Phosphorylation of β-Catenin by AKT Promotes β-Catenin Transcriptional Activity

Abstract

Increased transcriptional activity of ␤-catenin resulting from Wnt/Wingless-dependent or -independent signaling has been detected in many types of human cancer, but the underlying mechanism of Wnt-independent regulation is poorly understood. We have demonstrated that AKT, which is activated downstream from epidermal growth factor receptor signaling, phosphorylates ␤-catenin at Ser 552 in vitro and in vivo. AKTmediated phosphorylation of ␤-catenin causes its disassociation from cell-cell contacts and accumulation in both the cytosol and the nucleus and enhances its interaction with 14-3-3 via a binding motif containing Ser 552 . Phosphorylation of ␤-catenin by AKT increases its transcriptional activity and promotes tumor cell invasion, indicating that AKT-dependent regulation of ␤-catenin plays a critical role in tumor invasion and development.

A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells

“…Rac1 was included, as it functions upstream of PAK1. Forskolin, a potent activator of PKA, was used as a positive control (Hino et al, 2005;Fang et al, 2007). As expected, both S552 and S675 were heavily phosphorylated upon forskolin treatment (Figure 3b).…”

“…The key event of both Wnt signaling transduction and cancerous cell proliferation is the regulation of b-catenin stability and activity. In addition to its N-terminal residues, Ser552 (Fang et al, 2007) and Ser675 (Hino et al, 2005;Taurin et al, 2006) of b-catenin have also been identified as potential phosphorylation sites and may affect its signaling activity or protein stability.…”

Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of β-catenin and FOXO-1

“…AKT can phosphorylate β-catenin at the Ser 552 residue resulting in its activation and nuclear translocation from the cytosol. 11 Kinetic analysis in infected macrophages with phospho-β-catenin Ser552 antibodies showed increasing phosphorylation of β-catenin with a maximum of 3.0-fold over control at 6 h post infection (Figure 4a). This increased phosphorylation coincided with its nuclear localization (Figure 4b), thus indicating the role of AKT in β-catenin activation.…”

“…33 Phosphorylation of β-catenin by AKT at Ser 552 residue has been shown to enhance its transcriptional activity. 11 Upon AKT inhibition in L. donovani infection a decrease in nuclear translocation of β-catenin was observed indicating a role of AKT-mediated β-catenin regulation. β-catenin is known to be degraded upon phosphorylation by GSK-3β at the Ser 33/37 but no phosphorylation was observed at the Ser 33/37 in MG132 treated infected cells further validating that GSK-3β gets inactivated in infection as a result of which it fails to inactivate β-catenin.…”

“…However, recent evidences suggest a role of Wnt independent regulation of β-catenin in an AKT dependent manner. 11 AKT inactivates GSK-3β, 12 which in turn leads to stabilization and nuclear translocation of β-catenin 13 where it interacts with Tcf/Lef transcription factors to activate target anti-apoptotic genes such as Bcl-2, c-myc and cyclin D1 (ref 14). Overexpression of β-catenin has been shown to reduce apoptosis which is similar to the protection provided by inhibitors of GSK-3β 15 and accumulation of β-catenin in response to GSK-3β inhibitors has been correlated with an increase in the expression of the antiapoptotic proteins.…”