Fig. 1

Signaling pathways activated by ET-1 in cancer. The endothelin- 1 receptor (ET-1R) is a G-protein coupled receptor, that upon agonist binding, results in the activation of G-protein-dependent primary effectors including phospholipase Cβ (PLCβ), which cleaves phosphatidylinositol- 4,5-bisphosphate (PtdIns(4,5)P2) into diacylglycerol (DAG) and inositol triphosphate (IP3), leading to calcium mobilization and protein kinase C (PKC) activation, and downstream activation of MAPK family members, including ERK1/2. At the same time, ET-1R activation stimulates Ras/Raf/MEK activation, converging on ERK1/2 signaling. Moreover, ET-1R receptor stimulation activates phospholipase A (PLA) and downstream arachidonic acid (AA) and cyclooxygenase-1 (COX-1) and COX-2, leading to prostaglandin E2 (PGE2) release, as well as phosphatidylinositol-3-kinase (PI3K), leading to the activation of AKT, integrin-linked kinase (ILK) and glycogen synthase kinase (GSK)-3β, which stabilizes β-catenin. Notably, ET-1R can also signal via β-arrestin1 (β-arr1) to activate ERK1/2 and PI3K/AKT/β-catenin signaling. β-arr1 also controls the crosstalk between ET-1R and epidermal growth factor receptor (EGFR) through the recruitment and activation of c-Src, resulting in downstream pathway activation. Through β-arr1, ET-1 activates also nuclear factor-kB (NF-kB) signaling via inhibition of NF-kB inhibitor (IkB), resulting in the dissociation and subsequent nuclear localization of active NF-kB. On the other hand, β-arr1 mediates ET-1-induced hypoxia-inducible factor 1α (HIF-1α) activity promoting vascular endothelial growth factor (VEGF) release. Moreover, ET-1R activates PDZ-RhoGEF leading to Rho-A and -C GTPase activation, initiating Rho-dependent signaling events through RHO-associated coiled-coil containing protein kinase 1 (ROCK1), LIMK activation, causing cofilin inhibition and cytoskeletal remodelling. The cooperation of these intracellular signaling pathways promote cell growth, chemoresistance, angiogenesis, cytoskeleton remodelling, invadopodia formation, and metastasis