PMID- 20438709 OWN - NLM STAT- MEDLINE DCOM- 20100707 LR - 20211203 IS - 1090-2104 (Electronic) IS - 0006-291X (Print) IS - 0006-291X (Linking) VI - 396 IP - 2 DP - 2010 May 28 TI - Phospholipase D stabilizes HDM2 through an mTORC2/SGK1 pathway. PG - 562-5 LID - 10.1016/j.bbrc.2010.04.148 [doi] AB - Phosphatidic acid (PA), the primary metabolite of the phospholipase D (PLD)-mediated hydrolysis of phosphatidylcholine, has been shown to act as a tumor promoting second messenger in many cancer cell lines. A key target of PA is the mammalian target of rapamycin (mTOR), a serine-threonine kinase that has been widely implicated in cancer cell survival signals. In agreement with its ability to relay survival signals, it has been reported that both PLD and mTOR are required for the stabilization of the p53 E3 ubiquitin ligase human double minute 2 (HDM2) protein. Thus, by stabilizing HDM2, PLD and mTOR are able to counter the pro-apoptotic signaling mediated by p53 and promote survival. mTOR exists in at least two distinct complexes-mTORC1 and mTORC2-that are both dependent on PLD-generated PA. Although PLD and its metabolite PA are clearly implicated in the transduction of survival signals to mTOR, it is not yet apparent which of the two mTOR complexes is critical for the stabilization of HDM2. We report here that the PLD/mTOR-dependent stabilization of HDM2 involves mTORC2 and the AGC family kinase serum- and glucocorticoid-inducible kinase 1 (SGK1). This study reveals that mTORC2 is a critical target of PLD-mediated survival signals and identifies SGK1 as a downstream target of mTORC2 for the stabilization of HDM2. CI - Copyright (c) 2010 Elsevier Inc. All rights reserved. FAU - Lyo, Donggon AU - Lyo D AD - Department of Biological Sciences, Hunter College of the City University of New York, 695 Park Avenue, New York, NY 10065, USA. FAU - Xu, Limei AU - Xu L FAU - Foster, David A AU - Foster DA LA - eng GR - R01 CA046677-17/CA/NCI NIH HHS/United States GR - R01 CA046677-16A2/CA/NCI NIH HHS/United States GR - R01 CA046677-15S1/CA/NCI NIH HHS/United States GR - RR-03037/RR/NCRR NIH HHS/United States GR - G12 RR003037/RR/NCRR NIH HHS/United States GR - CA046677/CA/NCI NIH HHS/United States GR - R01 CA046677/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20100508 PL - United States TA - Biochem Biophys Res Commun JT - Biochemical and biophysical research communications JID - 0372516 RN - 0 (CRTC1 protein, human) RN - 0 (CRTC2 protein, human) RN - 0 (Immediate-Early Proteins) RN - 0 (Phosphatidic Acids) RN - 0 (Transcription Factors) RN - EC 2.3.2.27 (MDM2 protein, human) RN - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (serum-glucocorticoid regulated kinase) RN - EC 3.1.4.4 (Phospholipase D) SB - IM MH - Cell Line, Tumor MH - Enzyme Stability MH - Humans MH - Immediate-Early Proteins/*metabolism MH - Kidney Neoplasms/enzymology MH - Phosphatidic Acids/metabolism MH - Phospholipase D/*metabolism MH - Protein Serine-Threonine Kinases/*metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Proto-Oncogene Proteins c-mdm2/*metabolism MH - Transcription Factors/genetics/*metabolism MH - Ubiquitin-Protein Ligases/*metabolism PMC - PMC3010228 MID - NIHMS202730 EDAT- 2010/05/05 06:00 MHDA- 2010/07/08 06:00 PMCR- 2011/05/28 CRDT- 2010/05/05 06:00 PHST- 2010/04/15 00:00 [received] PHST- 2010/04/27 00:00 [accepted] PHST- 2010/05/05 06:00 [entrez] PHST- 2010/05/05 06:00 [pubmed] PHST- 2010/07/08 06:00 [medline] PHST- 2011/05/28 00:00 [pmc-release] AID - S0006-291X(10)00843-0 [pii] AID - 10.1016/j.bbrc.2010.04.148 [doi] PST - ppublish SO - Biochem Biophys Res Commun. 2010 May 28;396(2):562-5. doi: 10.1016/j.bbrc.2010.04.148. Epub 2010 May 8.