Figure 3. Interplay of PI 3‐phosphates in regulating signalling and membrane traffic.

(A) Schematic representation of the role of PI 3‐phosphates (3‐PI) in the reciprocal regulation of cell signalling and membrane traffic. Signals (i.e. extracellular ligand that binds to its receptor) lead to activation of PI 3‐kinases and the 3‐PIs generated recruit effector proteins that often regulate membrane traffic, leading to the generation of a secondary signal. Such a downstream secondary signal may then regulate traffic and/or the response to the primary signal (e.g. by altering receptor levels or receptor‐associated signalling components). (B) Endocytosis of activated signalling receptors (purple) from the cell surface via clathrin‐mediated endocytosis (CME, left) or fast‐endophilin‐mediated endocytosis (FEME, right) involves PI(3,4)P₂ and PI(3,4,5)P₃ synthesis by class II PI3Kα (PI3KC2α) and class I PI3Ks. In FEME, SHIP1/2 converts PI(3,4,5)P₃ to PI(3,4)P₂, which serves to recruit lamellipodin and thereby endophilin. PI(3,4)P₂ is hydrolysed to PI(3)P on endosomes by the PI(3,4)P₂‐specific PI 4‐phosphatase INPP4A. Activation of Akt signalling by PI(3,4,5)P₃ and PI(3,4)P₂ stimulates CME via dynamin 1, while dysregulated CME causes Akt overactivation. Endosomal sorting of internalized signalling receptors to internal vesicles of multivesicular bodies (MVBs) terminates signalling. (C) mTORC1 activation on the lysosome is downstream of PI(3,4,5)P₃ generated via class I PI3Ks and activated Akt. mTORC1 signalling represses PI(3)P generation via distinct Vps34‐containing class III PI3K complexes, thereby suppressing autophagosome formation and late endosome maturation.