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

Receptor tyrosine kinases such as EGF receptor (EGFR) stimulate phosphoinositide 3 kinases to convert phosphatidylinositol-4,5-bisphosophate [PtdIns(4,5)P ] into phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P ]. PtdIns(3,4,5)P then remodels actin and gene expression, and boosts cell surviv...

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Published in:	Molecular biology of the cell Vol. 35; no. 9; p. ar118
Main Authors:	Chan, Victoria, Camardi, Cristina, Zhang, Kai, Orofiamma, Laura A, Anderson, Karen E, Hoque, Jafarul, Bone, Leslie N, Awadeh, Yasmin, Lee, Daniel K C, Fu, Norman J, Chow, Jonathan T S, Salmena, Leonardo, Stephens, Len R, Hawkins, Phillip T, Antonescu, Costin N, Botelho, Roberto J
Format:	Journal Article
Language:	English
Published:	United States The American Society for Cell Biology 01-09-2024
Subjects:	Acyltransferases - metabolism Cell Line, Tumor Cell Proliferation Epidermal Growth Factor - metabolism Epidermal Growth Factor - pharmacology ErbB Receptors - metabolism Humans Phosphatidylinositol Phosphates - metabolism Phosphorylation Proto-Oncogene Proteins c-akt - metabolism Signal Transduction
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Summary:	Receptor tyrosine kinases such as EGF receptor (EGFR) stimulate phosphoinositide 3 kinases to convert phosphatidylinositol-4,5-bisphosophate [PtdIns(4,5)P ] into phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P ]. PtdIns(3,4,5)P then remodels actin and gene expression, and boosts cell survival and proliferation. PtdIns(3,4,5)P 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)P -Akt signaling promotes tumor progression. Interestingly, 50-70% of PtdIns and PtdInsPs have stearate and arachidonate at -1 and -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)P levels and perturbed endocytosis and endocytic trafficking. However, the role of LCLAT1 in receptor tyrosine kinase and PtdIns(3,4,5)P 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)P 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1059-1524 1939-4586 1939-4586
DOI:	10.1091/mbc.E23-09-0361