14-3-3 Proteins in Normal and Tumour Cell Biology - Therapeutic Strategies in Cancer Biology and Pathology - page 91

beta-catenin association with the multiprotein destruction complex. 14-3-3σ enhanced
Wnt3a-induced β-catenin level. This would possibly suggest a deregulated activation of
Wnt signalling. The expression of 14-3-3ζ has been reported to correlate with tumour
grade and progression to metastasis in NSCLC, in which higher 14-3-3ζ levels also
corresponded with higher β-catenin levels (Zang et al., 2010).
14-3-3 and Hh Signalling
Hh signalling can be distinguished into the canonical and non-canonical systems
which both seem to eventually target genes whose activity or suppression is required
in generating phenotypic outcomes. The canonical pathway involves Gli activation
and the non-canonical SMO-dependent and -independent routes. In the non-canonical
pathway, SMO can activate Gli via PI3K/Akt and MAPK/ERK route or Gli can be
activated by PI3K/Akt independently of SMO (see pp. 35-39). The Gli transcription
factors have been found to bind 14-3-3ε and this reduces their transcription activity.
This interaction requires phosphorylation of Gli by PKA, which is known to nega-
tively regulate Hh (Asaoka et al., 2010).
14-3-3 Proteins Interact with RASSF Signalling
The RASSF (Ras-association domain) gene family has received much attention on
account of frequent methylation and inactivation of its members in many human neo-
plasms. The RASSF pathways of apoptosis signalling have been discussed at length
in a later location (pp. 163-167). The wide diversity of 14-3-3 effects includes inter-
action with RASSF signalling to construct some of its phenotypic outcome.
A mode of involvement of 14-3-3 proteins has been proposed in the regulation
of RASSF1A mediation of apoptosis. 14-3-3σ and 14-3-3ε to a lesser extent are
closely bound to RASSF1A and this association is dissolved upon stimulation by
TNF-α or TRAIL. RASSF1A can now activate apoptosis via TNF-R1 or TRAIL-R1.
Furthermore, phosphorylation of certain serine residues seems to be essential for
RASSF1A to associate with 14-3-3, since mutations at these residues prevent the
association and lead to premature activation of apoptosis. To witness, the presence
of three mutations greatly enhanced apoptosis (Abu Ghazaleh et al., 2010). However,
RASSF can potentially interact with Hippo and Hh signalling, thus vitiating any
attempts to forge a direct link between RASSF and 14-3-3.
Do 14-3-3 Proteins Employ mTOR Signalling?
The mTOR signalling pathway has now pre-eminently associated itself with several
cellular processes such as cell proliferation, growth, apoptosis, angiogenesis, cell
motility and invasion. So its aberrant activation provides cancer cells with a huge