Role of phospholipase D1 in the regulation of mTOR activity by lysophosphatidic acid
Role of phospholipase D1 in the regulation of mTOR activity by lysophosphatidic acid
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DOI：
10.1096/fj.03-0731com
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发表时间：
2004-02-01
期刊：
影响因子：
4.8
通讯作者：
Exton, JH
中科院分区：
文献类型：
--
作者：
Kam, Y;Exton, JH
有丝分裂原通过由哺乳动物雷帕霉素靶蛋白（mTOR）或磷酸肌醇3-激酶（PI 3 K）介导的p7 S6激酶（p70（S6 K））和eIF 4 E结合蛋白1（4 E-BP 1）的磷酸化来激活蛋白质翻译。最近的报道（Science 294，1942，2001）暗示磷脂酶D（PLD）参与mTOR信号传导。我们研究了PLD在溶血磷脂酸（LPA）和血小板衍生生长因子（PDGF）诱导的p70（S6 K）和4 E-BP 1磷酸化中的作用，使用PLD活性缺陷的成纤维细胞和1-丁醇，其抑制磷脂酸的产生PLD。在两种情况下PLD活性的降低削弱了LPA对mTOR信号传导的作用，但没有抑制PDGF的作用。PDGF诱导Akt（PI 3 K靶点）的显著磷酸化，但这不受PLD缺陷的影响。LPA导致Akt磷酸化程度大大降低，这依赖于PLD活性。毒素B使Rho GTP酶失活，显著损害LPA诱导的PLD 1活化和Akt、p70（S6 K）和4 E-BP 1的磷酸化，但对PDGF的作用影响极小或没有影响。这些结果支持LPA通过PLD 1产生的PA对mTOR和PI 3 K/Akt通路的作用而激活蛋白质翻译的假设，而PDGF通过PI 3 K/Akt独立于PLD 1起作用。
Mitogens activate protein translation through phosphorylation of p7S6 kinase (p70(S6K)) and eIF4E binding protein 1 (4E-BP1) mediated by the mammalian target of rapamycin (mTOR) or phosphoinositide 3-kinase (PI3K). A recent report (Science 294, 1942, 2001) has implicated phospholipase D (PLD) in mTOR signaling. We studied the role of PLD in the phosphorylation of p70(S6K) and 4E-BP1 induced by lysophosphatidic acid (LPA) and platelet-derived growth factor (PDGF) using fibroblasts deficient in PLD activity and also 1-butanol, which inhibits phosphatidic acid production by PLD. The reduction in PLD activity in both situations impaired the effect of LPA on mTOR signaling but did not inhibit the effect of PDGF. PDGF induced marked phosphorylation of Akt (a PI3K target) but this was not affected by PLD deficiency. LPA caused much less phosphorylation of Akt and this was dependent on PLD activity. Toxin B, which inactivates Rho GTPases, markedly impaired PLD1 activation and phosphorylation of Akt, p70(S6K), and 4E-BP1 induced by LPA but had a minimal or no effect on the actions of PDGF. These results support the hypothesis that LPA activates protein translation through the action of PLD1-generated PA on mTOR and the PI3K/Akt pathway whereas PDGF acts through PI3K/Akt independent of PLD1.