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Fig. 1. A simplified prevailing view of Wnt/ß-catenin signaling (see
Box 1 for some alternative
views). (A) Without Wnt, the scaffolding protein Axin assembles a protein
complex that contains Apc, Gsk3, Ck1 and ß-catenin. In this complex,
ß-catenin is sequentially phosphorylated by Ck1 and Gsk3. Phosphorylated
ß-catenin is recognized by ß-Trcp, which is a component of an
ubiquitin-ligase complex that conjugates ß-catenin with ubiquitin.
Poly-ubiquitinated ß-catenin is degraded by the proteosome.
TCF/LEF-associated co-repressors, such as Groucho
(Cavallo et al., 1998), and
Axin-associated Diversin (Schwarz-Romond
et al., 2002), PP2A (Hsu et
al., 1999) and other proteins
(Kikuchi, 1999) are omitted
for simplicity. (B) In the presence of Wnt, ß-catenin phosphorylation and
degradation is inhibited. Accumulated ß-catenin forms a nuclear complex
with the DNA-bound TCF/LEF transcription factor, and together they activate
Wnt-responsive genes. This signaling cascade is perhaps initiated by a
Wnt-induced Fz-Lrp5/Lrp6 co-receptor complex, which recruits Axin to the
plasma membrane through Lrp5/Lrp6-Axin association. Fz-associated Dishevelled
(Dvl) protein may bind Axin and inhibit Axin-Gsk3 phosphorylation of
ß-catenin, either directly or indirectly via Dvl-associated proteins.
Lrp5/Lrp6-Axin binding may also promote Axin degradation. Either or both of
these events can lead to ß-catenin accumulation. This description
represents one of several possibilities. The composition of the Axin complex
upon Wnt stimulation is not well defined. Gsk3-binding protein (GBP/Frat)
(Farr et al., 2000;
Salic et al., 2000), and
nuclear ß-catenin-associated Legless/Bcl9 and Pygopus
(Belenkaya et al., 2002;
Kramps et al., 2002;
Parker et al., 2002;
Thompson et al., 2002) are
omitted for simplicity. Modified with permission from He
(He, 2003).
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