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doi: 10.1242/10.1242/jcs.00623
Commentary |
Department of Cancer Cell Biology, Division of Medicine, Imperial College, London W12 0NN, UK
* Author for correspondence (e-mail: r.kypta{at}ic.ac.uk)
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Summary |
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 Top Summary IntroductionDiscovery of the sFRP...Structure/function relationships...sFRP expression patterns during...sFRPs can potentiate Wnt...sFRPs and the regulation...WIF-1CerberusThe Dickkopf familyDkks and developmentPotential cellular functions of...Conclusion/perspectivesReferences |
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Key words: Wnt, Dickkopf, Frizzled, Cerberus
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Introduction |
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TopSummaryIntroductionDiscovery of the sFRP...Structure/function relationships...sFRP expression patterns during...sFRPs can potentiate Wnt...sFRPs and the regulation...WIF-1CerberusThe Dickkopf familyDkks and developmentPotential cellular functions of...Conclusion/perspectivesReferences |
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). Historically,
Wnt proteins have been grouped into two classes – canonical and
noncanonical – on the basis of their activity in cell lines or in vivo
assays. Canonical Wnts (e.g. Wnt1, Wnt3A and Wnt8) stabilise ß-catenin,
thereby activating transcription of Tcf/LEF target genes. This results in
secondary axis formation in Xenopus embryos and morphological
transformation of some mammalian cell lines. Noncanonical Wnts (e.g. Wnt4,
Wnt5A and Wnt11) activate other signalling pathways, such as the
planar-cell-polarity (PCP)-like pathway that guides cell movements during
gastrulation (Heisenberg et al.,
2000) and the Wnt/Ca2+ pathway (discovered in zebrafish
and Xenopus) (reviewed in Kuhl et
al., 2000). Noncanonical Wnts can even antagonise the canonical
pathway (Torres et al., 1996;
Kuhl et al., 2001;
Ishitani et al., 2003).
However, several Wnt proteins appear to have both canonical and noncanonical
properties – for example, Wnt5A, a noncanonical Wnt, induces secondary
axis formation when co-expressed with its receptor, Fz5
(He et al., 1997). Thus, the
functional classification of Wnts may depend on the repertoire of Wnt
receptors in a particular cell type.
The Wnt receptor complex that activates the canonical pathway contains two
components: a member of the frizzled (Fz) family (there are 10 of these
seven-transmembrane-span proteins in humans) and either one of two single-span
transmembrane proteins, low-density-lipoprotein-receptor-related proteins
[LRP-5 and LRP-6 (Pinson et al.,
2000; Tamai et al.,
2000; Wehrli et al.,
2000)] (Fig. 1A).
Activation of the noncanonical Wnt pathways is mediated by the Fz family Wnt
receptors; it is not clear whether this also requires LRP5/LRP6.
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Wnt antagonists can be divided into two functional classes, the sFRP class and the Dickkopf class: members of the sFRP class, which includes the sFRP family, WIF-1 and Cerberus, bind directly to Wnts, thereby altering their ability to bind to the Wnt receptor complex (Fig. 1b); members of the Dickkopf class, which comprises certain Dickkopf family proteins, inhibit Wnt signalling by binding to the LRP5/LRP6 component of the Wnt receptor complex (Fig. 1c). Thus, in theory, those antagonists of the sFRP class will inhibit both canonical and noncanonical pathways, whereas those of the Dickkopf class specifically inhibit the canonical pathway.
Most of our knowledge about the Wnt antagonists comes from developmental
studies in Xenopus and chick, and there are excellent reviews that
cover these aspects in more detail (Niehrs
et al., 2001; Yamaguchi,
2001). Here, we focus on what is known about Wnt antagonist
function at the molecular level.
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Discovery of the sFRP family |
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TopSummaryIntroductionDiscovery of the sFRP...Structure/function relationships...sFRP expression patterns during...sFRPs can potentiate Wnt...sFRPs and the regulation...WIF-1CerberusThe Dickkopf familyDkks and developmentPotential cellular functions of...Conclusion/perspectivesReferences |
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).
There are presently eight known members of the family. A unifying nomenclature
now exists for five of these (sFRP1 to sFRP5)
(Table 1), although sFRP3 is
still better known as FrzB (for Frizzled motif associated with bone
development). On the basis of sequence homology, sFRP1, sFRP2 and sFRP5 form a
subgroup, as do sFRP3 and sFRP4, which are quite distantly related to the
other sFRPs. Sizzled, Sizzled2 and Crescent form a third subgroup, but these
have not been identified in mammals. There are conflicting reports on the
ability of Sizzled to inhibit Wnt signalling
(Salic et al., 1997;
Bradley et al., 2000;
Collavin and Kirschner, 2003).
Note that, with one exception (Illies et
al., 2002), sFRPs (and the other Wnt antagonists) have not been
found in invertebrates. Despite this, many of them have been demonstrated to
inhibit the activity of the Drosophila Wnt homologue Wingless
(Wg).
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sFRP3/FrzB was first purified as a chondrogenic factor found in cartilage
(Hoang et al., 1996). It was
discovered at the same time in a screen for Xenopus dorsal-specific
factors – a screen that also led to the identification of Cerberus
(Bouwmeester et al., 1996).
FrzB contains a characteristic cysteine-rich domain (CRD) that shares homology
with the Fz CRD (Fig. 2a),
which led to the prediction that it regulates Wnt signalling. This was borne
out by experiments done primarily in Xenopus embryos: FrzB is present
in the Spemann organiser during early gastrulation in a complementary pattern
to Xwnt-8 (Leyns et al., 1997;
Wang et al., 1997a); it
interacts with Xwnt-8 (Wang et al.,
1997a) and Wnt-1 (Wang et al.,
1997b; Leyns et al.,
1997); it inhibits ectopic Xwnt-8 function
(Leyns et al., 1997;
Wang et al., 1997a); and it
inhibits Wnt-1-induced accumulation of ß-catenin in cultured cells
(Lin et al., 1997).
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Members of the sFRP family were also cloned in a search of the EST database
for homologs of Fz (Rattner et al.,
1997), during the purification of hepatocyte growth factor/scatter
factor from the heparin-binding fraction of human embryonic lung fibroblast
conditioned medium (Finch et al.,
1997), and as proteins secreted by quiescent 10T1/2 fibroblast
cells that modulate sensitivity to proapoptotic reagents
(Melkonyan et al., 1997). In
addition, the `secreted frizzled' Sizzled was found in an expression cloning
screen in Xenopus embryos (Salic
et al., 1997), and Crescent, another sFRP-related molecule, was
isolated from chick (Pfeffer et al.,
1997). Similarly to FrzB, the inhibitory effects of many of these
sFRP family members on Wnt signalling have been demonstrated in
Xenopus embryos and/or in cultured cells.
