Is MKK a Metastasis Suppressor? - Therapeutic Strategies in Cancer Biology and Pathology - page 119

isoforms have been identified; two of them are transmembrane proteins with the von
Willebrand factor I adhesion motif and the third isoform contains only the extracel-
lular domain and could be the secreted form (Bradley et al., 2001; Scobie and Young,
2005).
The receptors might also function synergistically in endocytosing LeTx
(Martchenko et al., 2010). The latter cleaves and inactivates MEKs and inhibits
p44/p42 MAPK (ERK1 and ERK2), p38 MAPK and the JNK arm of the MAPK
pathway (Chopra et al., 2003; Duesbery et al., 1998; Young and Collier, 2007).
LeTx and Cell Invasion/Motility
LeTx inhibits two basic traits of the cancer cell, that is migratory behaviour and
its ability to induce neovasculature. It appears to modify the cytoskeletal machin-
ery, alter junction complexes and focal adhesions. These alterations might inhibit
cell motility (Lehmann et al., 2009). It appears from a recent report that the oedema
factor, namely adenylate cyclase might remove and internalise integrins from the
cell surface and reduce cell adhesion (Martín et al., 2011). This is bound to have
consequences for cell invasion. LeTx increases actin stress fibres and also vascu-
lar endothelial cadherin (VE-cadherin) distribution (Warfel et al., 2005). Normally
VE-cadherin is selectively localised at intercellular contact points and forms adhe-
sive dimeric bridges between monomers on the cell-cell contact surfaces (Brasch
et al., 2011). Interestingly, LeTx seems able to bind to LRP6 and activate Wnt sig-
nalling as indicated by the nuclear accumulation of β-catenin. SiRNA mediated sup-
pression of both CMG2 and TEM8 receptors inhibited Wnt signalling (Abrami et al.,
2008). Wnt signalling has been closely implicated in the activation of EMT. It seems
eminently worthwhile to investigate if LeTx does indeed activate EMT. There is no
direct evidence of this at present. But it would be well to remember that LeTx has
been shown to inhibit Akt signalling and also inhibit E-cadherin mediated intercel-
lular adhesion and promote cell motility (Popova et al., 2009). Further elucidation
is required here of the mechanism involved, for one would recall that growth fac-
tors are known to induce cell migration by activating Akt signalling. But there are no
indications that LeTx alters the E-cadherin negative regulatory transcription factors.
LeTx Inhibits Angiogenesis
More important is the suppression of angiogenesis, which is an essential requirement
of metastasis. Ras mediated transformation of murine 3T3 fibroblasts upregulates
VEGF apparently by the intervention of MKK1 (Rak et al., 2000). As mentioned
above, LeTx (lethal factor) is a Zn 2+ -dependent MMP that cleaves and inactivates
most isoforms of MKKs. LeTx mediated inactivation of MKK signalling reduces
angiogenesis in tumours. It seems able to block the release of VEGF by endothe-
lial cells. Intravenous administration of LeTx reduced growth of tumour xenografts
together with loss of VEGF and VEGFR and reductions in microvessel density