Figure 1.

The canonical and the non-canonical Wnt signaling pathways. (A) In canonical Wnt signaling, β-catenin is phosphorylated by GSK-3β and CK1α in the absence of Wnts, followed by ubiquitination by β-TrCP and targeting for proteasomal degradation, without nuclear β-catenin; a repressive complex containing TCF/LEF and Groucho/TLE subsequently recruits HDACs to inhibit the transcriptional activation of β-catenin target genes. Conversely, the activation of canonical Wnt signaling is initiated from the binding of Wnts to Fzd and co-receptor LDL receptor-related protein (LRP5 or LRP6); then, the DVL is phosphorylated by GSK-3β and CK1α and begins to form a polymer that can inactivate the destruction complex through recruiting AXIN and GSK3β. Thereby, the accumulated β-catenin in the cytoplasm localizes to the nucleus and forms complexes with co-regulators of transcription factors such as TCF/LEF by removing Groucho/TLE complexes and recruiting transcriptional co-activators, including CBP/p300, BRG1, BCL9, and Pygopus. Next, downstream genes including cyclin D, MMPs, c-Myc, COX2, CD44, etc., are activated and give rise to the changes of the series of cellular activities, such as excessive cell proliferation, motility, and polarity. (B) The β-catenin-independent non-canonical Wnt signaling is initiated by binding certain Wnts and could regulate cellular polarity and migration-related signaling pathways. In the Wnt/PCP pathway, Wnts bind to the ROR1/2-Fzd complex to activate DVL, DVL binds to small Rho GTPases such as RAC1 and RhoA, RhoA and RAC1 together trigger JNK, and RhoA activates ROCK alone. This leads to the asymmetric cytoskeletal organization and/or coordination of cellular polarization via activating the transcription factors, such as c-JUN and ATF2. The Wnt/Ca²⁺ signaling triggers PLC activity and subsequently induces calcium influx; then, elevated Ca²⁺ activates several calcium-dependent signaling pathways, such as PKC and Ca²⁺/CAMKII, which finally leads to the accumulation of transcription factor NFAT in the nucleus. ATF2, activating transcription factor 2; BCL9, B-cell CLL/lymphoma 9; BRG1, brahma-related gene 1; β-TRCP, β-transducin repeat-containing protein; CAMKII, calmodulin-dependent protein kinase II; CK1α, casein kinase 1; COX2, cytochrome c oxidase subunit 2; DVL, disheveled; GSK-3β, glycogen synthase kinase; HDACs, histone deacetylases; JNK, JUN N-terminal kinase; LEF, lymphoid enhancer-binding factor; MMPs, matrix metalloproteinases; NFAT, nuclear factor of activated T cells; PCP, planar cell polarity; PKC, protein kinase C; PLC, phospholipase C; ROCK, rho kinase; ROR1/2, receptor tyrosine kinase-like orphan receptor 1/2; TCF, T-cell factor; TLE, transducin-like enhancer protein.