Fig. 3.

Regulation of lipid metabolism by PI3K–mTOR signalling. PI3K signalling is the most frequently dysregulated pathway in cancer, and stimulates growth, proliferation and survival. Activation of receptor tyrosine kinases recruits PI3Kα to the plasma membrane where it phosphorylates PIP₂ to PIP₃. AKT binds to PIP₃, allowing activation by PDK1 and mTORC2. AKT directly promotes lipogenesis by stabilising SREBP1c through inhibition of GSK3β, activation of ACLY to generate acetyl-CoA and phosphorylation of NADK to produce NADP⁺ for NADPH synthesis. PI3K signalling is also closely linked to mTORC1 and mTORC2. mTORC1 regulates lipogenesis through inhibition of lipin-1, which is a negative regulator of nuclear SREBP1c, and activation of the splicing factor SRPK2, thereby promoting the expression of lipogenic enzymes, including ACLY, FASN and ACSS2. Finally, mTORC2 activation supports lipogenesis through AKT-dependent and -independent mechanisms, with the latter encompassing phosphorylation of SGK1 and PKCs, and subsequent activation of SREBP1c. Abbreviations: PIP₃, phosphatidylinositol (3,4,5)-trisphosphate; PIP₂, phosphatidylinositol (4,5)-bisphosphate; mTORC, mammalian target of rapamycin complex; SREBP, sterol regulatory element-binding protein; SGK, serum- and glucocorticoid-induced protein kinase 1; PKC, protein kinase C; GSK3, glycogen synthase kinase; FBXW7, F-Box and WD repeat domain containing 7; ACLY, ATP–citrate lyase, PDK1, phosphoinositide-dependent kinase 1; NADK, NAD⁺ kinase; NAD⁺, nicotinamide adenine dinucleotide; NADP⁺, nicotinamide adenine dinucleotide phosphate; SRPK2; SR-protein-specific kinase 2; S6K1, ribosomal protein S6 kinase β-1; FASN, fatty acid synthase; ACC, acyl-CoA synthetase short-chain family member 2.