14-3-3 Proteins in Normal and Tumour Cell Biology - Therapeutic Strategies in Cancer Biology and Pathology - page 92

proliferative and invasive advantage and this contributes significantly to the process
of cancer metastasis. Several cellular functions, such as growth factor function, cell
proliferation, angiogenesis, response to hypoxia among others, see the participation
of mTOR (see Figure 3.1) signalling. Inevitably a link-up of 14-3-3 proteins with
mTOR signalling has also been sought. It has been proposed that14-3-3σ might
regulate the mTOR-RAPTOR signalling cascade. An inverse relationship has been
noticed in the expression of 14-3-3σ and mTOR activation in prostate cancer (Evren
et al., 2011). However mTOR signalling is also influenced by Wnt activation and as
noted earlier, there are suggested links of14-3-3σ with the Wnt pathway.
Effects of 14-3-3 Proteins on Cell Motility and Invasion
14-3-3 proteins influence cell motility and cell shape and cytokinesis among other
biological features by having recourse to Rac (Rac GTPase-activating protein)-1,
Cdc42 and other Rho-GTPases-mediated modulation of cytoskeletal dynamics.
14-3-3 proteins regulate cytoskeletal reorganisation and the interaction between
ECM components and the cytoskeletal machinery to bring about the phenotype of
invasion and motility.
14-3-3ζ has been reported to promote cell motility and diapedetic behaviour of
prostate carcinoma PC3 cell by activating the Rac signalling pathway. Mutants of
14-3-3ζ that are unable to form dimers inhibited Rac function and PAK1 and PAK2
activity (Goc et al., 2012). In certain cell lines, for example the lung fibroblast
IMR-90 cell line, MMP-1 is produced in response to 14-3-3α and 14-3-3β but not to
14-3-σ (Asdaghi et al., 2012). It seems possible therefore that 14-3-3σ has no effect
on cell migration unlike other 14-3-3s because of its inability to generate MMPs.
Some interesting cross connections have emerged recently from the work of Yoon
et al. (2012) who studied the cytoskeletal dynamics of Xenopus retinal ganglion
cell axon elongation. They noted that expression of 14-3-3ζ transcripts and pro-
teins in retinal growth cones was greater during the phase of rapid axonal extension.
Inhibition of 14-3-3 (all isoforms)/14-3-3ζ expression resulted in a marked diminu-
tion of axonal length. They also found that 14-3-3ζ co-localised with cofilin in the
growth cones and cofilin is an essential requirement for axon growth of neurons.
Now cofilin is a plasma membrane associated protein, promotes actin-depolymerisa-
tion, but primarily it is an F-actin binding protein. Its activity and subcellular locali-
sation is regulated by phosphorylation (Bamburg, 1999). Phosphorylated inactive
cofilin does inhibit cell migration (Popow-Wozniak et al., 2012). LIM kinase regu-
lates cofilin activity and is itself activated by Rho GTPases, namely Rho, Rac and
Cdc42, which are closely associated with cytoskeletal dynamics.
Therapeutic Approach with 14-3-3
With the broad spectrum of biological effects and the known ability to activate
and participate in several signalling systems, the 14-3-3 proteins have been often