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Structure/function relationships of sFRPs |
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TopSummaryIntroductionDiscovery of the sFRP...Structure/function relationships...sFRP expression patterns during...sFRPs can potentiate Wnt...sFRPs and the regulation...WIF-1CerberusThe Dickkopf familyDkks and developmentPotential cellular functions of...Conclusion/perspectivesReferences |
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). It is remains unclear whether sFRPs antagonise Wnt
signalling by interacting with Wnt ligands through the CRD
(Lin et al., 1997) or the
C-terminal domain, which lies outside the CRD
(Uren et al., 2000). The
conflicting data may result from differential affinities among sFRPs and their
Wnt partners or the use of different ligands (Wg by Uren et al., and Wnt-1 by
Lin et al.). Importantly, the CRD of sFRP1 also appears to interact with
itself and with Fz (Bafico et al.,
1999). Thus, sFRPs may block Wnt signalling either by interacting
with Wnt proteins to prevent them from binding to Fz proteins or by forming
nonfunctional complexes with Fz.
The C-terminal half of sFRPs contains a domain that shares weak sequence
similarity with the axon guidance protein netrin (NTR). This NTR module, which
is defined by six cysteine residues and several conserved segments of
hydrophobic residues, has also been found in tissue inhibitors of
metalloproteases and some complement proteins
(Banyai and Patthy, 1999).
Although sFRPs are secreted, several reports indicate that sFRPs synthesised
by cultured cells are mainly found at the plasma membrane and/or in the
extracellular matrix. In common with some Wnts, sFRP1 is released into the
culture medium upon addition of heparin
(Finch et al., 1997). It is
thought that the association of sFRPs with heparan sulfate proteoglycans
stabilises sFRP-Wnt complexes (Uren et
al., 2000) or determines antagonist localisation.
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sFRP expression patterns during development |
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TopSummaryIntroductionDiscovery of the sFRP...Structure/function relationships...sFRP expression patterns during...sFRPs can potentiate Wnt...sFRPs and the regulation...WIF-1CerberusThe Dickkopf familyDkks and developmentPotential cellular functions of...Conclusion/perspectivesReferences |
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). In
some cases, the patterns of sFRP expression complement those of specific Wnts,
which might support the idea that they antagonise Wnt function. One
interesting possibility is that sFRPs control morphogenetic gradients of Wnt
signalling activity. Indeed, it has been suggested that sFRPs facilitate
boundary definition in the developing organism by limiting the range of Wnt
activity. Thus a gradient of sFRP expression might produce gradients of active
Wnt protein in regions where a Wnt is expressed uniformly.
Another possibility is that the overlapping patterns of expression of sFRPs
simply reflect the regulation of sFRP expression by Wnts.
sFRP2 expression in the aggregating mesenchyme, for example, is
induced by Wnt-4, which is critical for kidney development at this early stage
(Lescher et al., 1998).
Interestingly, there is also evidence for opposing gradients of sFRP1
and sFRP3 expression in the developing mouse telencephalon
(Kim et al., 2001). In order
to understand the significance of these expression patterns, we first need to
know more precisely to which Wnts each sFRP can bind and whether the sFRP acts
as an antagonist or an agonist (see below).
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sFRPs can potentiate Wnt activity |
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). This and
other observations have led to the suggestion that sFRP1 has low-affinity and
high-affinity binding sites for Wg; binding to the high-affinity site would
promote Wg signalling whereas binding to the low-affinity site would inhibit
it. One caveat to these experiments is that they involve Wg rather than a
vertebrate Wnt. Although there is a high degree of conservation between Wg and
vertebrate Wnts, it is possible that sFRP1-Wg interactions do not represent
those between sFRP-1 and Wnts from the same species. An alternative hypothesis
is that, at high concentrations, sFRP1 binds to the Fz receptor to form a
nonfunctional receptor complex. Indeed, an interaction has been demonstrated
in the case of sFRP1 and HFz6 (Bafico et
al., 1999). Perhaps the primary role of sFRPs is to transport Wnts
to cellular sites that have a high concentration of receptors, where they can
be released as active ligands. In this scenario, sFRPs would appear to act as
antagonists only at sites where there are few receptors.
The story is further complicated by observations that sFRP1 and sFRP2
elicit different cellular responses when used at similar concentrations. For
example, they have opposite effects both on ß-catenin stability and cell
sensitivity to cytotoxic stimuli in MCF-7 breast cancer cells
(Melkonyan et al., 1997). In
addition, although both sFRP1 and sFRP2 are expressed in the metanephric
kidney, sFRP1 blocks kidney tubule formation and bud branching in cultures of
embryonic rat metanephros, whereas sFRP2 has no effect. In fact, sFRP2 blocks
the effects of sFRP1 (Yoshino et al.,
2001). The major Wnt family member implicated in this process is
Wnt-4, and both sFRP1 and sFRP2 are capable of regulating the activity of
Wnt-4. The discrepancy may result from differential affinities for Wnt-4 or
another Wnt expressed in the kidney. Perhaps, when purified Wnts become
available, analysis of the relative affinities of members of the sFRP family
for members of the Wnt family will help us to interpret these
observations.
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sFRPs and the regulation of cell growth |
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The sFRP1 gene is found at chromosome 8p21, a site of frequent
loss of heterozygosity in human tumours
(Wright et al., 1998). It is
downregulated in cervical carcinoma (Ko et
al., 2002), breast carcinoma
(Ugolini et al., 2001) and
ovary and kidney carcinomas (Zhou et al.,
1998). Moreover, hypermethylation of the sFRP1 promoter
(as well as those of sFRP2, sFRP4 and sFRP5) occurs at a
high frequency in primary colorectal carcinomas
(Suzuki et al., 2002). Tumour
cells may shut down the expression of sFRPs because these proteins can promote
apoptosis. sFRP1, for example, sensitises MCF-7 breast cancer cells to
TNF-induced apoptosis (Melkonyan et al.,
1997). sFRPs might also play a proapoptotic role in other
diseases. sFRP2, for example, is upregulated in the retinas of patients who
have retinitis pigmentosa, an apoptotic disease of the retina
(Jones et al., 2000).
There are examples in which sFRP expression appears to be incompatible with
cell growth in normal tissues. Bovine sFRP1 (called FrzA) is expressed during
the formation of neovessels and becomes undetectable when the vasculature is
fully mature. It inhibits the growth of endothelial cells
(Duplaa et al., 1999), induces
angiogenesis in chick chorioallantoic membranes and increases migration and
organisation of endothelial cells into capillary-like structures
(Dufourcq et al., 2002).
