Plasma membrane recruitment of dephosphorylated β-catenin upon activation of the Wnt pathway

Abstract

The standard model of Wnt signaling specifies that after receipt of a Wnt ligand at the membranous receptor complex, downstream mediators inhibit a cytoplasmic destruction complex, allowing β-catenin to accumulate in the cytosol and nucleus and co-activate Wnt target genes. Unexpectedly, shortly after Wnt treatment, we detected the dephosphorylated form of β-catenin at the plasma membrane, where it displayed a discontinuous punctate labeling. This pool of β-catenin could only be detected in E-cadherin–/– cells, because in E-cadherin+/+ cells Wnt-induced, membranous β-catenin was concealed by a constitutive junctional pool. Wnt-signaling-dependent dephosphorylated β-catenin colocalized at the plasma membrane with two members of the destruction complex – APC and axin – and the activated Wnt co-receptor LRP6. β-catenin induced through the Wnt receptor complex was significantly more competent transcriptionally than overexpressed β-catenin, both in cultured cells and in early Xenopus embryos. Our data reveal a new step in the processing of the Wnt signal and suggest regulation of signaling output beyond the level of protein accumulation.

Wnt Signaling from Development to Disease: Insights from Model Systems

“…LRP's phosphorylated tail can directly inhibit GSK3 activity (Cselenyi et al 2008;Piao et al 2008), which may contribute to destruction complex inhibition. Consistent with this, dephosphorylated bcat and APC are recruited to the plasma membrane on Wnt signaling (Hendriksen et al 2008). Interestingly, dephosphorylated bcat generated by LRP6 activation is much more potent (molecule for molecule) at activating Wnt target genes than overexpressed nonphosphorylatable bcat (Hendriksen et al 2008); thus, additional bcat activation events may occur on receptor activation.…”

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

“…However, there are evidences suggesting that different forms of b-catenin may have distinct transcriptional activities (Lu and Hunter, 2004;Hendriksen et al, 2008), arguing for further modifications on b-catenin protein. Subsequently, S191 and S605 of b-catenin were found to be phosphorylated by JNK2 and required for its nuclear localization (Wu et al, 2008).…”

The -Catenin Destruction Complex

“…Activation of the coreceptors LRP5/6 and Fzd results in recruitment of the destruction complex to the membrane and formation of membrane-associated puncta associated with b-catenin activation (Cliffe et al 2003;Tolwinski et al 2003;Bilic et al 2007;Schwarz-Romond et al 2007b;Hendriksen et al 2008; MacDonald and He 2012). The recently described WTX/AMER1 protein binds to the APC arm domain and to PIP 2 , and appears to be important for targeting the complex to the plasma membrane, although this protein appears to be specific to vertebrates (Grohmann et al 2007;Tanneberger et al 2011).…”