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the ubiquitination and destruction of p53 (Su et al., 2011). This does not in any way
exclude the stabilisation of p53 also by the direct binding of 14-3-3 proteins to spe-
cific C-terminal motifs of p53. Rajagopalan et al. (2010) have identified specific phos-
phorylation sites in p53 which serve as potential 14-3-3 binding sites. Phosphorylation
at these sites facilitated the binding of 14-3-3γ and 14-3-3ε, but not essential for the
binding of 14-3-3σ and 14-3-3τ.
The Function of 14-3-3 via PI3K/Akt Survival Pathway
The 14-3-3 proteins activate the PI3K/Akt survival signalling in many ways. They
have been putatively linked with the activation of PI3K/Akt survival pathway by
direct interaction with the pathway as well in collaboration with non-canonical
SMO-mediated activation of Hh signalling (see Figure 4.1). 14-3-3ζ binds to the
regulatory unit of PI3K and can activate it and promote its translocation to the cell
membrane (Neal et al., 2012a) and in this way generate a response to activated
RTK. Interestingly, these authors have reported the association between 14-3-3ζ
and Akt activation in human breast cancer and linked this with tumour recurrence.
Phosphorylation at Ser-58 is essential for interaction between the two (Powell
et al., 2002). MAPK-activated protein kinase 2 (MAPKAPK2) has also been shown
to phosphorylate 14-3-3ζ (Powell et al., 2003). Interaction with substrates such as
Raf-1 and Bax require phosphorylation at other residues and these phosphoryla-
tions are carried out by casein kinase 1 and JNK, respectively (Dubois et al., 1997;
Tsuruta et al., 2004). The phosphorylated-serine/threonine motifs facilitate the bind-
ing of 14-3-3 to its substrate proteins leading to alteration of their function.
The suppressor gene LKB1 (see pp. 179-194) is said to be a mediator in the activa-
tion by 14-3-3 of Akt. Akt seems to phosphorylate LKB1 at a specific serine residue
and appears to promote 13-3-3 binding to the suppressor and block its growth sup-
pressor function (Liu et al., 2012b). On the other hand, suppression of apoptosis and
promotion of cell survival may be mediated by miRNAs. The Akt survival pathway
is suppressed by miRNA-375 which inhibits PDK1 and prevents Akt activation, lead-
ing to the promotion of apoptosis. In gastric carcinomas, miRNA-375 is downregulated
and this could result in increased cell survival and tumorigenesis. Another reason for
this is the involvement of the anti-apoptosis 14-3-3ζ. Transfection of the miRNA-375
into gastric carcinoma cells inhibited the anti-apoptosis 14-3-3ζ and promoted apop-
tosis (Tsukamoto et al., 2010). Another route to apoptosis via TRAIL (TNF-related
apoptosis-inducing ligand) is also influenced by Akt and 14-3-3. PACS-2 (phospho-
furin acidic cluster sorting protein 2), which mediates apoptosis induced by TRAIL, is
phosphorylated by Akt in collaborative function with 14-3-3 (Aslan et al., 2009).
Growth Factors and Their Receptors in 14-3-3 Function
The signalling of many growth factors and their receptors is modulated by 14-3-3
proteins, among those modulated are the EGFR family, insulin receptor substrate
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