Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration.
Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration.
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DOI：
10.1083/jcb.201109112
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发表时间：
2012-01-23
期刊：
影响因子：
--
通讯作者：
Norman JC
中科院分区：
文献类型：
--
作者：
Rainero E;Caswell PT;Muller PA;Grindlay J;McCaffrey MW;Zhang Q;Wakelam MJ;Vousden KH;Graziani A;Norman JC
DGK-α产生磷脂酸对于rab11偶联蛋白定位于侵袭性假足以及随后肿瘤细胞的侵袭性迁移至关重要。抑制αvβ3整合素或p53致癌突变体的表达，在Rab11效应物rab偶联蛋白（RCP）的控制下，通过增强α5β1整合素的内体循环，促进侵袭性细胞迁移。在本文中，我们发现二酰基甘油激酶α (DGK-α)将二酰基甘油磷酸化为磷脂酸（PA），这是RCP被动员到侵入性假足的尖端并被系住所必需的，并允许RCP依赖的α5β1循环和由此产生的肿瘤细胞的侵袭性。在缺乏p53突变体表达或αvβ3抑制的情况下，DGK-α组成活性突变体的表达驱动RCP依赖的侵袭，相反，缺乏pa结合C2结构域的RCP突变体无法在假足尖端被系住。这些数据表明，DGK-α下游PA的产生对于将突变体p53s的表达或αvβ3的抑制与RCP联系起来，以及Rab11效应物通过三维基质驱动肿瘤细胞侵袭所需的α5β1的运输至关重要。
Phosphatidic acid generation by DGK-α is essential for the localization of Rab11-coupling protein to invasive pseudopods and subsequent invasive migration by tumor cells. Inhibition of αvβ3 integrin or expression of oncogenic mutants of p53 promote invasive cell migration by enhancing endosomal recycling of α5β1 integrin under control of the Rab11 effector Rab-coupling protein (RCP). In this paper, we show that diacylglycerol kinase α (DGK-α), which phosphorylates diacylglycerol to phosphatidic acid (PA), was required for RCP to be mobilized to and tethered at the tips of invasive pseudopods and to allow RCP-dependent α5β1 recycling and the resulting invasiveness of tumor cells. Expression of a constitutive-active mutant of DGK-α drove RCP-dependent invasion in the absence of mutant p53 expression or αvβ3 inhibition, and conversely, an RCP mutant lacking the PA-binding C2 domain was not capable of being tethered at pseudopod tips. These data demonstrate that generation of PA downstream of DGK-α is essential to connect expression of mutant p53s or inhibition of αvβ3 to RCP and for this Rab11 effector to drive the trafficking of α5β1 that is required for tumor cell invasion through three-dimensional matrices.
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影响因子：
3.9
作者：
Ktistakis, NT;Delon, C;Sugars, JM
通讯作者：
Sugars, JM
影响因子：
13.8
作者：
Hodgkin, MN;Pettitt, TR;Wakelam, MJO
通讯作者：
Wakelam, MJO
影响因子：
56.9
作者：
Cukierman, E;Pankov, R;Yamada, KM
通讯作者：
Yamada, KM
影响因子：
8
作者：
Baldanzi, G.;Cutrupi, S.;Graziani, A.
通讯作者：
Graziani, A.
影响因子：
1.7
作者：
Berrar, D;Sturgeon, B;Dubitzky, W
通讯作者：
Dubitzky, W