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regulated. For instance, Zhang et al. (2008b) have shown that YAP interacts directly
with and inactivates Lats1 but not Lats2. Suppression of Lats1 mimics the pheno-
typic effects of YAP overexpression. Possibly therefore Hippo signalling is trans-
duced down different sub-routes. Besides, YAP might function in collusion with
many transcriptional regulators such as Smads, Runx2 (Runt-related transcription
factor 2), ErbB4, p53BP-2 (p53 binding protein-2), among others which clearly link
it with cell proliferation and the function of growth factors and activation of EMT.
This reveals the potential of cross talk and switching of signalling sub-routes by
Lats/YAP between Hippo, Wnt, Hedgehog and growth factor signalling and provides
a patently plausible scenario of the interaction of signalling pathways associated
with developmental and pathogenetic processes (see Figure 25.1 ).
Hippo in Cross Talk with Growth Factor Signalling
Members of the TGF-β family transduce their effects through a relatively uncom-
plicated system of two types of receptor, the type I and type II (RI and RII) recep-
tors. These receptors are transmembrane proteins consisting of a ligand-binding
extracellular domain, a transmembrane domain and a cytoplasmic serine/threonine
kinase domain. TGF-β signals are then transduced through the canonical Smad
cascade. Of the Smad family transcription factors, Smad6 and Smad7 inhibit sig-
nalling downstream of TGF-β RI receptors. Smad7 is less discriminatory and can
inhibit signalling via TGF-β RI-related receptors such as BMP type I and activin
receptors (Sherbet, 2011a). Upon cytoplasmic localisation instigated by Hippo,
YAP sequesters Smad complexes and inhibits TGF-β signalling (Varelas et  al.,
2010). Ferrigno et  al. (2002) showed that YAP65 forms a complex with Smad7
and recruits Smad7 to the activated TGF-β receptor type I to inhibit Smad3/4-
dependent gene transactivation by TGF-β. TGF-β signalling is also implicated
by Fujii et  al. (2012) in the induction of CTGF (connective tissue growth factor)
expression and modulating the growth of mesothelioma cells. It may be recalled
here that TGF-β/BMP/Smad signalling also functions via the Runx2 to regulate
cell proliferation. Runx2 is also the effector of Wnt/β-catenin signalling in deter-
mining cells fate and pattern formation in embryonic development. This signalling
pathway involves Groucho4/TLE4 (transducing-like enhancer of split 4) in a com-
plex network of interaction with FGF (Burks et  al., 2009). EGFR-mediated sig-
nalling similarly involves Runx2. EGF/EGFR inhibits osteoblast differentiation not
by its proliferation inducing power but by inhibiting the expression of Runx2 and
osterix in differentiating osteoblasts (Zhu et  al., 2011). To complete the narration
and the direct relevance to Hippo and Wnt interactive signalling, Runx2 associates
with YAP65 and in complex increase anchorage-independent growth more effec-
tively than each component individually (Vitolo et al., 2007).
Direct evidence of EGFR involvement with Hippo is provided by the finding that
YAP-expressing MCF10A breast cancer cells can induce proliferation of neighbour-
ing cells not expressing YAP. YAP seems to target amphiregulin (AREG) gene and
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