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MBC in Press, published online ahead of print March 29, 2006
Mol. Biol. Cell 10.1091/mbc.E05-11-1094

A more recent version of this article appeared on June 1, 2006
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Submitted on December 1, 2005
Revised on March 16, 2006
Accepted on March 22, 2006

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

Ximing Du, Ika Kristiana, Jenny Wong, and Andrew J. Brown

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

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 which may be reconciled teleologically since synthesis of new membrane is an absolute requirement for cell growth and proliferation.

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




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