Fig. 2

Nuclear function of β-arrestin1 in ET-1 signaling. Binding of ET-1 to ET_AR leads to the recruitment of β-arr1 to the activated receptor, which mediates the phosphatidylinositol 3-kinase (PI3-K)/integrin linked kinase (ILK)/Akt signaling route, which causes the phosphorylation and inactivation of glycogen synthetase kinase 3β (GSK3-β) and accumulation of a non-Ser/Thr phosphorylated, active β-catenin. In parallel, ET_AR/β-arr1 complex binds axin, thereby promoting the release of GSK-3β from the β-transducin repeat containing protein (β-TrCP) and adenomatous polyposis coli (APC)-mediated degradation machinery, and its inactivation. In turn, β-arr1 shuttles with β-catenin to the nucleus and by interacting with p300 histone acetyltransferase enhances β-catenin/T-cell-specific transcription factor-4 (TCF4) activation, thus promoting the transcription of genes, such as ET-1, matrix metalloproteinase 2 (MMP-2), cyclin D1 and Axin 2, leading to enhanced cell motility and aggressiveness. Moreover, in ET-1-dependent manner, β-arr1 shuttles into the nucleus, where it interacts with HIF-1α to form a transcriptional complex with p300 required for histone acetylation and for the transcription of HIF-1α target genes, such as ET-1 and VEGF, a mechanism that can be amplified by hypoxia. Both these signals lead to the amplification of the ET-1 autocrine loop