This might reflect a complicated and paradoxical GSK-3β regulation system toward apoptosis in different cell states. Alternative apoptotic signalling other than GSK-3β-dependent apoptosis presumably occurs in quiescent conditions whereas GSK-3β-dependent apoptosis emerges upon the extracellular stimulation. Translocation of β-catenin, resulting from GSK-3β activation, was believed to be involved in the impaired cell proliferation by activation of TLR4.38 Here we provide an alternative explanation

for the impaired cell survival by TLR4. β-Arrestin 2 not only terminates G-protein couple receptor signalling but also regulates other signalling Selleck PD0325901 pathways.18β-Arrestin 2 signalling complex with Akt/GSK-3β has been well established by Beaulieu et al.,30,31 which illustrates the activation of GSK-3β by β-arrestin 2 through scaffolding PP2A to Akt.30 Conversely, β-arrestin 2 suppresses GSK-3β activity through stabilization

of pGSK-3β in the SD-induced apoptotic paradigm in the present study. The different regulation in specific physiological conditions may account for such discrepancy. Moreover, β-arrestin 2 is required for serum-dependent cell survival, just like the PI3K pathway, both of which converge on the inactivation of GSK-3β. It is currently uncertain how β-arrestin 2 stabilizes pGSK-3β, despite the confocal images supporting the effective co-localization of GSK-3β with β-arrestin 2 (data not shown) and our unpublished data suggest that β-arrestin 2 advances GSK-3β phosphorylation in the presence of LPS. However, our data Navitoclax molecular weight strongly indicate that β-arrestin-2-mediated inactivation of GSK-3β prevents SD-induced apoptosis. Apparently, over-activation of GSK-3β leads to the failure of inhibited apoptosis by β-arrestin 2. The egradation of β-arrestin 2 in HEK293/TLR4 is possibly responsible for the amplification of the GSK-3β-dependent apoptotic cascade. Hence, apart from the well-defined effects on NF-κB1, IκBα, TRAF6 and GRK5 FAD in the TLR4 cascade,18,19,39 GSK-3β is expected to be the additional potent effecter of β-arrestin 2 in the TLR4-primed

apoptotic cascade. Generally, β-arrestin 2 mediates signalling regulation through directly binding to the respective signalling molecules. It gives rise to the question of whether β-arrestin 2 scaffolds with GSK-3β, and subsequently a complex is formed to serve as a molecular switch for activation of proliferative or apoptotic pathways. We have tried but failed to resolve the problem by searching for the putative interaction between β-arrestin 2 and GSK-3β by co-immunoprecipitation, but the correlated study is well underway. However, β-arrestin 2 association of GSK-3β is strongly considered in a growing list of signal patterns that modulate the induction of apoptosis by TLR4. The mechanism by which SD influences the TLR4 signalling pathway is unclear.