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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 111

Inhibitors of Wnt signalling of colorectal cancer (CRC) (Module 12: Figure colon
There are various extracellular molecules that can inhibit cancer).
Wnt signalling. Some of these, such as the Wnt inhibit- • The canonical Wnt pathway inhibits the differentiation
ory factor 1 (WIF-1) and secreted frizzled-related protein of white fat cells (Module 8: Figure white fat cell dif-
(sFRP), bind to Wnt and thus prevent it from activating ferentiation)and the differentiation of brown fat cells
the Fz receptor. There is another group, such as Dickkopf (Module 8: Figure brown fat cell differentiation).
(Dkk) and sclerostin (SOST) that interfere with the activ-
ity of the lipoprotein receptor-related protein (LRP) co- The adenomatous polyposis coli (APC) protein, which
receptor LRP5/6. These inhibitors play an important role contributes to the cytoplasmic complex that degrades β-
in preventing the proliferation of stem cells until they are catenin in the cytoplasm, is a potent tumour suppressor
required for tissue repair as occurs for the epidermal stem that is frequently mutated in cancer cells and particularly
cells used for the hair follicle cycle (Module 8: Figure epi- in those that develop within the intestine such as colorectal
dermal stem cell). cancer (CRC). Germline mutations of APC are responsible
for familial adenomatous polyposis (FAP). Mutation in the
Wnt inhibitory factor 1 (WIF-1) LRP5 gene, which binds to the Wnt antagonist Dickkopf1
The Wnt inhibitory factor 1 (WIF-1) is a soluble extracel- (DKK1), causes osteoporosis pseudoglioma (OPPG) syn-
lular factor that binds to Wnt and prevents it from inter- drome.
acting with the frizzled receptor (Module 2: Figure Wnt
canonical pathway).
Wnt/planar cell polarity (PCP) pathway
Secreted frizzled-related protein (sFRP)
The secreted frizzled-related protein (sFRP) is a soluble The Wnt/planar cell polarity (PCP) pathway has been
inhibitor that binds to Wnt and prevents it from interacting characterized in insects, where it functions to establish
planar cell polarity (PCP) during development (Module
with the frizzled receptor (Module 2: Figure Wnt canonical 2: Figure Wnt signalling pathways). Just how this path-
pathway).
way functions is still unclear, but there are indications that
Dickkopf (Dkk) it relays information through the Rac signalling mechan-
Dickkopf (Dkk) binds to Kremen and the lipoprotein isms and the Rho signalling mechanism, both of which
receptor-related protein (LRP) co-receptor LRP5/6 and function in the remodelling of actin. The Rho pathway
this causes the complex to internalize and will thus inac- acts through the Rho kinase (ROK) to activate contrac-
tivate Wnt signalling. tion of the actin/myosin system (Module 2: Figure Rho
signalling). These effects on actin remodelling and con-
Sclerostin (SOST) traction may play an important role in planar cell polarity.
Sclerostin (SOST) inhibits Wnt signalling by binding to In vertebrates, there are similar PCP processes such as
the lipoprotein receptor-related protein (LRP) co-receptor neural tube closure, the orientation of hair cell stereociliary
LRP5/6 (Module 2: Figure Wnt canonical pathway). SOST bundles in the ear, mammalian hair follicle orientation and
is produced by the osteoclasts to inhibit the proliferation convergent extension (CE), during which there are large-
and differentiation of the osteoblasts (Module 8: Figure scale movements of cells that occur during gastrulation.
bone cell differentiation). Components of the insect planar cell polarity pathway
Van Buchem disease is causedbyamutation in SOST have also been described in vertebrates, where it includes
that results in excessive activation of the Wnt signalling signalling through Ca 2 + and has thus been referred to as
pathway. the Wnt/Ca 2 + signalling pathway.

Function of canonical Wnt signalling
The canonical Wnt pathway has an important role to play Wnt/Ca 2 + signalling pathway
in regulating processes such as development and prolifer- The Wnt/Ca 2 + signalling system (Module 2: Figure Wnt
ation: signalling pathways) has been implicated in a number of
planar cell polarity (PCP) processes in vertebrates. There
• It functions in dorsoventral specification, as has been are a number of similarities between this signalling path-
shown for amphibia and zebrafish (Module 8: Figure way and the PCP pathway in Drosophila. They both can
dorsoventral specification). activate Rho and contraction of the actin/myosin system.
• It functions in the control of stem cell proliferation The main difference is that the vertebrate system has an ad-
(Module 8: Figure stem cell function). For example, Wnt ditional signalling component in that it can activate Ca 2 +
signalling stimulates the proliferation of epidermal stem signalling. The activation of this Wnt/Ca 2 + signalling
cells during the hair follicle cycle (Module 8: Figure epi- pathway depends upon the frizzled receptor plugging into
dermal stem cell). the inositol 1,4,5-trisphosphate (InsP 3 )/Ca 2 + signalling
• It controls the processes of osteoblastogenesis,which cassette (Module 2: Figure InsP 3 and DAG formation).
is responsible for the development of the bone-forming There are reports that the Ca 2 + signalling events associ-
osteoblasts (Module 8: Figure bone cell differentiation). ated with this pathway may act to inhibit the canonical
• It controls the differentiation of intestinal cells and al- Wnt/catenin pathway during dorsal/ventral axis specific-
terations in its signalling components are a major cause ation (Module 8: Figure dorsoventral specification).

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