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首页> 外文期刊>Cellular Signalling >Mutation of Y-179 on phospholipase D2 (PLD2) upregulates DNA synthesis in a PI3K- and Akt-dependent manner
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Mutation of Y-179 on phospholipase D2 (PLD2) upregulates DNA synthesis in a PI3K- and Akt-dependent manner

机译：磷脂酶D2（PLD2）上的Y-179突变以PI3K和Akt依赖性方式上调DNA合成

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Phospholipase D2 (PLD2), one of the two mammalian members of the PLD family, has been implicated in cell proliferation, transformation, tumor progression and survival. However, as precise mechanistic details are still unknown, we investigated here if the PLD2 isoform would signal through the PI3K/AKT pathway. Transient expression of PLD2 in COS7 cells with either the WT or with a Y179F mutant, resulted in an increased basal phosphorylation of AKT in residues T-308 and S-473, in a PI3K-dependent manner. Transfection of PLD2-Y179F (but not the wild type) caused an increased (>2-fold) DNA synthesis even in the absence of extracellular stimuli. Other signaling mechanisms downstream such PLD/PI3K dependence (that might lead to DNA synthesis regulation) were further studied. PLD2-Y179F caused an increase in phosphorylation of p42/p44(ERK) and in the expression of GO/G1 phase transition markers (p21(CIP), PCNA), and these effects, too, were dependent on PI3K. Interestingly, Akt, once activated induced the phosphorylation of PLD2 on residue T 175, an effect that was inhibited by LY296004. Lastly, if PLD2-Y179F is further mutated in residue K758 (PLD2 Y179F-K758R), which renders inactive a catalytic site, DNA synthesis is then abrogated, indicating that the activity of the enzyme (i.e. synthesis of PA) is necessary for the observed effects. In conclusion, the unavailability of residue Y179 on PLD2 to become phosphorylated leads to an augmentation of DNA synthesis concomitantly with MEK and AKT phosphorylation, in a process that is dependent on PI3K and independent of any extracellular stimuli. This might be critical for the maintenance of the PLD2-regulated proliferative status. (C) 2007 Elsevier Inc. All rights reserved.
机译：磷脂酶D2（PLD2）是PLD家族的两个哺乳动物成员之一，与细胞增殖，转化，肿瘤进展和存活有关。但是，由于精确的机械细节仍然未知，因此我们在这里研究了PLD2亚型是否会通过PI3K / AKT途径发出信号。带有WT或带有Y179F突变体的COS7细胞中PLD2的瞬时表达，以PI3K依赖性方式导致残基T-308和S-473中AKT的基础磷酸化增加。即使没有细胞外刺激，PLD2-Y179F（而不是野生型）的转染也导致DNA合成增加（> 2倍）。进一步研究了下游的其他信号传导机制，如PLD / PI3K依赖性（可能导致DNA合成调控）。 PLD2-Y179F导致p42 / p44（ERK）磷酸化和GO / G1相变标记（p21（CIP），PCNA）的表达增加，这些作用也取决于PI3K。有趣的是，一旦激活，Akt就会诱导残基T 175上PLD2的磷酸化，这一作用被LY296004抑制。最后，如果PLD2-Y179F在K758残基中进一步突变（PLD2 Y179F-K758R），从而使催化位点失活，则DNA合成被废止，表明观察到该酶的活性（即PA的合成）是必需的。效果。总之，在依赖于PI3K且不依赖任何细胞外刺激的过程中，PLD2上的残基Y179无法磷酸化导致DNA合成增加，同时伴随MEK和AKT磷酸化。这对于维持PLD2调节的增殖状态可能至关重要。 （C）2007 Elsevier Inc.保留所有权利。

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