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 |
---|
Key words: Wnt, Dickkopf, Frizzled, Cerberus
![]() |
Introduction |
---|
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.
|
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.
![]() |
Discovery of the sFRP family |
---|
|
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
).
|
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.
![]() |
Structure/function relationships of sFRPs |
---|
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.
![]() |
sFRP expression patterns during development |
---|
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).
![]() |
sFRPs can potentiate Wnt activity |
---|
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.
![]() |
sFRPs and the regulation of cell growth |
---|
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.
![]() |
WIF-1 |
---|
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.
![]() |
Cerberus |
---|
![]() |
The Dickkopf family |
---|
![]() |
Dkks and development |
---|
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
KrmDkk-1LRP6 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.
![]() |
Potential cellular functions of Dkks |
---|
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
).
![]() |
Conclusion/perspectives |
---|
![]() |
Acknowledgments |
---|
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