Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.01.26.524308v1?rss=1

Authors: Chan, V., Bone, L., Anderson, K. E., Zhang, K., Orofiamma, L., Awadeh, Y., Lee, D. K. C., Fu, N. J., Chow, J. T. S., Salmena, L., Stephens, L. R., Hawkins, P. T., Antonescu, C. N., Botelho, R. J.

Abstract:
Receptor tyrosine kinases such as epidermal growth factor (EGF) receptor (EGFR) stimulate phosphatidylinositol 3-kinases (PI3Ks) to convert phosphaitydlinositol-4,5-bisphosophate [PtdIns(4,5)P2] into phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3]. PtdIns(3,4,5)P3 then promotes various pathways leading to actin remodelling, changes in gene expression, and enhanced anabolic activity, cell survival and proliferation. In part, PtdIns(3,4,5)P3 achieves these functions by stimulating the kinase Akt, which phosphorylates numerous targets like Tsc2 and GSK3{beta}. Overall, unchecked upregulation of PtdIns(3,4,5)P3-Akt signalling can promote tumourgenesis and cancer 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. It is thought that LCLAT1/LYCAT and MBOAT7/LPIAT1 acyltransferases are respectively responsible for enriching PtdIns with this acyl composition. We previously showed that disruption of LCLAT1 altered the acyl profile of bis-phosphorylated PtdInsPs, lowered PtdIns(4,5)P2, 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 signalling. Importantly, LCLAT1-silenced cells were also impaired for EGF-mediated Akt activation and downstream signalling, and consequently, were depressed for cell proliferation and survival. Thus, our work provides first evidence that the LCLAT1 acyltransferase supports receptor tyrosine kinase signalling through the PtdIns(3,4,5)P3-Akt axis and may represent a novel target for therapeutic development against cancers.

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