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β-arrestins, including β-arrestin1 and β‑arrestin2, two ubiquitously expressed members of the arrestin family in various types of tissue, are adaptor proteins that modulate the desensitization and trafficking of seven membrane‑spanning receptors. Recently, β‑arrestins have been shown to bind to numerous signaling molecules, including c‑Src and mitogen‑activated protein kinase family members. In addition, accumulating evidence has suggested that β‑arrestins are involved in the anti‑apoptosis signaling pathway by associating with kinases, such as Akt and ERK, and altering their activities. However, the role of β‑arrestins in tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL)‑induced apoptosis remains unclear. In the present study, β‑arrestin2, but not β‑arrestin1, was observed to modulate TRAIL‑triggered HepG2 cell apoptosis by regulating activation of the Src‑extracellular signal‑regulated kinase (ERK) signaling pathway. Using overexpression and RNA interference experiments, β‑arrestin2 was demonstrated to prevent TRAIL‑induced HepG2 cell apoptosis. Additionally, β‑arrestin2 exerted an additive effect on TRAIL‑induced activation of Src and ERK. Furthermore, downregulating β‑arrestin2 expression attenuated the TRAIL‑induced activation of Src and ERK survival signaling and enhanced TRAIL‑induced apoptosis. PP2, a pharmacological inhibitor of Src, reduced activation of the Src‑ERK signaling pathway and enhanced TRAIL‑induced HepG2 cell apoptosis. Co-immunoprecipitation experiments demonstrated a physical association between β‑arrestin2 and Src, and TRAIL stimulation resulted in enhanced quantities of the β‑arrestin2/Src complex. A notable interaction was identified between β‑arrestin2 and death receptors (DR)4 and 5, but only in the presence of TRAIL stimulation. To the best of our knowledge, these findings are the first to demonstrate that β‑arrestin2 mediates TRAIL‑induced apoptosis by combing with DRs and Src, and regulates the activation of Src‑ERK signaling in HepG2 cells. It is hypothesized that the formation of a signaling complex comprising DR, β‑arrestin2 and Src is required for the action of TRAIL on HepG2 cell apoptosis, which provides a novel insight into analyzing the effects of β‑arrestin2 on protecting cells from TRAIL‑induced apoptosis.

β-arrestin2 regulates TRAIL-induced HepG2 cell apoptosis via the Src-extracellular signal-regulated signaling pathway