The Essence of the Hippo Signalling System - Therapeutic Strategies in Cancer Biology and Pathology - page 140

(Visser-Grieve et al., 2012). NF2 is mutated in many cancers. The presence of inac-
tivating mutations and LOH has suggested that it is a tumour suppressor. Merlin
participates in several cellular functions such as intercellular and cell-substratum
interaction and adhesion, regulation of cell proliferation and apoptosis. This it does
by virtue of functioning as a link between ECM receptors such as CD44, integrins
and the actin cytoskeleton and by regulating the function of a number of RTKs and
so modulating growth factor signalling, thus integrating ligand binding, cell adhe-
sion and motility and cell proliferation and survival with tumour development. The
suppressor function of Merlin seems to derive from its molecular configuration. It
assumes a closed conformation as a result of head-to-tail association of the molecule.
An open-configured protein results from the phosphorylation of certain C-terminal
amino acid residues. In the folded conformation, Merlin exerts its inhibitory activ-
ity. But it is a target of several kinases, including PKA, PAK1 and PAK2, and the
anti-apoptotic PIKE (phosphoinositide-3-kinase enhancers), which binds and acti-
vates Akt. Akt phosphorylates Merlin, abolishes the folded conformation and renders
it liable to ubiquitination and proteasome degradation (Stamenkovic and Yu, 2010;
Ye, 2007). Subcellular disposition of Merlin is also a possible cause of modulation
of function. PAK2-mediated phosphorylation alters its cellular location (Kissil et al.,
2002). An interesting observation of relevance is the report by Zhou et al. (2011a)
that active Merlin localises Wnt/β-catenin at the cell membrane which renders the
proliferative signalling by Wnt ineffective.
Merlin is an upstream regulator of Hippo signalling. Suppression of Merlin leads
to enhanced organ growth and eventually to tumorigenesis. It regulates the Hippo
kinases MST1 and MST2, activation of Lats and inactivation of YAP. Merlin has also
been attributed with the ability to suppress Ras mediation of cell transformation by
modulating the disposition or suppressing the functions of downstream effectors of
the Ras cascade. It is said to be able to suppress Ras/Rac activation or stop the trans-
location of Rac to the plasma membrane and in this way contact inhibition of growth
(Okada et al., 2005). Equally, it may be as Shaw et al. (2001) found Rac induced the
phosphorylation of Merlin and reduced its association with the cytoskeleton. STAT3
and STAT5 signalling is also enhanced in the background of mutated NF2, whilst
wild-type NF2 negatively regulates mTORC1 signalling (Stamenkovic and Yu, 2010;
Figure 3.1). Merlin has been shown to inhibit the MAP3K kinase MLK3 together
with the inactivation of B-Raf/ERK/JNK pathway thus potentially linking its sup-
pressor function with the inhibition of this pathway and Rho GTPase signalling
(Zhan et al., 2011).
That Merlin produces changes in the ECM and ECM-mediated function of the
cell is established on a reasonable basis. Lallemand et al. (2003) showed some years
ago that loss of Merlin led to the deregulation of contact-mediated growth arrest
and destabilised cell-to-cell adhesive contacts, which could potentially have led to
enhanced cell motility. Merlin might inhibit cell invasion by suppressing the function
of FAKs (Poulikakos et al., 2006). More recently, Galcheva-Gargova et al. (2008)
transfected NF2 into B16 melanoma cells with metastasising ability and found
the transfectants overexpressing NF2 showed reduced metastatic spread in murine
models. They also noticed alterations in growth properties in soft agar and in vitro