ARF6 also results in increased activation of phospholipase D (PLD), and inhibition of PLD activity also inhibits motility. However, inhibition of PLD does not prevent activation of Rac. Together, these data suggest that ARF6 activation stimulates two distinct signaling pathways, one leading to Rac activation, the other to changes in membrane phospholipid composition, and that both pathways are required for cell motility.
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影响因子：
3.3
作者：
Frank, SR;Hatfield, JC;Casanova, JE
通讯作者：
Casanova, JE
影响因子：
7.5
作者：
Chavrier, P;Goud, B
通讯作者：
Goud, B
影响因子：
7.8
作者：
Gimond, C;van der Flier, A;Sonnenberg, A
通讯作者：
Sonnenberg, A
影响因子：
4.8
作者：
Maranda, B;Brown, D;Marshansky, V
通讯作者：
Marshansky, V
影响因子：
4.8
作者：
Klarlund, JK;Tsiaras, W;Czech, MP
通讯作者：
Czech, MP