Fig. 2

Extracellular signals regulate the biogenesis of exosomes. Extracellular signals regulate different events during the biogenesis of exosomes in different cell types. Activated GPCR regulates neutral sphingomyelinase activity and ceramide to effect exosome release, induces the formation of ILVs via DAG/PKD, triggers exosome release via PLC/IP3/Ca²⁺ and participates in MVBs fusion with the plasma membrane via DAG/PKC. Activated EGFR activate ERK and HRS to promote cargo loading and exosome release. Inhibitory AKT/mTORC1 signals delivered by EGFR stimulate release from Rab11a compartments of exosomes. TNF-α triggers the release of exosomes which depends on sphingomyelinase. Cell death inducer stimulate TNFR, then TNFR promotes endosomal trafficking via RIPK3/MLKL pathway and enhances exosomes release. Wnt-mediated GSK3 inactivation regulates the expression of Rab27, and Wnt/β-catenin/TCF-4 activates the expression of Rab27B, therefore participating in the regulation of exosomes biogenesis. Hypoxia regulates exosome release through HIF-1α, Rab27A, Rab7, LAMP-1/2, neuraminidase-1 and ATM. Circadian clock and mechanical force also regulate exosome release, but specific mechanisms are unclear