The LCLAT1/LYCAT acyltransferase is required for EGF-mediated phosphatidylinositol-3,4,5-trisphosphate and Akt signalling

Abstract

AbstractReceptor tyrosine kinases such as epidermal growth factor receptor (EGFR) stimulate phosphoinositide 3-kinases (PI3Ks) 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)P3then remodels actin and gene expression patterns, and boosts cell survival and proliferation. PtdIns(3,4,5)P3partly achieves these functions by stimulating the kinase Akt, which phosphorylates targets like Tsc2 and GSK3β. Consequently, unchecked upregulation of PtdIns(3,4,5)P3-Akt signalling promotes tumourgenesis. Interestingly, 50-70% of PtdIns and PtdInsPs have stearate and arachidonate atsn-1 andsn-2 positions of glycerol, respectively, forming a species known as 38:4-PtdIns/PtdInsPs. LCLAT1 and MBOAT7 acyltransferases are respectively responsible for enriching PtdIns in this acyl format. We previously showed that disruption of LCLAT1 lowered PtdIns(4,5)P2levels and perturbed endocytosis and endocytic trafficking. However, the role of LCLAT1 in receptor tyrosine kinase and PtdIns(3,4,5)P3signaling 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)P3in response to EGF signalling. Importantly, LCLAT1-silenced cells were also impaired for EGF-driven Akt activation and downstream signalling, and consequently, were depressed for cell proliferation and survival. Thus, our work provides first evidence that the LCLAT1 acyltransferase is required for receptor tyrosine kinase signalling and may represent a novel target for therapeutic development against cancers.