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motility, and somewhat less convincingly have argued that cell motility and metas-
tasis of the non-transfected parental melanoma cells were inhibited by treatment
with cell surface heparan sulphate glycosaminoglycans (HSGAGs) derived from
the transfected cells overexpressing NF2. It would be worth noting in this context
that HSGAGs occur ubiquitously in or associated with the ECM. Cellular adhesion,
migration and proliferation responses to HSGAG demand specific ligand-binding
properties of HSGAG, for many ligands such as ECM components and growth fac-
tors may be implicated in HSGAG-mediated cellular responses. Hence much further
investigation of the molecular specificities of the HSGAGs derived from the trans-
fected cells is necessary before one can firmly deduce the significance of these find-
ings. However, a clear link with aggressive tumour behaviour is endorsed by studies
of NF2 expression in breast cancer. NF2 expression is markedly reduced in these
tumour tissues and this occurs in parallel with enhanced expression of osteopontin
(OPN). Here the loss of Merlin seems to have resulted from induced degradation of
the protein by OPN-mediated phosphorylation (Morrow et al., 2011). As discussed
earlier OPN was identified as a metastasis-promoter protein some time ago, with
the convincing demonstration of its association with metastatic progression in a
murine tumour cell model (Oates et al., 1996). OPN expression has generally cor-
related with poor patient survival (Rudland et al., 2002). A mutual regulatory sys-
tem might be operating here. Merlin inhibits PI3K/Akt signalling, whilst Morrow
et al. (2011) have linked OPN with Akt-mediated phosphorylation and degradation
of Merlin. Furthermore, the regulatory link between OPN and Merlin is supported
by the fact that CD44, which acts as an OPN receptor and routes its signals down-
stream, is antagonistic in function to Merlin. Either way OPN negates the function of
Merlin and its negative regulation of growth. So prevention of degradation of Merlin
by PI3K or by inhibition of OPN could be a valuable approach to respond to the deg-
radation and the insidious effects of loss of Merlin.
Kibra in Tumour Suppression
Kibra was identified, isolated and characterised as a cytoskeletal protein possessing
two amino-terminal WW domains, an internal C-2-like domain and a carboxyl-ter-
minal glutamic acid-rich stretch (Kremerskothen et al., 2003). WW-domain proteins
participate in cohering together proteins into physiologically important network by
specific binding to proline-rich motifs but inter-protein interactions might be more
discriminatory since WW domains within the same protein might possess different
specificities towards potential interacting proteins (Ingham et al., 2005). Kibra has
been implicated in memory dysfunction and genetic alterations of the Kibra gene
have been associated with Alzheimer's disease. It has been linked with failure of
mammary development. Its notoriety has risen with its recognition and increasing
appreciation as an upstream regulator of the Hippo system with a distinctive role of
regulating cell proliferation and disease processes. At the molecular level, function
of Kibra seems to be regulated by phosphorylation. Buther et al. (2004) reported that
Kibra was a target of phosphorylation, for example by PKCζ. Recently phosphoryla-
tion of Kibra by mitotic Aurora kinase in conjunction with cell cycle progression has
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