Phospohoinositide-3-kinase (PI3K) is activated directly by the G-protein subunits of 5-HT1A and 5-HT2A/B (Masson et al., 2012). While PI3K activation by serotonin receptors leads to Akt activation and signalling (Masson et al., 2012; Sahu et al., 2018), PI3K also regulates multiple modes of clathrin-independent endocytosis by producing phosphoinositide(3,4,5)phosphate [PI(3,4,5)P3] from PI(4,5)P2 (Araki et al., 2007; Chan Wah Hak et al., 2018; Redpath et al., 2020). Active PI3K is directly required for FEME (Chan Wah Hak et al., 2018), macropinocytosis (Araki et al., 2007) and phagocytosis (Araki et al., 1996). In FEME, PI(3,4,5)P3 is required to recruit FBP17 and CIP4, which recruits the phosphatases SHIP1/2 to hydrolyse PI(3,4,5)P3 to phosphoinositide(3,4)phosphate [PI(3,4)P2]. PI(3,4)P2 is required for endophilin recruitment and for endocytosis to occur (Boucrot et al., 2015; Chan Wah Hak et al., 2018) (Fig. 3A, left). In macropinocytosis, membrane ruffling forms a ‘cup’ in which the cargo is captured. PI(3,4,5)P3 is produced from PI(4,5)P2 by PI3K on the inner leaflet of forming macropinocytic cups and is further enriched following macropinosome closure (Araki et al., 2007; Yoshida et al., 2009) (Fig. 3A, right). PI(3,4,5)P3 is hydrolysed to phosphoinositide(3)phosphate [PI(3)P] by sequential action of SHIP2 and INPP4B (Egami et al., 2014), and is required for Rab5 recruitment to the enclosed macropinosome (Yoshida et al., 2009). In phagocytosis, PI3K generates PI(3,4,5)P3 from PI(4,5)P2 immediately following receptor binding to the phagocytic cargo (Levin et al., 2015). PI(3,4,5)P3 levels increase in the phagocytic cup as it engulfs the cargo, and depletion of PI(3,4,5)P3 results in aborted cup formation around the cargo (Levin et al., 2015).