ReviewLipid Signaling

Following the trail of lipids: Signals initiated by PI3K function at multiple cellular membranes

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Sci. Signal.  17 May 2016:
Vol. 9, Issue 428, pp. re4
DOI: 10.1126/scisignal.aad7885

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Gloss

Lipids can serve as cellular signaling molecules. Phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] is one such lipid that is the key molecular product of the pathway involving phosphoinositide 3-kinase (PI3K), which synthesizes PtdIns(3,4,5)P3, and the kinase AKT, which is activated at sites where PtdIns(3,4,5)P3 is produced. This pathway is referred to as the PI3K/AKT pathway. PtdIns(3,4,5)P3 triggers cell division, growth, and survival programs, among other cellular processes. The production of PtdIns(3,4,5)P3 depends on the enzymes responsible for its synthesis, and quenching of PI3K/AKT signaling depends on the enzymes that metabolize PtdIns(3,4,5)P3. This Review with 1 figure and 67 references highlights how understanding the cellular locations where PtdIns(3,4,5)P3 is formed and the kinetics and regulation of the enzymes that produce and metabolize this lipid reveals the spatiotemporal specificity of PI3K/AKT-mediated signaling.

Abstract

Phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] is the signaling currency of the phosphoinositide 3-kinase (PI3K)/AKT pathway; transduction through this axis depends on this signaling lipid. Formation of PtdIns(3,4,5)P3 is dictated not only by PI3K activation but also by the localization and access of PI3K to its substrate PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate). PI3K/AKT-mediated signaling is antagonized by PtdIns(3,4,5)P3 dephosphorylation. Although previously typically considered an event associated with the plasma membrane, it is now appreciated that the formation and metabolism of PtdIns(3,4,5)P3 occur on multiple membranes with distinct kinetics. Modulated activity of phosphatidylinositol lipid kinases and phosphatases contributes to intricately orchestrated lipid gradients that define the signaling status of the pathway at multiple sites within the cell.

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