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increase its expression and AREG seems to promote cell proliferation via activation
of EGFR (Zhang et al., 2009b). It may be noted here that AREG participates in cell
proliferation and adhesion-related biological function, namely cell motility and inva-
sion. There is ample evidence that AREG is aberrantly expressed in many human
neoplasms and AREG expression correlates with both in disease progression and
prognosis (Sherbet, 2011a). Of much interest is the induction of CTGF by AREG
and HB-EGF that activate EGFR. This was dependent upon YAP. Also this study has
identified elements in the CTGF promoter that binds to YAP complexes (Urtasun
et al., 2011).
Hippo Interacts with the Wnt Signalling System
The activation of Wnt signalling begins with the binding of Wnt proteins to the
Frizzled family of protein receptors and co-receptors. Many Wnt ligands are known.
These bind to its receptor Frizzled or Frizzled and LRP5/6complex and the signal
is transduced to the cytoplasmic hosphoprotein DVL (Dishevelled), which in turn
relays the signal to non-canonical and the canonical β-catenin pathway. β-Catenin is
localised in the membrane as a part of a multi-protein complex. The ligand/receptor
complex releases β-catenin from the Axin/APC/GSK3 complex. In the absence of
Wnt, GSK3 (glycogen synthase kinase-3β) phosphorylates β-catenin leading to its
degradation and TCF forms a repressor complex with the transcriptional repressor
Groucho and HDAC to inhibit target gene transcription. With the activation of Wnt
signalling, GSK3 is inactivated and unphosphorylated β-catenin accumulates, enters
the nucleus and displaces Groucho from its binding to TCF and the complex turns
into an activator transcription complex and transcribes the target genes (Habas and
Dawid, 2005; Sherbet, 2011a).
YAP has been viewed as a co-ordinator of cross talk between Hippo and Wnt.
Xin et  al. (2011) found that YAP inhibition suppressed proliferation of murine car-
diomyocytes, whilst active YAP produced the opposite effect. They further showed
that YAP can function via the IGF pathway, inactivate GSK3 and promote accumu-
lation of β-catenin, clearly suggesting an interaction with Wnt signalling. YAP and
TAZ have been found to be able to bind to and interfere with nuclear translocation of
β-catenin thus blocking Wnt signalling. Hippo kinases phosphorylate YAP inducing
its translocation to the cytoplasm thus assisting the sequestration of β-catenin in the
cytoplasm and aiding the inhibition of Wnt/β-catenin signalling (Imajo et al., 2012).
Not only this, but β-catenin/TCF4 complexes bind to an enhancer element within the
first intron of the YAP gene and induce YAP expression (Konsavage et  al., 2012).
On the other hand, YAP-mediated promotion of cell proliferation and inhibition of
neuronal differentiation intersects with Sonic Hh signalling rather than Wnt (Lin
et  al., 2012). How YAP might switch signalling in this way is yet to be elucidated.
The subtlety of the Hippo system is explained by the possibility that the loss of any
one signalling component is compensated by the activation of another component
(Hergovich, 2012). So it is conceivable that a similar compensatory activation of one
or more interacting signalling systems might occur.
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