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Vol. 17, Issue 6, 2735-2745, June 2006

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Involvement of Akt in ER-to-Golgi Transport of SCAP/SREBP: A Link between a Key Cell Proliferative Pathway and Membrane Synthesis

School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2052, Australia

Submitted December 1, 2005; Revised March 16, 2006; Accepted March 22, 2006
Monitoring Editor: Ben Margolis

Akt is a critical regulator of cell growth, proliferation, and survival that is activated by phosphatidylinositol 3-kinase (PI3K). We investigated the effect of PI3K inhibition on activation of sterol regulatory element binding protein-2 (SREBP-2), a master regulator of cholesterol homeostasis. SREBP-2 processing increased in response to various cholesterol depletion approaches (including statin treatment) and this increase was blunted by treatment with a potent and specific inhibitor of PI3K, LY294002, or when a plasmid encoding a dominant-negative form of Akt (DN-Akt) was expressed. LY294002 also suppressed SREBP-2 processing induced by insulin-like growth factor-1. Furthermore, LY294002 treatment down-regulated SREBP-2 or -1c gene targets and decreased cholesterol and fatty acid synthesis. Fluorescence microscopy studies indicated that LY294002 disrupts transport of the SREBP escort protein, SCAP, from the endoplasmic reticulum to the Golgi. This disruption was also shown by immunofluorescence staining when DN-Akt was expressed. Taken together, our studies indicate that the PI3K/Akt pathway is involved in SREBP-2 transport to the Golgi, contributing to the control of SREBP-2 activation. Our results provide a crucial mechanistic link between the SREBP and PI3K/Akt pathways that may be reconciled teleologically because synthesis of new membrane is an absolute requirement for cell growth and proliferation.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Andrew J. Brown ( aj.brown{at}unsw.edu.au)

Abbreviations used: 25HC, 25-hydroxycholesterol; CHO, Chinese hamster ovary; ER, endoplasmic reticulum; FAS, fatty acid synthase; GFP, green fluorescent protein; HMG-CoA reductase, 3-hydroxy-3-methylglutaryl co-enzyme A reductase; IGF-1, insulin-like growth factor-1; LDL, low-density lipoprotein; NBS, newborn calf serum; PI3K, phosphatidylinositol 3-kinase; PLAP, placental alkaline phosphatase; QRT-PCR, quantitative reverse transcriptase-polymerase chain reaction; SCAP, SREBP cleavage-activating protein; SREBP, sterol-regulatory element-binding protein; TLC, thin-layer chromatography.

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