We recently demonstrated that Daple, a multi-modular signal transducer, is an enhancer of noncanonical Wnt signaling downstream of Frizzled receptors (FZDRs) ( Aznar et al., 2015). Little is known as to how noncanonical Wnt signaling switches from being a protective pathway to one that enhances cancer progression. 2) In transformed cells, however, noncanonical Wnt signaling enhances cancer invasion/metastasis by activation of Rac1 and remodeling of the actin cytoskeleton ( Yamamoto et al., 2009) and by upregulating CamKII and PKC ( Weeraratna et al., 2002 Dissanayake et al., 2007). What is well-accepted though, is that inhibition of noncanonical Wnt signaling fuels neoplastic transformation ( Ishitani et al., 2003 Medrek et al., 2009 Grumolato et al., 2010). 1) In the normal epithelium, noncanonical Wnt signaling is protective it suppresses tumorigenesis by antagonizing the canonical β-catenin/TCF/LEF pathway due in part by compartmentalizing β-catenin at the cell membrane to prevent its transcriptional activity ( Bernard et al., 2008) how such compartmentalization is accomplished remains unknown. Dysregulation of the noncanonical Wnt pathway is widely believed to drive cancer via a two-faceted mechanism ( McDonald and Silver, 2009). The noncanonical Wnt pathway induces the elevation of intracellular Ca 2+ and activation of the small G proteins RhoA and Rac1 ( Kuhl et al., 2000 Niehrs, 2001 Winklbauer et al., 2001), which regulate polarized cell movements and the planar polarity of epithelial cells ( Sheldahl et al., 1999 Kuhl et al., 2000 Mayor and Theveneau, 2014). This canonical Wnt pathway is antagonized by a noncanonical Wnt signaling paradigm ( Torres et al., 1996 Olson and Gibo, 1998 Ishitani et al., 2003), although it is unclear how this occurs. The well-characterized canonical Wnt signaling pathway enhances the stability, nuclear localization, and activity of β-catenin, and the downstream activation of genes targeted by the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription machinery. Dysregulated expression of components within the Wnt pathway triggers many diseases and, most importantly, heralds cancer ( Klaus and Birchmeier, 2008). The Wnt signaling pathway plays a crucial role in embryonic development, in tissue regeneration, and in many other cellular processes, including cell fate, adhesion, polarity, migration, and proliferation. This work not only identifies Daple as a platform for cross-talk between Akt and the noncanonical Wnt pathway but also reveals the impact of such cross-talk on tumor cell phenotypes that are critical for cancer initiation and progression.
Cancer-associated Daple mutants that are insensitive to Akt mimic a constitutively dephosphorylated state. Dephosphorylation compartmentalizes β-catenin on PCREs, a specialized compartment for prolonged unopposed canonical Wnt signaling, and enhances colony growth.
Phosphorylation compartmentalizes Daple/β-catenin/E-cadherin complexes to cell–cell contact sites, enhances noncanonical Wnt signals, and thereby suppresses colony growth. By phosphorylating the phosphoinositide- (PI) binding domain of Daple, Akt abolishes Daple’s ability to bind PI3-P-enriched endosomes that engage dynein motor complex for long-distance trafficking of β-catenin/E-cadherin complexes to pericentriolar recycling endosomes (PCREs). Here we demonstrate that the PI3-K→Akt pathway serves as a positive feedback loop that further enhances noncanonical Wnt signals by compartmentalizing β-catenin.
We previously showed that a multimodular signal transducer, Daple, enhances PI3-K→Akt signals within the noncanonical Wnt signaling pathway and antagonistically inhibits canonical Wnt responses. Cellular proliferation is antagonistically regulated by canonical and noncanonical Wnt signals their dysbalance triggers cancers.