The Essence of the Hippo Signalling System - Therapeutic Strategies in Cancer Biology and Pathology - page 136

MST1 and MST2 to Lats. YAP and TAZ possess WW domains composed of mod-
ules with 38-40 amino acid residues that may be required for interaction with other
proteins with proline-rich motifs (see pawsonlab.mshri.on.ca ; Hergovich, 2012).
Lats2 phosphorylates YAP and leads to its cytoplasmic translocation and inactiva-
tion and so interferes with the expression of genes relevant to the processes of cell
proliferation or apoptosis. On the other hand, inhibition of phosphorylation results
in the promotion of growth (Zhao et al., 2007a). The deregulation of Hippo is evi-
dent from the increased expression of YAP in HCC cells and inhibition of YAP using
siRNA reduces cell survival (Li et al., 2012c). Lats has also been shown to phos-
phorylate TAZ, lead to its retention in the cytoplasm and inactivation. Also ectopi-
cally expressed TAZ induces cell proliferation and activates EMT (Lei et al., 2008).
These findings are confirmed overall by Zhou et al. (2011c) who showed that TAZ is
overexpressed in NSCLC cells and forced overexpression in experimental situations
induces cell proliferation and transformation ( Figure 25.1 ).
Mats (the Mob as tumour suppressor) also acts as a co-activator of Lats (Lai
et al., 2005). Overexpression of the human homologue Mob1 inhibits proliferation
and induces apoptosis of MCF-7 and HeLa cells. Several human isoforms of Mob
have been identified. These display tissue specific expression but the significance of
this is unclear at present. Only Mob1A and Mob1b feature in interactions with Lats
(Chow et al., 2010). Mutation or inactivation of Mobs does occur in human cancers
and these naturally affect Lats and YAP.
The attribution of tumour suppressor property of Lats has flowed from the
reported loss of heterozygosity, promoter methylation and mutations of the gene
reported in human tumours. In certain tumour types, genetic polymorphism has
been encountered but mutations might be infrequent (Hansen et al., 2002; Hisaoka
et al., 2002; Ishizaki et al., 2002). Furthermore, Lats genes might be differentially

RASSF1A Ras/ERK

Hedgehog Hippo/Salvador

Lats/Mats

p53

Wnt

YAP/Yorkie
TA Z

Phenotypic effects
Morphogenesis EMT Cell proliferation/growth

Figure 25.1 Several pathways intersect with the Lats/YAP axis in determining phenotypic
effect of morphogenesis, cell transformation, cell proliferation and EMT. Many upstream
modulators of Hippo are known to subserve tumour suppressor function. Note that ectopically
expressed TAZ promotes EMT, but it is sequestered in the cytoplasm by phosphorylation by
Lats and inactivated. Here only RASSF1A is shown. This figure is based on references cited
in the text.