Unraveling the Molecular Nexus between GPCRs, ERS, and EMT

Figure 2

Crosstalk of GPCR signaling and ERS during EMT. Activation of GPCRs and ERS facilitates the EMT process of cancer cells. Upon ligand binding, GPCRs transmit signals via heterotrimeric G proteins, β-arrestins, and crosstalk with receptor tyrosine kinases (RTKs) through signaling mediators. The activation of RTKs by growth factors drives EMT through ERK/MAPK and PI3K/AKT signaling cascades which in turn lead to induction of ERS. GPCRs controlling downstream effectors and multiple signaling pathways regulate ERS by interacting with IRE1, PERK, and ATF6 arms of the UPR. The UPR signaling is stimulated by ER stressors including oxidative stress, hypoxia, nutrient deprivation, acidosis, and activated oncogenes. Bidirectional crosstalk between UPR and cell signaling pathways refines cellular stress responses (dotted double arrow). GPCRs can either activate (curved arrow) or inhibit (curved dotted line) ERS. GPCR-ERS-induced UPR signaling pathways concurrently induce EMT during tumorigenesis. Activation of EMT occurs in response to GPCR-mediated signaling and ERS by upregulation of EMT-TFs (Snail1/2, Twist, and ZEB1/2), accompanied by an increase of mesenchymal markers and a decrease of epithelial markers. Reciprocal regulation between EMT and UPR signaling is observed during tumor progression (curved double arrow).