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Phosphatidylserine (PS) is the major anionic phospholipid class particularly enriched in the inner leaflet of the plasma membrane in neural tissues. PS is synthesized from phosphatidylcholine or phosphatidylethanolamine by exchanging the base head group with serine, and this reaction is catalyzed by phosphatidylserine synthase 1 and phosphatidylserine synthase 2 located in the endoplasmic reticulum. Activation of Akt, Raf-1 and protein kinase C signaling, which supports neuronal survival and differentiation, requires interaction of these proteins with PS localized in the cytoplasmic leaflet of the plasma membrane. Furthermore, neurotransmitter release by exocytosis and a number of synaptic receptors and proteins are modulated by PS present in the neuronal membranes. Brain is highly enriched with docosahexaenoic acid (DHA), and brain PS has a high DHA content. By promoting PS synthesis, DHA can uniquely expand the PS pool in neuronal membranes and thereby influence PS-dependent signaling and protein function. Ethanol decreases DHA-promoted PS synthesis and accumulation in neurons, which may contribute to the deleterious effects of ethanol intake. Improvement of some memory functions has been observed in cognitively impaired subjects as a result of PS supplementation, but the mechanism is unclear., (Published by Elsevier Ltd.)

Akt activation relies on the binding of Akt to phosphatidylinositol-3,4,5-trisphosphate (PIP(3)) in the membrane. Here, we demonstrate that Akt activation requires not only PIP(3) but also membrane phosphatidylserine (PS). The extent of insulin-like growth factor-induced Akt activation and downstream signaling as well as cell survival under serum starvation conditions positively correlates with plasma membrane PS levels in living cells. PS promotes Akt-PIP(3) binding, participates in PIP(3)-induced Akt interdomain conformational changes for T308 phosphorylation, and causes an open conformation that allows for S473 phosphorylation by mTORC2. PS interacts with specific residues in the pleckstrin homology (PH) and regulatory (RD) domains of Akt. Disruption of PS-Akt interaction by mutation impairs Akt signaling and increases susceptibility to cell death. These data identify a critical function of PS for Akt activation and cell survival, particularly in conditions with limited PIP(3) availability. The novel molecular interaction mechanism for Akt activation suggests potential new targets for controlling Akt-dependent cell survival and proliferation.

Akt is activated upon growth factor stimulation via translocation to the plasma membrane through interaction of its PH domain with membrane PIP3 and subsequent phosphorylation of T308 and S473. In this study, we demonstrated a novel Akt activation scheme involving its interaction with phosphatidylserine (PS), the major anionic phospholipids in eukaryotic biomembranes. Using biomolecular interaction analysis we found that Akt interacted with not only PIP3 but also PS. In addition to PIP3, PS dose-dependently enhanced Akt-membrane interaction as well as phosphorylation of both T308 and S473. The regulatory domain, in particular, interacted with PS significantly even in the absence of PIP3, enabling the phosphorylation at S473 by MAPKAP kinase 2 in vitro. The subcellular localization of the regulatory domain in response to IGF stimulation was similar to that of full-length Akt and affected by the PS content manipulated by DHA enrichment in Neuro 2A cells. Mass spectrometric characterization of Akt inter-domain conformational changes due to membrane interaction revealed that both PS and PIP3 in the membrane are required to expose T308 and S473 for phosphorylation and activation. PS can substitute PIP3 for the regulatory domain interaction in Akt signaling, suggesting an important role of PS in cell survival, particularly under adverse conditions where PIP3 formation is compromised. [ABSTRACT FROM AUTHOR]