There are also examples in which sFRPs appear to play a positive role in
cell growth; sFRP4, for example, is expressed in the stromal cells surrounding
endometrial and breast carcinomas but is barely detectable in the stroma of
secretory or menstrual endometrium
(Abu-Jawdeh et al., 1999).
Moreover, in contrast to sFRP1, sFRP2 enables MCF-7 cells to resist
TNF-induced apoptosis (Melkonyan et al.,
1997). Similar disparities are found in glioma-derived cell lines
in which sFRP1 and sFRP2 are upregulated. Although neither sFRP affects glioma
cell proliferation nor sensitivity to apoptotic stimuli in vitro, they both
confer resistance to serum starvation, and sFRP2 (but not sFRP1) promotes
tumour growth in nude mice (Roth et al.,
2000). Given the limited number of systems studied, the precise
mechanism by which sFRPs regulate cell proliferation and apoptosis remains
poorly understood. As we have already discussed, the contradictory effects of
sFRPs in some studies might reflect the repertoire of Wnts present, the
relative affinities of different sFRPs for Wnts, tissue-specific responses to
growth and apoptotic stimuli or biphasic responses to different concentrations
of sFRPs.
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WIF-1 |
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TopSummaryIntroductionDiscovery of the sFRP...Structure/function relationships...sFRP expression patterns during...sFRPs can potentiate Wnt...sFRPs and the regulation...WIF-1CerberusThe Dickkopf familyDkks and developmentPotential cellular functions of...Conclusion/perspectivesReferences |
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). The
phenotype induced by injection of RNA encoding WIF-1 into early
Xenopus embryos, namely induction of a partial secondary axis and
abnormal somitogenesis, suggested it played a role in the Wnt signalling
pathway (Hsieh et al., 1999).
Indeed, although WIF-1 does not share any sequence similarity with the CRD
domain of Fz or sFRPs, it can bind to XWnt-8 and Drosophila Wg in the
extracellular space and inhibit Xwnt-8–Dfz2 interactions and Armadillo
stabilisation in Xwnt-8-treated Drosophila clone-8 cells.
WIF-1 has an N-terminal signal sequence, a unique WIF domain (WD) that is
highly conserved across species, and five epidermal growth factor (EGF)-like
repeats highly similar to those of tenascin
(Fig. 2c). Interestingly, the
WIF domain is also found in the extracellular domain of RYK family (for
related to tyrosine kinase) receptor tyrosine kinases, and this has led to the
suggestion that RYKs are involved in Wnt signalling
(Patthy, 2000). Indeed, the
Drosophila RYK family member Derailed was recently found to interact
both genetically and biochemically with Drosophila Wnt5 (but not with
Drosophila Wnt4 or Wg) to regulate axon guidance
(Yoshikawa et al., 2003).
However, Drosophila Wnt5 is almost twice as large as other Wnt family
members, and it is not clear whether Derailed binds to the Wnt domain of
Drosophila Wnt5 or to the unique N-terminal domain.
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Cerberus |
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). It is expressed in the anterior endoderm, including
the Spemann's organiser, and has the unique property of inducing an ectopic
head without trunk formation. Trunk formation relies on Nodal and Wnt
signalling, whereas head induction requires inhibition of Wnt and bone
morphogenetic protein (BMP) signalling. Cerberus, as a multivalent
growth-factor antagonist, inhibits all three signalling pathways, which leads
to simultaneous head formation and trunk inhibition. It has a cysteine-knot
domain that is found in several cytokines, including members of the
transforming growth factor-ß (TGF-ß) superfamily and their
antagonists (Biben et al.,
1998; Piccolo et al.,
1999). Proteolytically processed isoforms of Xenopus
Cerberus (XCer), which still contain the cysteine-knot, can bind to
nodal-related-1 but not to Wnt-8 and BMP-4; so the ability of XCer to act as a
Wnt antagonist might be regulated by proteolysis
(Piccolo et al., 1999). XCer
is distantly related to the mouse protein, Cerberus-like (mCer1), but mCer1
has not been shown to affect Wnt signalling, and it is unclear whether it is a
true mouse orthologue (Belo et al.,
2000). Recently, another Xenopus Cerberus-like molecule
was discovered, named Coco, which can also inhibit Wnt signalling
(Bell et al., 2003). |
The Dickkopf family |
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; Krupnik et al.,
1999) (Fig. 2b).
Cys-2, in particular, is highly conserved among all members of the family and
contains 10 conserved cysteine residues; this is similar to the proteins of
the colipase family, with which Dkk proteins share weak sequence similarity
(Aravind and Koonin, 1998;
Krupnik et al., 1999).
Detailed protein sequence and structural analysis suggested that Dkks and
colipase have the same disulfide-bonding pattern and a similar fold. Colipases
are essential for lipid hydrolysis by pancreatic lipases and interact with
lipid micelles (van Tilbeurgh et al.,
1999). It is not known whether the structural similarity between
colipases and Dkks implies a common function such as lipid interaction. |
Dkks and development |
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TopSummaryIntroductionDiscovery of the sFRP...Structure/function relationships...sFRP expression patterns during...sFRPs can potentiate Wnt...sFRPs and the regulation...WIF-1CerberusThe Dickkopf familyDkks and developmentPotential cellular functions of...Conclusion/perspectivesReferences |
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). Dkk-1
is expressed in the anterior endomesoderm of the Spemann organiser, where
head-inducing activity exists, and injection of Dkk-1 mRNA results in
anteriorisation with an `enlarged head' phenotype. Moreover, Xenopus
embryos injected with an anti-Dkk-1 antibody
(Glinka et al., 1998) and
Dkk-1-knockout mice (Mukhopadhyay et al.,
2001) lack anterior head structures, indicating that Dkk-1 is
essential for head formation.
Similarly to sFRP3/FrzB, Dkk-1 blocks both the early and late effects of
ectopic Xwnt-8 in Xenopus embryos
(Glinka et al., 1998) and
inhibits Wnt-induced stabilisation of ß-catenin
(Fedi et al., 1999) and
ß-catenin/Tcf-dependent transcription of both artificial and endogenous
genes in mammalian and amphibian cells, respectively
(Wu et al., 2000;
Brott and Sokol, 2002).
However, unlike sFRPs, Dkk-1 prevents activation of the Wnt signalling pathway
by binding to LRP5/6 rather than to Wnt proteins
(Bafico et al., 2001;
Mao, B. et al., 2001;
Semenov et al., 2001).
