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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 109

Module 2: Figure Wnt signalling pathways

2+
Canonical Wnt/catenin pathway Wnt/planar cell polarity pathway Wnt/Ca signalling pathway
Wnt
? Wnt5A,11
CRD CRD CRD Wnt
Wnt
Fz Fz Fz2, Fz6
PtdIns4,5P 2
PLC
Dsh Dsh Dsh
LRP5/6
DAAM1
InsP DAG
3
-catenin Rac Rho
? Ca 2+ PKC
JNK ROK
CaMKII
NFAT
p300 Wnt
-catenin genes
P
Myosin II
LEF-1 TCF

Summary of the signalling mechanisms used by the canonical and non-canonical Wnt signalling pathways.
All three signalling pathways are activated by frizzled (Fz) receptors that depend upon the dishevelled protein (Dsh) as part of the transduction
mechanism to transfer information into the cell. Most is known about the canonical Wnt/β-catenin pathway (Module 2: Figure Wnt canonical pathway)
with less information on the two non-canonical pathways. In the Wnt/planar cell polarity (PCP) pathway, Dsh transfers information to the small GTP-
binding proteins Rho and Rac. The Wnt/Ca 2 + signalling pathway is connected to the dishevelled-associated activator of morphogenesis 1 (DAAM1),
which relays information to the Rho pathway. In addition, Dsh also relays information to phospholipase C (PLC) to produce InsP 3 and diacylglycerol
(DAG).

Canonical Wnt/β-catenin pathway gradation complex, the GSK-3β phosphorylates β-
The defining feature of the canonical Wnt/β-catenin path- catenin and thus targets it for destruction by the pro-
way is the transcription factor β-catenin, which is respons- teasome. Before β-catenin can be phosphorylated by
ible for regulating the transcription of Wnt target genes GSK-3β it must first be primed by phosphorylat-
(Module 2: Figure Wnt canonical pathway). However, this ingSer-45by casein kinase Iα (CKIα). PP2A, which
is not the sole function of β-catenin, which also functions consists of a scaffolding A subunit and a regulat-
as a scaffolding protein in cell adhesion by providing a link ory B subunit (Module 5: Figure PP2A holoenzyme),
between cadherin and the actin cytoskeleton. Here we con- may inactivate the complex by dephosporylating
sider how β-catenin functions in Wnt signalling to regulate GSK-3β.
gene transcription. There are a number of transcription 3. The phosphorylated β-catenin is recognized by the F-
factor activation mechanisms,and β-catenin belongs to box/β-TrCP/ubiquitin ligase complex, which targets it
those that depend on cell-surface receptors that generate for destruction by the proteasome.
cytosolic signals to activate latent transcription factors in 4. In the absence of β-catenin, the monomeric high-
the cytoplasm, which are then imported into the nucleus mobility group (HMG) DNA-binding proteins lymph-
(Mechanism 2 in Module 4: Figure transcription factor ac- ocyte enhancer factor-1 (LEF-1) and T cell factor
tivation). In the case of β-catenin, its cytosolic level is kept (TCF) inhibit the transcription of Wnt genes. An addi-
low because it is constantly being degraded by the pro- tional component of this repressor complex is histone
teasome as shown in the sequence of events shown in the deacetylase (HDAC), which prevents chromatin re-
left-hand panel in Module 2: Figure Wnt canonical path- modelling through histone deacetylation. Wnt acts to
way: inhibit the destruction of β-catenin, which then accu-
mulates in the cytoplasm and can enter the nucleus to
1. Formation of β-catenin by protein synthesis occurs promote transcription as shown in the right-hand panel
continuously. in Module 2: Figure Wnt canonical pathway.
2. β-Catenin is drawn into a β-catenin degradation com- 5. Wnt initiates the signalling process by binding together
plex, which consists of the scaffolding protein axin, two cell-surface proteins: it binds to the cysteine-rich
which binds the adenomatous polyposis coli (APC) domain (CRD) of the frizzled (Fz) receptor and it
tumour suppressor,the protein phosphatase PP2A, also draws in the Fz co-receptor LRP5 and LRP6
casein kinase Iα (CKIα), glycogen synthase kinase-3β (LRP5/6), which are members of the low-density lipo-
(GSK-3β) and β-catenin. Within this multiprotein de- protein (LDL) receptor superfamily.

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