The PA-mediated activation of mTORC1 signaling

Model for the PA-mediated activation of mTORC1 signaling. PA is hydrolyzed by phospholipase A (PLA), and resulting LPA activates the endothelial differentiation gene (EDG-2) receptor. Activation of the EDG-2 receptor results in upregulated signaling through the MEK-ERK pathway via 2 distinct mechanisms. One mechanism involves a G protein-mediated increase in PLD activity, leading to hydrolysis of phosphatidylcholine (PC) to choline and PA. PA then binds to Raf, allowing for activation of the ERK cascade. The second mechanism involves G proteins acting through Ras to activate the MEK-ERK pathway. Subsequently, ERK acts to inhibit tuberous sclerosis complex (TSC1/2), thereby increasing GTP loading on Ras homolog enriched in brain (Rheb) and, thus, upregulating mTORC1 activation. mTORC1 then phosphorylates downstream targets, such as S6K1 and eukaryotic initiation factor 4E-binding protein (4E-BP1), ultimately leading to increased mRNA translation. Leucine also activates mTORC1, although the mechanism involved in the effect is not understood.

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Phosphatidic acid mediates activation of mTORC1 through the ERK signaling pathway. (2010) Jeremiah N. Winter, et al. Am J Physiol Cell Physiol. 2010 Aug;299(2):C335-C344. Figure: F8. All organisms Drosophila melanogaster Homo sapiens

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