In addition to LRP5/6, Dkk-1 interacts with another class of receptor, the
single-pass transmembrane proteins Kremen1 (Krm1) and Kremen2 (Krm2)
(Mao et al., 2002). Krm, Dkk-1
and LRP6 form a ternary complex that disrupts Wnt/LRP6 signalling by promoting
endocytosis and removal of the Wnt receptor from the plasma membrane
(Mao et al., 2002). Studies in
Xenopus indicate that Krm proteins inhibit Wnt activity during early
anteroposterior patterning of the central nervous system: overexpression of
Krm anteriorises embryos and rescues embryos posteriorised by Wnt8, and
antisense knockdown of Krm1 and Krm2 leads to deficiency of anterior neural
development (Davidson et al.,
2002). Although a precise molecular mechanism describing how the
Krm–Dkk-1–LRP6 complex inhibits the canonical Wnt signalling
pathway remains unclear, there are some clues. A key component of the
canonical Wnt pathway is Axin, which negatively regulates Wnt signalling by
facilitating the phosphorylation of ß-catenin, marking it for proteosomal
degradation. Wnt-activated LRP-5 recruits Axin to the plasma membrane and
promotes its degradation, thereby leading to the stabilisation of
ß-catenin (Mao, J. et al.,
2001). By promoting the internalisation of LRP5/6 through Krm,
Dkk-1 might inhibit recruitment of Axin to the plasma membrane.
Activation of the noncanonical Wnt PCP-like pathway, which triggers
convergent extension movements during gastrulation, is inhibited by
dominant-negative Fz, but not by Dkk-1 or by dominant-negative LRP6
(Semenov et al., 2001). Thus,
the antagonistic effect of Dkk-1, mediated by LRP5/6, is likely to be specific
to the Wnt/ß-catenin pathway. However, is too early to draw a definitive
conclusion since it was recently shown that Dkk-1 could activate the
noncanonical PCP-like pathway (Pandur et
al., 2002) (although GSK-3ß, which also inhibits the
canonical pathway, had a similar effect in these experiments).
To date, the Wnt antagonist activity of Dkk-4 appears to be
indistinguishable from Dkk-1, whereas Dkk-3 and Sgy have no effect on Wnt
signalling (Krupnik et al.,
1999; Mao and Niehrs,
2003). However, Dkk-2 is more complicated. Although both Dkk-1 and
Dkk-2 can bind to LRP6 and Krm2 (Mao et
al., 2002) and antagonise ß-catenin/Tcf-dependent
transcription induced by Wnt-1 and Xwnt-8
(Wu et al., 2000;
Brott and Sokol, 2002), Dkk-2
is a poor inhibitor of Xwnt-8-induced axis duplication
(Krupnik et al., 1999;
Wu et al., 2000). [This may,
in part, be because Dkk-2 cannot be expressed to such high levels as Dkk-1
(Brott and Sokol, 2002).]
Moreover, ectopic expression of Dkk-2 (but not Dkk-1) activates
Wnt/ß-catenin signalling in Xenopus embryos
(Wu et al., 2000), and Dkk-2
(but not Dkk-1) synergises with LRP6 to promote axis duplication and
activation of the Siamois promotor
(Brott and Sokol, 2002).
Analysis of deletion mutants and chimeric proteins indicates that the
C-terminal domains of Dkk-1 and Dkk-2, which contain the Cys-2 region, behave
similarly to one another: in isolation they are necessary and sufficient for
association with LRP6, potentiation of LRP6-induced axis induction, and
transcriptional activation of reporter genes
(Brott and Sokol, 2002;
Li et al., 2002;
Mao and Niehrs, 2003), and
they inhibit Xwnt-8-dependent secondary axis formation and cooperate with a
dominant-negative BMP-4 receptor to promote head induction
(Brott and Sokol, 2002). This
suggests that the different activities of Dkk-1 and Dkk-2 might result from
differences in their N-terminal domains. Indeed, when the N-terminal domain of
Dkk-1 is fused to the C-terminal domain of Dkk-2, it inhibits the ability of
the latter to synergise with LRP6 to activate Wnt signalling
(Brott and Sokol, 2002). One
possibility is that the N-terminal domain of Dkk-1 prevents LRP6-Fz
interactions. The Cys-2 region also contains the binding site for Krm1/2, and
the co-expression of Krm2 is sufficient to convert Dkk-2 from an LRP6 agonist
into an LRP6 antagonist (Mao and Niehrs,
2003). This suggests that the relative levels of expression of
LRP5/6 and Krm1/2 proteins might determine the ability of Dkk-2 to act as an
agonist or an antagonist.
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Potential cellular functions of Dkks |
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; Grotewald and Ruther, 2002), and the loss of Dkk-1
expression results in the fusion of digits and formation of ectopic digits
similar to those found in mice possessing mutations in other proteins that
regulate programmed cell death in the limb
(Mukhopadhyay et al., 2001).
It remains to be seen whether Dkk-1 inhibition of the Wnt/ß-catenin
pathway is required for induction of apoptosis. Dkk-1 may be an important
mediator of apoptosis induced by a variety of stimuli. The Dkk-1
promoter contains a p53-responsive element and the expression of Dkk-1 is
induced by p53 (Wang et al.,
2000). Moreover, genotoxic stress caused by UV and
chemotherapeutic agents enhances Dkk-1 expression, and Dkk-1 sensitises glioma
cells to ceramide-induced apoptosis (Shou
et al., 2002). The increase in Dkk-1 expression induced by several
apoptotic agents appears to involve the transcription factor Jun (Grotewald
and Ruther, 2002).
It is still unclear whether aberrant expression of Dkk-1 is a causative
agent in human disease. However, studies of an inherited LRP5
mutation indicate a potential role for Dkk-1 in pathogenesis. A congenital
Gly171Val mutation occurs in all affected members of a kindred with an
autosomal dominant syndrome characterised by high bone density
(Boyden et al., 2002;
Little et al., 2002). This
mutation is refractory to Dkk-1 antagonism and thus may augment the activity
of the Wnt pathway (Boyden et al.,
2002). This suggests that other Wnt antagonists cannot compensate
for this function of Dkk-1/LRP. In mice, disruption LRP5 leads to a
decrease in osteoblast proliferation, which results in a low bone mass
phenotype (Kato et al.,
2002).
The biological roles of Dkk-3 and Sgy in the Wnt pathway remain unclear
because they do not inhibit canonical Wnt signalling
(Krupnik et al., 1999;
Mao, B. et al., 2001), and
Dkk-3 (Sgy has not been tested) does not interact with LRPs or Krm1/2
(Mao, B. et al., 2001;
Mao et al., 2002).
