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Fig. 2. The spatial and functional organization of the core mechanism of
Wnt/β-catenin signalling. (A) In the absence of ligand,
a destruction complex assembles around the scaffolding protein Axin (see C for
details), which binds and then labels β-catenin for proteolysis via
phosphorylation of specific residues at its N-terminus. (B) Wnt binds
to Frizzled (a) and triggers signalling by initiating a chain of events, which
at a biochemical level are not well characterized. At the cell surface, the
Wnt-Frizzled complex forms a trimeric complex with LRP5/6 (Arrow in
Drosophila) and this triggers the activity of Dishevelled (Dsh),
which promotes the association of the destruction complex with the
LRP5/6-Frizzled complex (b,c). A chain of events (detailed in C) leads to the
LRP5/6-mediated degradation of Axin (d) and the release of β-catenin from
Axin (e). Free hypophosphorylated β-catenin can then enter the nucleus
(f), where it nucleates a transcription modulator complex around TCF.
(C) Structure and function of the Axin-based destruction complex. In
the absence of Wnt, the complex is assembled and can bind β-catenin,
which is then phosphorylated by GSK3β. Phosphorylated β-catenin is
targeted for ubiquitination and proteasomal degradation. In the presence of
Wnt, the destruction complex is recruited to the cell surface, where a series
of phosphorylation events results in the degradation of Axin and the release
of β-catenin. For further details, see text and published literature
(Logan and Nusse, 2004;
Tolwinski and Wieschaus,
2004b). APC, Adenomatous polyposis coli; β-TrCP,
β-transducin repeat-containing protein (also known as Ebi); CKI, Casein
kinase; DSH, Dishevelled; CtBP, C-terminal-binding protein; GSK3β,
Glycogen synthase kinase 3β; Lgs, Legless; LRP, Low density lipoprotein
receptor-related protein; Pol II, RNA polymerase II; PP2A, Protein phosphatase
2A; TCF, T cell factor (also known as Pangolin); Ub, ubiquitination.
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