Lysophosphatidic Acid Acyltransferase Beta Regulates mTOR Signaling

Lysophosphatidic acid acyltransferase (LPAAT-beta) is a phosphatidic acid (PA) generating enzyme that plays an essential role in triglyceride synthesis. However, LPAAT-beta is now being studied as an important regulator of cell growth and differentiation and as a potential therapeutic target in cancer since PA is necessary for the activity of key proteins such as Raf, PKC-zeta and mTOR. In this report we determine the effect of LPAAT-beta silencing with siRNA in pancreatic adenocarcinoma cell lines. We show for the first time that LPAAT-beta knockdown inhibits proliferation and anchorage-independent growth of pancreatic cancer cells. This is associated with inhibition of signaling by mTOR as determined by levels of mTORC1- and mTORC2-specific phosphorylation sites on 4E-BP1, S6K and Akt. Since PA regulates the activity of mTOR by modulating its binding to FKBP38, we explored the possibility that LPAAT-beta might regulate mTOR by affecting its association with FKBP38. Coimmunoprecipitation studies of FKBP38 with mTOR show increased levels of FKBP38 associated with mTOR when LPAAT-beta protein levels are knocked down. Furthermore, depletion of LPAAT-beta results in increased Lipin 1 nuclear localization which is associated with increased nuclear eccentricity, a nuclear shape change that is dependent on mTOR, further confirming the ability of LPAAT-beta to regulate mTOR function. Our results provide support for the hypothesis that PA generated by LPAAT-beta regulates mTOR signaling. We discuss the implications of these findings for using LPAAT-beta as a therapeutic target.