Lysophosphatidic acid acyltransferase beta regulates mTOR signaling.
Lysophosphatidic acid acyltransferase (LPAAT-β) is a phosphatidic acid (PA) generating enzyme that plays an essential role in triglyceride synthesis. However, LPAAT-β 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-ζ and mTOR. In this report we determine the effect of LPAAT-β silencing with siRNA in pancreatic adenocarcinoma cell lines. We show for the first time that LPAAT-β 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-β 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-β protein levels are knocked down. Furthermore, depletion of LPAAT-β 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-β to regulate mTOR function. Our results provide support for the hypothesis that PA generated by LPAAT-β regulates mTOR signaling. We discuss the implications of these findings for using LPAAT-β as a therapeutic target.
Mesh Terms:
Active Transport, Cell Nucleus, Acyltransferases, Adaptor Proteins, Signal Transducing, Adenocarcinoma, Base Sequence, Cell Line, Tumor, Cell Nucleus, Cell Proliferation, Gene Expression Regulation, Enzymologic, Gene Knockdown Techniques, Humans, Pancreatic Neoplasms, Phosphatidate Phosphatase, Phosphatidic Acids, Phosphoproteins, Phosphorylation, Proto-Oncogene Proteins c-akt, RNA, Small Interfering, Signal Transduction, TOR Serine-Threonine Kinases
Active Transport, Cell Nucleus, Acyltransferases, Adaptor Proteins, Signal Transducing, Adenocarcinoma, Base Sequence, Cell Line, Tumor, Cell Nucleus, Cell Proliferation, Gene Expression Regulation, Enzymologic, Gene Knockdown Techniques, Humans, Pancreatic Neoplasms, Phosphatidate Phosphatase, Phosphatidic Acids, Phosphoproteins, Phosphorylation, Proto-Oncogene Proteins c-akt, RNA, Small Interfering, Signal Transduction, TOR Serine-Threonine Kinases
PLoS ONE
Date: Nov. 10, 2013
PubMed ID: 24205284
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