Dkk-3 was independently cloned as a gene that has reduced expression
in immortalised cells and tumour cell lines
(Tsuji et al., 2000). It is
frequently downregulated in non-small cell lung cancer and has growth
inhibitory effects on tumor cells (Tsuji
et al., 2001). It remains to be seen whether Dkk-3 antagonises
other growth factor pathways by mechanisms that involve direct association
with ligands or transmembrane receptors in a manner similar to that in which
Dkk-1 inhibits Wnt signalling. Sgy is related in sequence to Dkk-3 (22%
residue identity in humans), in particular within the N-terminal domain, but
does not share any homology with other Dkks
(Krupnik et al., 1999) and so
is not expected to function as a Wnt antagonist. Sgy is expressed specifically
in developing spermatocytes, which indicates that it might have a role in
spermatogenesis (Kaneko et DePamphilis,
2000).
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Conclusion/perspectives |
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) to help
determine the binding affinities and specificities of each antagonist. |
Acknowledgments |
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References |
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TopSummaryIntroductionDiscovery of the sFRP...Structure/function relationships...sFRP expression patterns during...sFRPs can potentiate Wnt...sFRPs and the regulation...WIF-1CerberusThe Dickkopf familyDkks and developmentPotential cellular functions of...Conclusion/perspectivesReferences |
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 H.-S. Kwon, H.-S. Lee, Y. Ji, J. S. Rubin, and S. I. Tomarev Myocilin Is a Modulator of Wnt Signaling Mol. Cell. Biol., April 15, 2009; 29(8): 2139 - 2154. [Abstract] [Full Text] [PDF]
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 J. You, D. Mi, X. Zhou, L. Qiao, H. Zhang, X. Zhang, and L. Ye A Positive Feedback between Activated Extracellularly Regulated Kinase and Cyclooxygenase/Lipoxygenase Maintains Proliferation and Migration of Breast Cancer Cells Endocrinology, April 1, 2009; 150(4): 1607 - 1617. [Abstract] [Full Text] [PDF]
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A. J. G. Dickinson and H. L. Sive The Wnt antagonists Frzb-1 and Crescent locally regulate basement membrane dissolution in the developing primary mouth Development, April 1, 2009; 136(7): 1071 - 1081. [Abstract] [Full Text] [PDF]
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 S. Zuklys, J. Gill, M. P. Keller, M. Hauri-Hohl, S. Zhanybekova, G. Balciunaite, K.-J. Na, L. T. Jeker, K. Hafen, N. Tsukamoto, et al. Stabilized {beta}-Catenin in Thymic Epithelial Cells Blocks Thymus Development and Function J. Immunol., March 1, 2009; 182(5): 2997 - 3007. [Abstract] [Full Text] [PDF]
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E. Hay, E. Laplantine, V. Geoffroy, M. Frain, T. Kohler, R. Muller, and P. J. Marie N-Cadherin Interacts with Axin and LRP5 To Negatively Regulate Wnt/{beta}-Catenin Signaling, Osteoblast Function, and Bone Formation Mol. Cell. Biol., February 15, 2009; 29(4): 953 - 964. [Abstract] [Full Text] [PDF]
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 E. Kress, A. Rezza, J. Nadjar, J. Samarut, and M. Plateroti The Frizzled-related sFRP2 Gene Is a Target of Thyroid Hormone Receptor {alpha}1 and Activates {beta}-Catenin Signaling in Mouse Intestine J. Biol. Chem., January 9, 2009; 284(2): 1234 - 1241. [Abstract] [Full Text] [PDF]
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 D. Romaker, M. Puetz, S. Teschner, J. Donauer, M. Geyer, P. Gerke, B. Rumberger, B. Dworniczak, P. Pennekamp, B. Buchholz, et al. Increased Expression of Secreted Frizzled-Related Protein 4 in Polycystic Kidneys J. Am. Soc. Nephrol., January 1, 2009; 20(1): 48 - 56. [Abstract] [Full Text] [PDF]
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 S. Suzuki, S. Sembon, M. Iwamoto, D. Fuchimoto, and A. Onishi Identification of genes downregulated during differentiation of porcine mesenteric adipocytes J Anim Sci, December 1, 2008; 86(12): 3367 - 3376. [Abstract] [Full Text] [PDF]
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 M. P. Alfaro, M. Pagni, A. Vincent, J. Atkinson, M. F. Hill, J. Cates, J. M. Davidson, J. Rottman, E. Lee, and P. P. Young The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair PNAS, November 25, 2008; 105(47): 18366 - 18371. [Abstract] [Full Text] [PDF]
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 Y. Li, S. A. Rankin, D. Sinner, A. P. Kenny, P. A. Krieg, and A. M. Zorn Sfrp5 coordinates foregut specification and morphogenesis by antagonizing both canonical and noncanonical Wnt11 signaling Genes & Dev., November 1, 2008; 22(21): 3050 - 3063. [Abstract] [Full Text] [PDF]
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T. Yokota, K. Oritani, K. P. Garrett, T. Kouro, M. Nishida, I. Takahashi, M. Ichii, Y. Satoh, P. W. Kincade, and Y. Kanakura Soluble Frizzled-Related Protein 1 Is Estrogen Inducible in Bone Marrow Stromal Cells and Suppresses the Earliest Events in Lymphopoiesis J. Immunol., November 1, 2008; 181(9): 6061 - 6072. [Abstract] [Full Text] [PDF]
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 J. Liu, J. B.B. Lam, K. H.M. Chow, A. Xu, K. S.L. Lam, R. T. Moon, and Y. Wang Adiponectin stimulates Wnt inhibitory factor-1 expression through epigenetic regulations involving the transcription factor specificity protein 1 Carcinogenesis, November 1, 2008; 29(11): 2195 - 2202. [Abstract] [Full Text] [PDF]
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 C S Chim, R Pang, and R Liang Epigenetic dysregulation of the Wnt signalling pathway in chronic lymphocytic leukaemia J. Clin. Pathol., November 1, 2008; 61(11): 1214 - 1219. [Abstract] [Full Text] [PDF]
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X. Cheng, T. L. Huber, V. C. Chen, P. Gadue, and G. M. Keller Numb mediates the interaction between Wnt and Notch to modulate primitive erythropoietic specification from the hemangioblast Development, October 15, 2008; 135(20): 3447 - 3458. [Abstract] [Full Text] [PDF]
