受体酪氨酸激酶如表皮生长因子受体(EGFR)刺激磷酸肌醇3-激酶(PI3K)将磷脂酰肌醇-4,5-双磷酸[PtdIns(4,5)P2]转化为磷脂酰肌醇-3,4,5-三磷酸[PtdIns(3,4,5)P3]。PtdIns(3,4,5)P3然后重塑肌动蛋白和基因表达,并促进细胞存活和增殖。PtdIns(3,4,5)P3通过触发激酶Akt的激活部分实现这些功能,它磷酸化Tsc2和GSK3β等靶标。因此,PtdIns(3,4,5)P3-Akt信号的未经检查的上调促进肿瘤进展。有趣的是,50-70%的PtdIns和PtdInsP在甘油的sn-1和sn-2位置具有硬脂酸酯和花生四烯酸酯,分别,形成一个被称为38:4-PtdIns/PtdInsPs的物种。LCLAT1和MBOAT7酰基转移酶以这种酰基形式部分富集PtdIns。我们先前表明,LCLAT1的破坏降低了PtdIns(4,5)P2的水平,并干扰了内吞和内吞运输。然而,LCLAT1在受体酪氨酸激酶和PtdIns(3,4,5)P3信号传导中的作用尚未研究。这里,我们显示MDA-MB-231和ARPE-19细胞中的LCLAT1沉默降低了响应EGF信号传导的PtdIns(3,4,5)P3的水平。重要的是,LCLAT1沉默的细胞也因EGF驱动和胰岛素驱动的Akt激活和下游信号传导而受损。因此,我们的工作提供了第一个证据,证明LCLAT1酰基转移酶是受体酪氨酸激酶信号传导所必需的.
Receptor tyrosine kinases such as EGF receptor (EGFR) stimulate phosphoinositide 3 kinases to convert phosphatidylinositol-4,5-bisphosophate [PtdIns(4,5)P2] into phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3]. PtdIns(3,4,5)P3 then remodels actin and gene expression, and boosts cell survival and proliferation. PtdIns(3,4,5)P3 partly achieves these functions by triggering activation of the kinase Akt, which phosphorylates targets like Tsc2 and GSK3β. Consequently, unchecked upregulation of PtdIns(3,4,5)P3-Akt signaling promotes tumor progression. Interestingly, 50-70% of PtdIns and PtdInsPs have stearate and arachidonate at sn-1 and sn-2 positions of glycerol, respectively, forming a species known as 38:4-PtdIns/PtdInsPs. LCLAT1 and MBOAT7 acyltransferases partly enrich PtdIns in this acyl format. We previously showed that disruption of LCLAT1 lowered PtdIns(4,5)P2 levels and perturbed endocytosis and endocytic trafficking. However, the role of LCLAT1 in receptor tyrosine kinase and PtdIns(3,4,5)P3 signaling was not explored. Here, we show that LCLAT1 silencing in MDA-MB-231 and ARPE-19 cells abated the levels of PtdIns(3,4,5)P3 in response to EGF signaling. Importantly, LCLAT1-silenced cells were also impaired for EGF-driven and insulin-driven Akt activation and downstream signaling. Thus, our work provides first evidence that the LCLAT1 acyltransferase is required for receptor tyrosine kinase signaling.