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co-receptors for Wnt ligands, namely the LDL receptor-related proteins LRP5/6,
(3) the secreted proteins Dickkopf (Dkk), inhibitor of Wnt signalling, which also
bind LPR5/6, (4) SFRPs (secreted Fzd-related proteins), (5) the downstream com-
ponents β-catenin/TCF, (6) Axin which negatively correlates with β-catenin/TCF and
(7) the non-canonical signalling via mitogen activated protein kinase.
Fzd and LRP Inhibition, Dkk and SFRPs
Several natural inhibitors of Wnt signalling have been identified. Wnt ligands bind
to the Fzd receptor and the LRP5/6 co-receptors. The ligands bind to the cysteine-
rich domain of Fzd. The Dkks and SFRPs are established inhibitors of the pathway.
The Dkk are a small family of four secreted proteins which function by blocking the
interaction between Wnt ligand and the LRP5/6 co-receptors. Dkks act as ligands
for and bind with high affinity to the transmembrane proteins Kremen 1 and 2.
The LRP5/6 co-receptors may be endocytosed upon formation of a complex with
the Kremen proteins. In this way, Kremens can inhibit Wnt signalling. There is a
view that Kremens can indeed enhance Wnt signalling when Dkks are absent, which
leaves the LRPs unaffected at the membrane, and further that Dkks might indeed be
the determinants of the functioning of the Wnt pathway (see Niehrs, 2006; Cselenyi
and Lee, 2008). Five SFRPs have been identified. SFRPs contain around 300 amino
acid residues with a signal sequence, an Fzd-like cysteine-rich domain suggestive
therefore of Wnt binding, plus a short hydrophobic C-terminal domain (Rattner
et al., 1997). SFRPs have generally been regarded as antagonists of canonical Wnt
signalling on account of this sequence homology with the Wnt-binding domain of
Fzd. Their potential role in pathogenesis is being scrutinised with vigour.
The SFRPs have been suggested to possess tumour suppressor ability possibly
by inhibiting Wnt signalling. The expression of SFRPs is reduced in medulloblasto-
mas by methylation and a majority of tumours have shown loss of SFRP1. Induced
expression of SFRPs reduces the expression of phosphorylated DVL2 (Kongkham
et al., 2010). Epigenetic silencing might involve both promoter methylation and
histone acetylation (Meng et al., 2011; Shin et al., 2012). All SFRPs 1, 2, 4 and 5
were almost uniformly methylated in head and neck cancers (Marsit et al., 2006).
In contrast, SFRP1 was hypermethylated and silenced in a majority of colorectal
cancers (Caldwell et al., 2004). The degree of silencing of SFRP2 by methylation
in these tumours might be related with progression. Takeda et al. (2011) identified
two methylation sensitive regions in the SFRP2 promoter. In adenomatous polypo-
sis, the methylation SFRP2 was only partial, that is it occurred in either of the two
sensitive regions, as compared with rather extensive methylation of both regions in
carcinomas (Takeda et al., 2011). These authors also found that mutation of Ki-Ras
appeared to be associated with SFRP methylation. Ki-Ras mutations are found fre-
quently in the later stages of adenomas before carcinomatous foci are noticed.
Epigenetic alterations seem to begin early in the progression of colonic neoplasia
(Belshaw et al., 2008). So by and large there is a distinct possibility that methylation
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