Lipid Rafts and Keratinocyte Apoptosis: Regulation via Death Receptors and Akt
Robert Gniadecki*, 1, Yves Poumay2
Identifiers and Pagination:Year: 2009
First Page: 163
Last Page: 165
Publisher Id: TODJ-3-163
Article History:Received Date: 25/06/2009
Revision Received Date: 04/07/2009
Acceptance Date: 04/07/2009
Electronic publication date: 4/11/2009
Collection year: 2009
open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Lipid rafts are cholesterol-rich plasma membrane domains that regulate signal transduction. Lipid rafts can be disrupted by perturbing cholesterol metabolism, either by inhibition of cholesterol synthesis (e.g. by statins), by cholesterol sequestration or removal from the membrane (e.g. by methyl-β-cyclodextrin or filipin III) or by substitution with cholesterol derivatives, which do not support raft assembly (e.g. 5-cholestene 5-β-ol). Work performed in our laboratories as well as by others documented that lipid raft disruption precipitates classic apoptosis in normal and transformed keratinocytes and inhibited cell proliferation. Two mechanisms seem to play a particularly important role. One is mediated via the membrane death receptors such as Fas and TRAIL. Cholesterol depletion causes a ligandindependent activation of these receptors and activation of caspases. The other is mediated via the survival kinase Akt. Raft disruption causes a rapid inhibition of Akt via dephospphorylation of the regulatory sites Thr308 and Ser473. The mechanism of this was the abrogation the binding of Akt and the major Akt kinase, PDK-1 to the membrane via pleckstrin homology (PH) domains. Diminished Akt activity results in deactivation of mTOR, activation of FoxO3a and an increased sensitivity to apoptotic stimuli. Thus, the integrity of lipid rafts is required for the activity of Akt and cell survival and may serve as a potential pharmacological target in the treatment of epidermal cancers.