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Abstract
Heterotrimeric G proteins are signal transduction proteins involved in regulating numerous signaling events. In particular, previous studies have demonstrated a role for G-proteins in regulating β-catenin signaling. However, the link between G-proteins and β-catenin signaling is controversial and appears to depend on G-protein specificity. We describe a detailed analysis of a link between specific G-alpha subunits and β-catenin using G-alpha subunit genetic knockout and knockdown approaches. The Pasteurella multocida toxin was utilized as a unique tool to activate G-proteins, with LiCl treatment serving as a β-catenin signaling agonist. The results show that Pasteurella multocida toxin (PMT) significantly enhanced LiCl-induced active β-catenin levels in HEK293T cells and mouse embryo fibroblasts. Evaluation of the effect of specific G-alpha proteins on the regulation of β-catenin showed that Gq/11 and G12/13 knockout cells had significantly higher levels of active and total β-catenin than wild-type cells. The stimulation of active β-catenin by PMT and LiCl was lost upon both constitutive and transient knockdown of G12 and G13 but not Gq Based on our results, we conclude that endogenous G-alpha proteins are negative regulators of active β-catenin; however, PMT-activated G-alpha subunits positively regulate LiCl-induced β-catenin expression in a G12/13-dependent manner. Hence, G-alpha subunit regulation of β-catenin is context dependent.
Highlights
Heterotrimeric G proteins are signal transduction proteins involved in regulating numerous signaling events
The heterotrimeric G proteins represented by the Gs, Gi/o, Gq/11, and G12/13 families serve as essential links between the large number of G-protein-coupled receptors (GPCRs) that respond to many agonists and the activation of several defined intracellular signaling pathways [1,2,3]
As Pasteurella multocida toxin (PMT) treatment stimulates the activation of various G-proteinmediated downstream events, it offers a unique opportunity to explore the differences between the effects of basal and activated G-proteins on -catenin signaling in the absence of exogenous stimulation
Summary
Heterotrimeric G proteins are signal transduction proteins involved in regulating numerous signaling events. Activation of -catenin signaling following stimulation of the canonical Wnt/Frizzled pathway has been shown to be dependent in part on Gq through inhibition of GSK3, suggesting that some G-alpha subunits positively regulate the canonical Wnt pathway [26,27,28,29]. In contrast to the findings described above, studies on fibrous dysplasia showed that activated Gq, G11, G12, and G13 proteins had no significant roles in regulating -catenin, while only activated Gs was shown to stimulate the Wnt signaling pathway [35]. We have investigated the role of basal and activated Gq/11 and G12/13 families in the regulation of active -catenin In this regard, the Pasteurella multocida toxin (PMT) provides a novel tool to dissect these pathways. Our findings suggest that the link between G-alpha subunits and -catenin signaling is purely dependent on G-protein abundance and activity
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