Interaction between LRP5 and Frat1 Mediates the Activation of the Wnt Canonical Pathway

Abstract

Low density lipoprotein receptor-related protein 5 (LRP5) has been identified as a Wnt co-receptor involved in the activation of the ␤-catenin signaling pathway. To improve our understanding of the molecular mechanisms by which LRP5 triggers the canonical Wnt signaling cascade, we have screened for potential partners of LRP5 using the yeast two-hybrid system and identified Frat1 as a protein interacting with the cytoplasmic domain of LRP5. We demonstrate here that LRP5/Frat1 interaction is involved in ␤-catenin nuclear translocation and TCF-1 transcriptional activation. The addition of Wnt3a or overexpression of constitutively active truncated LRP5 (LRP5C) induces Frat1 recruitment to the cell membrane. Overexpression of a dominant negative form of disheveled (Dvl) shows that this protein positively affects LRP5/Frat1 interaction. Furthermore, the fact that dominant negative Dvl does not interfere with LRP5C/Frat1 interaction can explain how LRP5C is capable of acting independently of this major Wnt signaling player. Axin, which has been shown to interact with LRP5 and to be recruited to the membrane through this interaction, was found to co-immunoprecipitate with Frat1 and LRP5. We propose that recruitment of Axin and Frat1 to the membrane by LRP5 leads to both Axin degradation and Frat1-mediated inhibition of glycogen synthase kinase-3. As a consequence, ␤-catenin is no longer bound to Axin or phosphorylated by glycogen synthase kinase-3, resulting in TCF-1 activation.

The overexpression of the putative gut stem cell marker Musashi-1 induces tumorigenesis through Wnt and Notch activation

“…We show that the expression of Msi1 is regulated in a cell-autonomous way by the Wnt pathway. Lentiviral-mediated increase in the expression of Msi1, in turn, stimulates the Wnt pathway through the induction of Frat1, a potent activator of -catenin stabilization (Hay et al, 2005;van Amerongen et al, 2005). Finally, we also show that Msi1 overexpression has the potential to induce tumor formation in a xenograft model.…”

“…More importantly, our data also showed that Frat1 mRNA was significantly increased by Msi1 overexpression, as compared with the level in the control cells. Interestingly, Frat1 is known to be a potent activator of the canonical Wnt pathway (Hay et al, 2005). This protein is dispensable with regard to Wnt--catenin signaling, but it can enhance the accumulation of activated -catenin (van Amerongen et al, 2005).…”

Stability elements in the LRP6 cytoplasmic tail confer efficient signalling upon DIX-dependent polymerization

“…We consider it unlikely that the ctail binds to itself directly: it does not form puncta on its own (Fig. 2C,D), was not found in any of the yeast two-hybrid screens with ctail baits (Hay et al, 2005;Mao et al, 2001b;Mi et al, 2006;Tolwinski et al, 2003), and is predicted to be intrinsically disordered (Piao et al, 2008). Therefore, in all probability, the stability of the DIX>ctail puncta is conferred by ctail-binding factor(s) that function to stabilize ('cross-link') the labile DIX-mediated self-interaction, e.g.…”

Axin2 controls bone remodeling through the β-catenin–BMP signaling pathway in adult mice

“…In this complex, β-catenin is phosphorylated and degraded by the ubiquitin-proteasome pathway. Wnt binding recruits Axin1 to the receptor complex, where it binds the cytoplasmic domain of LRP5 (Cong et al, 2004;Hay et al, 2005;Mao et al, 2001). Axin1 is a central component of the canonical Wnt pathway and acts as a scaffold for the protein complex involved in β-catenin degradation.…”