P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration
P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration
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DOI：
10.1074/jbc.m703771200
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发表时间：
2007-08-10
影响因子：
4.8
通讯作者：
Vazquez-Prado, Jose
中科院分区：
文献类型：
--
作者：
Hernandez-Negrete, Ivette;Carretero-Ortega, Jorge;Vazquez-Prado, Jose
极化细胞迁移是由细胞外信号转导引起的，在多域蛋白（包括鸟嘌呤交换因子）的干预下促进 Rho GTP 酶的激活。 P-Rex1 和 P-Rex2 是将 G beta gamma 和磷脂酰肌醇 3 激酶信号转导与 Rac 激活连接起来的 Rac GEF。它们复杂的结构表明它们是通过蛋白质-蛋白质相互作用进行调节的。 Rho GTPases 激活的新机制与哺乳动物雷帕霉素靶标 (mTOR) 相关，雷帕霉素是一种丝氨酸/苏氨酸激酶，被称为细胞生长和增殖的中央调节因子。最近，已经描述了两种含有 mTOR 的独立多蛋白复合物。 mTORC1 与蛋白质合成相关的经典雷帕霉素敏感途径相关； mTORC2 通过未定义的机制与 Rho GTPases 的激活和细胞骨架事件相关。在这里，我们证明 P-Rex1 和 P-Rex2 通过其串联 DEP 结构域与 mTOR 建立相互作用，表明它们在 mTOR 信号传导至 Rac 激活和细胞迁移中作为效应器的潜力。这种可能性与显性失活结构和短发夹 RNA 介导的 P-Rex1 敲低的效果一致，后者减少了 mTOR 依赖性亮氨酸诱导的 Rac 激活和细胞迁移。雷帕霉素是一种广泛使用的 mTOR 信号传导抑制剂，它不会抑制亮氨酸诱导的 Rac 活性和细胞迁移，这表明我们发现与两种 mTOR 复合物相关的 P-Rex1 仅在 mTORC2 复合物中才具有活性。 mTORC2 被描述为一种催化复合物，可在 Ser-473 位点磷酸化 AKT/PKB，并引发 Rho GTPases 激活和细胞骨架重组。因此，P-Rex1 将 mTOR 信号传导与 Rac 激活和细胞迁移联系起来。
Polarized cell migration results from the transduction of extracellular cues promoting the activation of Rho GTPases with the intervention of multidomain proteins, including guanine exchange factors. P-Rex1 and P-Rex2 are Rac GEFs connecting G beta gamma and phosphatidylinositol 3-kinase signaling to Rac activation. Their complex architecture suggests their regulation by protein-protein interactions. Novel mechanisms of activation of Rho GTPases are associated with mammalian target of rapamycin ( mTOR), a serine/threonine kinase known as a central regulator of cell growth and proliferation. Recently, two independent multiprotein complexes containing mTOR have been described. mTORC1 links to the classical rapamycin-sensitive pathways relevant for protein synthesis; mTORC2 links to the activation of Rho GTPases and cytoskeletal events via undefined mechanisms. Here we demonstrate that P-Rex1 and P-Rex2 establish, through their tandem DEP domains, interactions with mTOR, suggesting their potential as effectors in the signaling of mTOR to Rac activation and cell migration. This possibility was consistent with the effect of dominant-negative constructs and short hairpin RNA-mediated knockdown of P-Rex1, which decreased mTOR-dependent leucine-induced activation of Rac and cell migration. Rapamycin, a widely used inhibitor of mTOR signaling, did not inhibit Rac activity and cell migration induced by leucine, indicating that P-Rex1, which we found associated to both mTOR complexes, is only active when in the mTORC2 complex. mTORC2 has been described as the catalytic complex that phosphorylates AKT/PKB at Ser-473 and elicits activation of Rho GTPases and cytoskeletal reorganization. Thus, P-Rex1 links mTOR signaling to Rac activation and cell migration.