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A. Smerdel-Ramoya, S. Zanotti, L. Stadmeyer, D. Durant, and E. Canalis Skeletal Overexpression of Connective Tissue Growth Factor Impairs Bone Formation and Causes Osteopenia Endocrinology, September 1, 2008; 149(9): 4374 - 4381. [Abstract] [Full Text] [PDF]
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Y.-K. I. Lau, L. B. Murray, S. S. Houshmandi, Y. Xu, D. H. Gutmann, and Q. Yu Merlin Is a Potent Inhibitor of Glioma Growth Cancer Res., July 15, 2008; 68(14): 5733 - 5742. [Abstract] [Full Text] [PDF]
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Y.-W. Qiang, Y. Chen, O. Stephens, N. Brown, B. Chen, J. Epstein, B. Barlogie, and J. D. Shaughnessy Jr Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma Blood, July 1, 2008; 112(1): 196 - 207. [Abstract] [Full Text] [PDF]
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 K. S. Carmon and D. S. Loose Secreted Frizzled-Related Protein 4 Regulates Two Wnt7a Signaling Pathways and Inhibits Proliferation in Endometrial Cancer Cells Mol. Cancer Res., June 1, 2008; 6(6): 1017 - 1028. [Abstract] [Full Text] [PDF]
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Y. Guo, J. Xie, E. Rubin, Y.-X. Tang, F. Lin, X. Zi, and B. H. Hoang Frzb, a Secreted Wnt Antagonist, Decreases Growth and Invasiveness of Fibrosarcoma Cells Associated with Inhibition of Met Signaling Cancer Res., May 1, 2008; 68(9): 3350 - 3360. [Abstract] [Full Text] [PDF]
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 Y. Yamaguchi, T. Passeron, T. Hoashi, H. Watabe, F. Rouzaud, K.-i. Yasumoto, T. Hara, C. Tohyama, I. Katayama, T. Miki, et al. Dickkopf 1 (DKK1) regulates skin pigmentation and thickness by affecting Wnt/{beta}-catenin signaling in keratinocytes FASEB J, April 1, 2008; 22(4): 1009 - 1020. [Abstract] [Full Text] [PDF]
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M. Loscertales, A. J. Mikels, J. K.-H. Hu, P. K. Donahoe, and D. J. Roberts Chick pulmonary Wnt5a directs airway and vascular tubulogenesis Development, April 1, 2008; 135(7): 1365 - 1376. [Abstract] [Full Text] [PDF]
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P. Bovolenta, P. Esteve, J. M. Ruiz, E. Cisneros, and J. Lopez-Rios Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease J. Cell Sci., March 15, 2008; 121(6): 737 - 746. [Abstract] [Full Text] [PDF]
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 K. R. Badri, Y. Zhou, and L. Schuger Embryological Origin of Airway Smooth Muscle Proceedings of the ATS, January 1, 2008; 5(1): 4 - 10. [Abstract] [Full Text] [PDF]
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 P. Dufourcq, L. Leroux, J. Ezan, B. Descamps, J.-M. D. Lamaziere, P. Costet, C. Basoni, C. Moreau, U. Deutsch, T. Couffinhal, et al. Regulation of Endothelial Cell Cytoskeletal Reorganization by a Secreted Frizzled-Related Protein-1 and Frizzled 4- and Frizzled 7-Dependent Pathway: Role in Neovessel Formation Am. J. Pathol., January 1, 2008; 172(1): 37 - 49. [Abstract] [Full Text] [PDF]
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H. Sato, H. Suzuki, M. Toyota, M. Nojima, R. Maruyama, S. Sasaki, H. Takagi, Y. Sogabe, Y. Sasaki, M. Idogawa, et al. Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors Carcinogenesis, December 1, 2007; 28(12): 2459 - 2466. [Abstract] [Full Text] [PDF]
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J. L. Green, T. Inoue, and P. W. Sternberg The C. elegans ROR receptor tyrosine kinase, CAM-1, non-autonomously inhibits the Wnt pathway Development, November 15, 2007; 134(22): 4053 - 4062. [Abstract] [Full Text] [PDF]
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E. Gazzerro, A. Smerdel-Ramoya, S. Zanotti, L. Stadmeyer, D. Durant, A. N. Economides, and E. Canalis Conditional Deletion of Gremlin Causes a Transient Increase in Bone Formation and Bone Mass J. Biol. Chem., October 26, 2007; 282(43): 31549 - 31557. [Abstract] [Full Text] [PDF]
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Z. Khan, S. Vijayakumar, T. V. de la Torre, S. Rotolo, and A. Bafico Analysis of Endogenous LRP6 Function Reveals a Novel Feedback Mechanism by Which Wnt Negatively Regulates Its Receptor Mol. Cell. Biol., October 15, 2007; 27(20): 7291 - 7301. [Abstract] [Full Text] [PDF]
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M. Suzuki, H. Shigematsu, T. Nakajima, R. Kubo, S. Motohashi, Y. Sekine, K. Shibuya, T. Iizasa, K. Hiroshima, Y. Nakatani, et al. Synchronous Alterations of Wnt and Epidermal Growth Factor Receptor Signaling Pathways through Aberrant Methylation and Mutation in Non Small Cell Lung Cancer Clin. Cancer Res., October 15, 2007; 13(20): 6087 - 6092. [Abstract] [Full Text] [PDF]
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M. E. Binnerts, K.-A. Kim, J. M. Bright, S. M. Patel, K. Tran, M. Zhou, J. M. Leung, Y. Liu, W. E. Lomas III, M. Dixon, et al. R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6 PNAS, September 11, 2007; 104(37): 14700 - 14705. [Abstract] [Full Text] [PDF]
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 A. A. Zaghetto, S. Paina, S. Mantero, N. Platonova, P. Peretto, S. Bovetti, A. Puche, S. Piccolo, and G. R. Merlo Activation of the Wnt {beta}Catenin Pathway in a Cell Population on the Surface of the Forebrain Is Essential for the Establishment of Olfactory Axon Connections J. Neurosci., September 5, 2007; 27(36): 9757 - 9768. [Abstract] [Full Text] [PDF]
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 C.H. Li and S. Amar Inhibition of SFRP1 Reduces Severity of Periodontitis Journal of Dental Research, September 1, 2007; 86(9): 873 - 877. [Abstract] [Full Text] [PDF]
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K. S. Shanmugam, H. Brenner, M. Hoffmeister, J. Chang-Claude, and B. Burwinkel The functional genetic variant Arg324Gly of frizzled-related protein is associated with colorectal cancer risk Carcinogenesis, September 1, 2007; 28(9): 1914 - 1917. [Abstract] [Full Text] [PDF]
