title: Lysophosphatidic acid acyltransferase beta regulates mTOR signaling.
abstract: 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.
authors.affiliation: Department of Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Blaskovich
authors.forename: Vimala
authors.initials: V
authors.lastname: Yendluri
authors.forename: Harshani R
authors.initials: HR
authors.lastname: Lawrence
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lawrence
authors.forename: Saïd M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Springett
mesh_terms: D021581:Active Transport, Cell Nucleus; D000217:Acyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000230:Adenocarcinoma / Q000473:pathology; D001483:Base Sequence; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D010190:Pancreatic Neoplasms / Q000473:pathology; D010711:Phosphatidate Phosphatase / Q000378:metabolism; D010712:Phosphatidic Acids / Q000096:biosynthesis; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010712:Phosphatidic Acids; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D000217:Acyltransferases; C018764:2-acylglycerophosphate acyltransferase; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C485999:LPIN1 protein, human; D010711:Phosphatidate Phosphatase