Figure 3.

PI3K/AKT/mTOR signalling pathway and its regulation by EVs. The PI3K/AKT/mTOR signalling pathway is a central pathway that regulates cell growth, metabolism and survival. The pathway is activated by various growth factors and cytokines, such as epidermal growth factor (EGF), transforming growth factor-beta (TGF-β), interferon-gamma (IFN-γ), vascular endothelial growth factor (VEGF), interleukin-4 (IL-4) and IL-15, which bind to their respective receptors on the cell membrane and trigger the activation of phosphatidylinositol 3-kinase (PI3K). PI3K converts phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3), which recruits and activates protein kinase B (AKT) and phosphoinositide-dependent kinase 1 (PDK1). AKT phosphorylates and inhibits tuberous sclerosis complex 1 and 2 (TSC1/2), which releases the inhibition of Ras homologue enriched in brain (RHEB). RHEB activates mammalian target of rapamycin complex 1 (mTORC1), which regulates various cellular processes, such as protein synthesis, lipid synthesis, mitochondrial metabolism, angiogenesis and inflammatory response. mTORC1 also activates hypoxia-inducible factor 1-alpha (HIF1α), which forms a heterodimer with HIF1β and induces the expression of target genes, such as TGF-β, platelet-derived growth factor (PDGF), and VEGF. EVs are small membrane-bound vesicles that can modulate the PI3K/AKT/mTOR signalling pathway by delivering various molecules to target cells. For example, EVs can carry EGF, IL-15 or VEGF to activate the pathway, or microRNAs (miRNAs) such as miR-let7a, miR-21 and miR-222 to activate the pathway by targeting its different components. EVs can also affect the crosstalk between the PI3K/AKT/mTOR signalling pathway and other pathways, such as the Wnt/β-catenin pathway or the NF-κB pathway. EVs extracellular vesicles