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O. Aguilera, C. Pena, J. M. Garcia, M. J. Larriba, P. Ordonez-Moran, D. Navarro, A. Barbachano, I. Lopez de Silanes, E. Ballestar, M. F. Fraga, et al. The Wnt antagonist DICKKOPF-1 gene is induced by 1{alpha},25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells Carcinogenesis, September 1, 2007; 28(9): 1877 - 1884. [Abstract] [Full Text] [PDF]
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 E. Canalis, A. Giustina, and J. P. Bilezikian Mechanisms of Anabolic Therapies for Osteoporosis N. Engl. J. Med., August 30, 2007; 357(9): 905 - 916. [Full Text] [PDF]
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M. L. Gumz, H. Zou, P. A. Kreinest, A. C. Childs, L. S. Belmonte, S. N. LeGrand, K. J. Wu, B. A. Luxon, M. Sinha, A. S. Parker, et al. Secreted Frizzled-Related Protein 1 Loss Contributes to Tumor Phenotype of Clear Cell Renal Cell Carcinoma Clin. Cancer Res., August 15, 2007; 13(16): 4740 - 4749. [Abstract] [Full Text] [PDF]
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 K. Schlessinger, E. J. McManus, and A. Hall Cdc42 and noncanonical Wnt signal transduction pathways cooperate to promote cell polarity J. Cell Biol., July 24, 2007; 178(3): 355 - 361. [Abstract] [Full Text] [PDF]
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V. H. Cowling, C. M. D'Cruz, L. A. Chodosh, and M. D. Cole c-Myc Transforms Human Mammary Epithelial Cells through Repression of the Wnt Inhibitors DKK1 and SFRP1 Mol. Cell. Biol., July 15, 2007; 27(14): 5135 - 5146. [Abstract] [Full Text] [PDF]
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M. Katoh and M. Katoh WNT Signaling Pathway and Stem Cell Signaling Network Clin. Cancer Res., July 15, 2007; 13(14): 4042 - 4045. [Abstract] [Full Text] [PDF]
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X. Zhong, T. Desilva, L. Lin, P. Bodine, R. A. Bhat, E. Presman, J. Pocas, M. Stahl, and R. Kriz Regulation of Secreted Frizzled-related Protein-1 by Heparin J. Biol. Chem., July 13, 2007; 282(28): 20523 - 20533. [Abstract] [Full Text] [PDF]
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 M. Wagner and M. A. Q. Siddiqui Signal Transduction in Early Heart Development (I): Cardiogenic Induction and Heart Tube Formation Experimental Biology and Medicine, July 1, 2007; 232(7): 852 - 865. [Abstract] [Full Text] [PDF]
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 A. Shimoyama, M. Wada, F. Ikeda, K. Hata, T. Matsubara, A. Nifuji, M. Noda, K. Amano, A. Yamaguchi, R. Nishimura, et al. Ihh/Gli2 Signaling Promotes Osteoblast Differentiation by Regulating Runx2 Expression and Function Mol. Biol. Cell, July 1, 2007; 18(7): 2411 - 2418. [Abstract] [Full Text] [PDF]
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S. Zhang, T. Cagatay, M. Amanai, M. Zhang, J. Kline, D. H. Castrillon, R. Ashfaq, O. K. Oz, and K. A. Wharton Jr. Viable Mice with Compound Mutations in the Wnt/Dvl Pathway Antagonists nkd1 and nkd2 Mol. Cell. Biol., June 15, 2007; 27(12): 4454 - 4464. [Abstract] [Full Text] [PDF]
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V. A. McLin, S. A. Rankin, and A. M. Zorn Repression of Wnt/{beta}-catenin signaling in the anterior endoderm is essential for liver and pancreas development Development, June 15, 2007; 134(12): 2207 - 2217. [Abstract] [Full Text] [PDF]
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V. I. DeAlmeida, L. Miao, J. A. Ernst, H. Koeppen, P. Polakis, and B. Rubinfeld The Soluble Wnt Receptor Frizzled8CRD-hFc Inhibits the Growth of Teratocarcinomas In vivo Cancer Res., June 1, 2007; 67(11): 5371 - 5379. [Abstract] [Full Text] [PDF]
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I. Olivera-Martinez and K. G. Storey Wnt signals provide a timing mechanism for the FGF-retinoid differentiation switch during vertebrate body axis extension Development, June 1, 2007; 134(11): 2125 - 2135. [Abstract] [Full Text] [PDF]
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A. Suzuki, H. Urushitani, T. Sato, T. Kobayashi, H. Watanabe, Y. Ohta, and T. Iguchi Gene Expression Change in the Mullerian Duct of the Mouse Fetus Exposed to Diethylstilbestrol In Utero Experimental Biology and Medicine, April 1, 2007; 232(4): 503 - 514. [Abstract] [Full Text] [PDF]
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 H. Komekado, H. Yamamoto, T. Chiba, and A. Kikuchi Glycosylation and palmitoylation of Wnt-3a are coupled to produce an active form of Wnt-3a Genes Cells, April 1, 2007; 12(4): 521 - 534. [Abstract] [Full Text] [PDF]
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K. Kaji, J. Nichols, and B. Hendrich Mbd3, a component of the NuRD co-repressor complex, is required for development of pluripotent cells Development, March 15, 2007; 134(6): 1123 - 1132. [Abstract] [Full Text] [PDF]
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P. V. Bodine Wnt Signaling in Bone IBMS BoneKEy, March 1, 2007; 4(3): 108 - 123. [Abstract] [Full Text] [PDF]
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A. N.T. Strehlow, J. Z. Li, and R. M. Myers Wild-type huntingtin participates in protein trafficking between the Golgi and the extracellular space Hum. Mol. Genet., February 15, 2007; 16(4): 391 - 409. [Abstract] [Full Text] [PDF]
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L. Caneparo, Y.-L. Huang, N. Staudt, M. Tada, R. Ahrendt, O. Kazanskaya, C. Niehrs, and C. Houart Dickkopf-1 regulates gastrulation movements by coordinated modulation of Wnt/betacatenin and Wnt/PCP activities, through interaction with the Dally-like homolog Knypek Genes & Dev., February 15, 2007; 21(4): 465 - 480. [Abstract] [Full Text] [PDF]
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M. Mirotsou, Z. Zhang, A. Deb, L. Zhang, M. Gnecchi, N. Noiseux, H. Mu, A. Pachori, and V. Dzau Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair PNAS, January 30, 2007; 104(5): 1643 - 1648. [Abstract] [Full Text] [PDF]
