Biomedical Engineering Reference
In-Depth Information
3.3. Divergence of the pathways: Wnt/PCP, Wnt/Ca
2+
,
and Fat/Ds
It has become evident that noncanonical Wnt11 and Wnt5 utilize different
receptors and their downstream effectors although
wnt11
and
wnt5b
act
redundantly in regulating CE in zebrafish (
Kilian et al., 2003
). Wnt11 binds
to Fzd7 and acts through the core transducer of PCP signal Dsh which in
turn activates RhoA and Rok2 to modulate actin cytoskeleton (
Djiane
et al., 2000; Habas et al., 2003; Marlow et al., 2002; Tada & Smith,
2000
). In contrast, it has been shown that Wnt5 can bind to the receptor
tyrosine kinase Ror2 and potentially form a complex with Fzd through
the secreted glycoprotein Cthrc1 (
Yamamoto et al., 2008
). Wnt5/Ror2
signal regulates CE to activate JNK then the transcription factor ATF2,
mediating activation of target genes, independently of Wnt11 function
(
Hikasa et al., 2002; Schambony & Wedlich, 2007
) and perhaps through
Ca
2
þ
signal as in cultured cells (
Oishi et al., 2003
).
There is emerging evidence for mutual antagonistic actions between the
Wnt/
b
-catenin and Wnt/PCP/Wnt/Ca
2
þ
pathways. In addition, regula-
tors for Wnt/
b
-catenin signal can also modulate the Wnt/PCP pathway
at different levels. The newly identified module that positively regulates
Wnt/
b
-catenin signal at the cell surface along with the receptors Fzd and
Lrp is the secreted glycoprotein R-spondin and its G-protein-coupled
receptor Lgr (
Carmon et al., 2011; de Lau et al., 2011; Glinka et al.,
2011
). Interestingly, R-spondin3 via Lgr4/5 modulates CE by positively
regulating the Wnt/PCP pathway in the presence of the proteoglycan
Syndecan4 (
Glinka et al., 2011; Ohkawara et al., 2011
), which has been
shown to regulate CE through PCP signal in
Xenopus
(
Munoz et al., 2006
).
Conversely, Lrp disrupts CE by negatively regulating the Wnt/PCP
pathway in
Xenopus
(
Tahinci et al., 2007
).
It appears that downstream of Dsh is further divergent, and this can be
explained by the presence of a variety of Dsh-binding proteins that bias one
branch of the noncanonical Wnt pathway to another. The forming-
homology protein Daam1, being identified as a binding protein for Dsh
and RhoA, mediates CE through activation of RhoA and Rac based on
overexpression of mutant forms of Daam1 (
Habas et al., 2001
) although it
remains to be clarified whether Daam1 fulfills downstream mediator of
Dsh based on loss-of-function studies. Casein kinase I
e
binds to Dsh and
is capable of modulating CE but rather acts by negatively regulating
