Autophagy negatively regulates Wnt signalling by promoting Dishevelled degradation

Abstract

In eukaryotic cells, autophagy is a highly conserved self-digestion process to promote cell survival in response to nutrient starvation and other metabolic stresses. Autophagy is regulated by cell signalling such as the mTOR (mammalian target of rapamycin) pathway. However, the significance of autophagy in modulation of signal transduction is unclear. Here we show that autophagy negatively regulates Wnt signalling by promoting Dishevelled (Dvl) degradation. Von Hippel-Lindau protein-mediated ubiquitylation is critical for the binding of Dvl2 to p62, which in turn facilitates the aggregation and the LC3-mediated autophagosome recruitment of Dvl2 under starvation; the ubiquitylated Dvl2 aggregates are ultimately degraded through the autophagy-lysosome pathway. Moreover, a reverse correlation between Dvl expression and autophagy is observed in late stages of colon cancer development, indicating that autophagy may contribute to the aberrant activation of Wnt signalling in tumour formation.

The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells

“…The assays were performed as previously described 47 . The following antibodies were used for immunoblotting: a-Akt (Cell Signaling, 1:2,000), a-Cleaved caspase-3 (Cell Signaling, 1:1,000), a-GAPDH (Santa Cruz, 1:2,000), a-GFP (Santa Cruz, 1:1,000), a-MLC (Abcam, 1:1,000), a-Myc (Santa Cruz,…”

The role of ALFY in selective autophagy

“…Some LIR-containing proteins are recruited to autophagic membranes to facilitate autophagosome formation, 16,17 whereas others interact with LC3 to facilitate autophagosome transport and maturation 18,19 or use their LIR motif to be targeted for degradation themselves. 20 The list of autophagy receptors is rapidly expanding and it is also becoming evident that a particular cargo may be recognized by several autophagy receptors. Autophagy receptors have so far been implicated in the degradation of bacteria (p62/SQSTM1, [21][22][23] and optineurin 25 ), viral particles (p62), 26 mitochondria (p62, Nix/Bnip3L and Atg32), [27][28][29][30][31] peroxisomes (p62 and Atg30), 32,33 midbody remnant (p62 and NBR1), 34,35 glycogen particles 36 and in the Cvt pathway (Atg19 and Atg34).…”

p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells

“…8,9 At the molecular level, p62/SQSTM1 acts as a pro-tumoral molecule by ensuring efficient and selective activation of cell signaling axes involved in cell survival, proliferation, and metabolism (i.e., NF-kB, mTOR, and Nrf-2 pathways). 3,[5][6][7][10][11][12][13] p62/ SQSTM1 can also signal anti-tumoral responses either by inactivating the pro-oncogenic signaling through BCR-ABL 14 and Wnt pathways 15,16 or by inducing the activation of caspase 8, a pro-death protein. 17,18 Interestingly, in response to stress, autophagy promotes the degradation of p62, thus limits the activation of p62-regulatory pathways that control tumorigenesis.…”