Diacylglycerol Signaling

13 PKCs as Mediators of the Hedgehog and Wnt Signaling Pathways
Dishevelled
Axin
APC GSK-3
β-catenin
Wnt target genes
β-cat
TCF
LRP5/6
Wnt
FRIZZLED
Dishevelled
Daam1
Rho Cdc42
JNK
Go protein
Cytoskeletal changes
transcriptional activator (Clevers 2006). A negative regulatory step at the level of
the TCF/b-catenin complex is the phosphorylation of TCF by the MAP kinaserelated
protein kinase NLK/Nemo, which reduces the complex affinity for DNA
and, therefore, inhibits the expression of Wnt target genes (Ishitani et al. 1999).
The Wnt target genes regulated by the b-catenin/TCF complex are cell-type
specific. The most relevant for cancer progression are c-myc and cyclin D1, which
are shared with the Hh pathway. The most ubiquitous Wnt target genes, frequently
used to evaluate the degree of the canonical pathway activation, are Axin2 and SP5
(Clevers 2006). Wnt signaling is regulated by an autoinhibitory loop, since the
expression of negative regulators such as Fzs, LRPs, HSPGs, Axin2, and TCF/Lef
are all controlled by the b-catenin/TCF complex.
13.4.3 Canonical Wnt Signaling in Cancer
The role of Wnt signaling in cancer was first evidenced by the finding of a recessive
mutation of the APC gene in the hereditary cancer syndrome Familiar Adenomatous
Polyposis (FAP) (Kinzler et al. 1991; Nishisho et al. 1991). FAP patients develop
PLC
PKC
Ca 2+
CamKII
WNT/β-catenin WNT/PCP WNT/Calcium
Fig. 13.3 The Wnt signaling pathway. Binding of Wnt ligands to Frizzled receptors and LRP5/6
co-receptor activates the Wnt canonical pathway (Wnt/b-catenin); while LRP5/6 is not engaged for
activation of the non-canonical Wnt pathways (Wnt/PCP and Wnt/Calcium). Abbreviations: APC,
Adenomatous Polyposis Coli; TCF, T cell factor; JNK, c-Jun N-terminal kinase; PLC, phospholipase
C; PKC, protein kinase C; GSK-3, glycogen synthase kinase 3; PCP, planar cell polarity
277