Encountering Aberrant Wnt Signalling - Therapeutic Strategies in Cancer Biology and Pathology - page 41

Wnt

Fzd/LRP5/6 Fzd/LRP5/6

Multi-protein complex Dishevelled P/Axin

[APC/Axin/GSK-3β/CK1/
β-catenin] APC GSK-3β

β-catenin-P/
β-TrCP

β-catenin CK1

TCF/Lef

β-catenin β-catenin/TCF/Lef

degradation -------- --- -------------

β-catenin/TCF/Lef

Genetic transcription
---------------------------

Figure 6.1 A schematic portrayal of the canonical Wnt/ β-catenin signalling pathway. DVL
contains DIX, the protein interacting PDZ (PSD-95 a synaptic signalling protein, DLG and the
zonula occludens ZO-1 protein) module and the DEP and functions directly downstream of
Fzd, and transduces the Wnt signal into the several pathways listed in the text. These are not
shown here.

ligand bind the phosphorylated LRP5/6 co-receptor engages Axin. This process leads
to the breakup of the multiprotein complex and accumulation of β-catenin in the
nucleus. In the canonical pathway, the binding of Wnt ligand to the receptor inhibits
GSK-3β and stabilises β-catenin. β-Catenin now forms a complex with the transcrip-
tion factor TCF/Lef and the complex is translocated into the nucleus leading to the
transcription of responsive genes.
The phosphoprotein DVL (Dishevelled) is involved in the disintegration of the
multiprotein complex. DVL is multidomain proteins containing DIX (DVL and
axin domain), the protein interacting PDZ (PSD-95 a synaptic signalling protein,
DLG and the zonula occludens ZO-1 protein) module and the DEP (DVL, Egl-10
G-protein signalling regulator, Pleckstrin) domain. By virtue of the presence of these
domains, the DVL effector functions directly downstream of Fzd and transduces the
Wnt signal into the several pathways. Among those identified are (a) the CamKII
(calcium/calmodulin-dependent kinase II) and PKC; (b) the phospholipase C (PLC)
and phosphodiesterase (PDE) activated by the recruitment of heterotrimeric GTP
binding proteins; (c) the non-canonical or planar cell polarity pathway) with Rho/
Rac and Ra/JNK pathway with implications for cell motility; (d) the Wnt/mTOR
pathway and (e) the conventionally recognised one with β-catenin as the main medi-
ator leading to genetic activation. These pathways are integrated into specific devel-
opmental patterns and cell fate decisions and markedly implicated in tumorigenic
conduits ( Figure 6.1 ).
Several elements can be identified in the canonical and non-canonical Wnt sig-
nalling pathways that could be targeted for impeding or preventing the flow of sig-
nals along these pathways. The salient ones are (1) the Wnt receptor Fzd, (2) the