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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 110

Module 2: Figure Wnt canonical pathway

LRP5/6 LRP5/6 WIF1 Wnt 5 WIF1
SOST Dkk1 Wnt CRD SFRP
CRD SFRP Wnt
Kremen Fz LRP5/6 Fz

CKI CKI P Dsh P P
P P
Dsh
6 Axin
Proteasome GSK3 CKI
P P P APC
P -catenin APC B P
3 A PP2A
Axin B A Amino
Amino -catenin protein GSK3 acids
acids synthesis and 2 -catenin PP2A 7 -catenin
degradation cycle CKI Protein -catenin accumulates and
synthesis -catenin translocates into
-catenin -catenin the nucleus
Protein 1 degradation -catenin
synthesis -catenin complex
8 9
HDAC
4 Wnt
p300
-catenin genes
TCF
LEF-1
Ac Ac Ac Ac Ac TCF
LEF-1
Deacetylation
Acetylation
The canonical Wnt/β-catenin signalling pathway.
The primary function of this signalling pathway is to regulate the activity of β-catenin, which controls transcription of the Wnt genes. The left-hand
panel illustrates the resting condition where the cytosolic level of β-catenin is kept low by its continuous degradation. In response to the arrival of Wnt
(as shown on the right), this degradation is inhibited and the level of β-catenin rises enabling it to induce the transcription of the Wnt genes.

6. The LRP5/6 co-receptor is then phosphorylated by ative effects that characterize the operation of the Wnt
membrane-bound casein kinase Iγ (CKIγ) isoform, signalling pathway.
which adds phosphates to multiple sites that have
PPPSP motifs. Some of these motifs are also phos- In summary, the Wnt signalling pathway acts by switch-
phorylated by a membrane-associated GSK-3β.These ing off the GSK-3β-dependent degradation pathway, thus
phosphorylated motifs then provide binding sites for enabling β-catenin to accumulate in the cytosol and to
the attachment of the scaffolding protein axin. Another enter the nucleus to activate transcription of the Wnt tar-
key event is the binding of Dishevelled (Dsh),which get genes.
is another scaffolding protein containing various signal
transduction domains (e.g. DIX, PDZ and DEP). Dsh
becomes hyperphosphorylated by an unknown mech- Low density lipoprotein (LDL) receptor-related
anism and this contributes to its role in inhibiting the protein family (LRP)
degradation complex. Axin and Dsh also bind to each Members of the low-density lipoprotein (LDL) receptor
other through their DIX domains. As the multiprotein superfamily are cell-surface proteins with multiple func-
complex associates with the membrane, the organiza- tions. The LDL receptor-related protein (LRP) family has
tion of the subunits is altered so that the activity of multiple members (LRP1--6, LRP8, LRP10--12) with mul-
GSK-3β is inhibited, thus reducing the degradation of tiple functions:
β-catenin. Loss-of-function mutations of LRP5 have
been linked to osteoporosis pseudoglioma (OPPG). • LRP11 is an endocytic receptor for apolipoprotein E
7. When GSK-3β is inhibited, the newly synthesized β- (ApoE), which plays an important role in the onset of
catenin is stabilized and accumulates within the cyto- Alzheimer’s disease (AD) (Module 12: Figure amyloid
plasm, from where it can enter the nucleus to activate cascade hypothesis).
transcription. • LRP5 and LRP6 function as co-receptors in the ca-
8. β-Catenin binds to LEF-1 and TCF to reduce their nonical Wnt/β-catenin pathway (Module 2: Figure
repressor activity to initiate the transcription of the Wnt Wnt canonical pathway). Mutations in LRP5 can cause
genes. β-Catenin replaces HDAC with p300, which either extremely high or low bone mass traits. A high
facilitates transcription by acetylating histones to re- bone mass syndrome (HBM) is caused by gain-of-
model chromatin. function mutations of LRP5. On the other hand, loss-
9. Activation of transcription of the Wnt target genes res- of-function LRP5 mutations are linked to osteoporosis
ults in the activation of the developmental and prolifer- pseudoglioma (OPPG).

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