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S. Urakami, H. Shiina, H. Enokida, H. Hirata, K. Kawamoto, T. Kawakami, N. Kikuno, Y. Tanaka, S. Majid, M. Nakagawa, et al. Wnt Antagonist Family Genes as Biomarkers for Diagnosis, Staging, and Prognosis of Renal Cell Carcinoma Using Tumor and Serum DNA Clin. Cancer Res., December 1, 2006; 12(23): 6989 - 6997. [Abstract] [Full Text] [PDF]
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P. Bovolenta, J. Rodriguez, and P. Esteve Frizzled/RYK mediated signalling in axon guidance Development, November 15, 2006; 133(22): 4399 - 4408. [Full Text] [PDF]
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M. Kurayoshi, N. Oue, H. Yamamoto, M. Kishida, A. Inoue, T. Asahara, W. Yasui, and A. Kikuchi Expression of Wnt-5a Is Correlated with Aggressiveness of Gastric Cancer by Stimulating Cell Migration and Invasion Cancer Res., November 1, 2006; 66(21): 10439 - 10448. [Abstract] [Full Text] [PDF]
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R. L. Vessella and E. Corey Targeting factors involved in bone remodeling as treatment strategies in prostate cancer bone metastasis. Clin. Cancer Res., October 15, 2006; 12(20): 6285s - 6290s. [Abstract] [Full Text] [PDF]
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S. H. Ralston and B. de Crombrugghe Genetic regulation of bone mass and susceptibility to osteoporosis Genes & Dev., September 15, 2006; 20(18): 2492 - 2506. [Abstract] [Full Text] [PDF]
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G. Peng and M. Westerfield Lhx5 promotes forebrain development and activates transcription of secreted Wnt antagonists Development, August 15, 2006; 133(16): 3191 - 3200. [Abstract] [Full Text] [PDF]
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C. Christodoulides, M. Laudes, W. P. Cawthorn, S. Schinner, M. Soos, S. O'Rahilly, J. K. Sethi, and A. Vidal-Puig The Wnt antagonist Dickkopf-1 and its receptors are coordinately regulated during early human adipogenesis J. Cell Sci., June 15, 2006; 119(12): 2613 - 2620. [Abstract] [Full Text] [PDF]
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J.-S. Nam, T. J. Turcotte, P. F. Smith, S. Choi, and J. K. Yoon Mouse Cristin/R-spondin Family Proteins Are Novel Ligands for the Frizzled 8 and LRP6 Receptors and Activate beta-Catenin-dependent Gene Expression J. Biol. Chem., May 12, 2006; 281(19): 13247 - 13257. [Abstract] [Full Text] [PDF]
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B. Gustafson and U. Smith Cytokines Promote Wnt Signaling and Inflammation and Impair the Normal Differentiation and Lipid Accumulation in 3T3-L1 Preadipocytes J. Biol. Chem., April 7, 2006; 281(14): 9507 - 9516. [Abstract] [Full Text] [PDF]
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C.H. Li and S. Amar Role of Secreted Frizzled-related Protein 1 (SFRP1) in Wound Healing Journal of Dental Research, April 1, 2006; 85(4): 374 - 378. [Abstract] [Full Text] [PDF]
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J. Pollheimer, T. Loregger, S. Sonderegger, L. Saleh, S. Bauer, M. Bilban, K. Czerwenka, P. Husslein, and M. Knofler Activation of the Canonical Wingless/T-Cell Factor Signaling Pathway Promotes Invasive Differentiation of Human Trophoblast Am. J. Pathol., April 1, 2006; 168(4): 1134 - 1147. [Abstract] [Full Text] [PDF]
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S. Urakami, H. Shiina, H. Enokida, T. Kawakami, K. Kawamoto, H. Hirata, Y. Tanaka, N. Kikuno, M. Nakagawa, M. Igawa, et al. Combination analysis of hypermethylated Wnt-antagonist family genes as a novel epigenetic biomarker panel for bladder cancer detection. Clin. Cancer Res., April 1, 2006; 12(7 Pt 1): 2109 - 2116. [Abstract] [Full Text] [PDF]
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W. Satoh, T. Gotoh, Y. Tsunematsu, S. Aizawa, and A. Shimono Sfrp1 and Sfrp2 regulate anteroposterior axis elongation and somite segmentation during mouse embryogenesis Development, March 15, 2006; 133(6): 989 - 999. [Abstract] [Full Text] [PDF]
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K. M. Cadigan and Y. I. Liu Wnt signaling: complexity at the surface J. Cell Sci., February 1, 2006; 119(3): 395 - 402. [Abstract] [Full Text] [PDF]
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S. Urakami, H. Shiina, H. Enokida, T. Kawakami, T. Tokizane, T. Ogishima, Y. Tanaka, L.-C. Li, L. A. Ribeiro-Filho, M. Terashima, et al. Epigenetic Inactivation of Wnt Inhibitory Factor-1 Plays an Important Role in Bladder Cancer through Aberrant Canonical Wnt/{beta}-Catenin Signaling Pathway Clin. Cancer Res., January 15, 2006; 12(2): 383 - 391. [Abstract] [Full Text] [PDF]
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R. Singh, J. N. Artaza, W. E. Taylor, M. Braga, X. Yuan, N. F. Gonzalez-Cadavid, and S. Bhasin Testosterone Inhibits Adipogenic Differentiation in 3T3-L1 Cells: Nuclear Translocation of Androgen Receptor Complex with {beta}-Catenin and T-Cell Factor 4 May Bypass Canonical Wnt Signaling to Down-Regulate Adipogenic Transcription Factors Endocrinology, January 1, 2006; 147(1): 141 - 154. [Abstract] [Full Text] [PDF]
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C. S. Moreno, C.-O. Evans, X. Zhan, M. Okor, D. M. Desiderio, and N. M. Oyesiku Novel Molecular Signaling and Classification of Human Clinically Nonfunctional Pituitary Adenomas Identified by Gene Expression Profiling and Proteomic Analyses Cancer Res., November 15, 2005; 65(22): 10214 - 10222. [Abstract] [Full Text] [PDF]
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X. Zi, Y. Guo, A. R. Simoneau, C. Hope, J. Xie, R. F. Holcombe, and B. H. Hoang Expression of Frzb/Secreted Frizzled-Related Protein 3, a Secreted Wnt Antagonist, in Human Androgen-Independent Prostate Cancer PC-3 Cells Suppresses Tumor Growth and Cellular Invasiveness Cancer Res., November 1, 2005; 65(21): 9762 - 9770. [Abstract] [Full Text] [PDF]
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