Autophagy negatively regulates Wnt signalling by promoting Dishevelled degradation

Gao C. et al. Nature cell biology 12, 781-790, 2010

Speaker：Yu-Chan Yang (楊于嬋)                               Time：15:00~16:00, Oct. 06 2010

Commentator：Dr. Chiou-Feng Lin (林秋烽 博士)   Place：Room 601

Abstract：

Autophagy is a self-degradative process to balance the sources of energy at critical time during development and provides nutrients in response to cellular metabolic stress in eukaryotic cells. Autophagy is related to pathophysiologic processes such as aging, neuronal degeneration, and cancer. Many signal pathways are involved in regulation of autophagy, however, the signalling pathways regulated by autophagy are not fully understood ^{1, 2}. Wnt signalling plays an important role in development and homeostasis. Deregulation of Wnt signaling is associated with cancer formation including colon cancer. There are two different Wnt signalling pathways, canonical and nocanonical pathways. In the canonical pathway, Wnt proteins, a large family of secreted and cysteine-rich molecules, bind to the Frizzled/low density lipoprotein receptor-related protein(LRP) complex and transduce a signal to Dishevelled(Dvl, a scaffold protein) and Axin to inihibit β-catenin degradation by glycogen synthase kinase-3β protein complex ³. In colon cancers and other tumor types, mutations in Axin and β-catenin genes have been found. The authors reported that β-catenin activity in response to Wnt3a, a ligand of canonical pathway, was decreased when the cells were treated with rapamycin, the mammalian target of rapamycin(mTOR) inhibitor, or under nutrient deprivation situation, both of which induce autophagy. In this study, the authors revealed that Von Hippel-Lindau protein (pVHL), a component of a ubiquitin E3 ligase complex, facilitates the ubiquitylation of Dvl2. p62(also known as SQSTM1), an autophagic receptor, promotes Dvl2 and LC3 interaction and mediates the recruitment of p62-Dvl2-LC3 complex to the autophagosome.Ultimately, the ubiquitylated Dvl2 aggregates was degraded after autophagosome fused with lysosome. The authors also found that in the late-stage of colon cancer, impaired autophagy accompanied with increased Dvl protein level and attenuated Wnt signaling pathway. All together, autophagy causes aberrant activation of Wnt signaling through degradation of Dvl, which may be responsible for late stages of colon cancer development.

References：

1. Mizushima, N. Autophagy: process and function. Genes Dev. (2007) 21, 2861–2873

2. Baehrecke, E. H. Autophagy: dual roles in life and death? Nat. Rev. Mol. Cell Biol. (2005) 6, 505–510

3. Gao, C. & Chen, Y. G. Dishevelled: the hub of Wnt signaling. Cell Signal. (2010) 22, 717–727