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MEK/ERK signalling via the PI3K/Akt cascade (Laprise et al., 2004). But then MEK/
ERK signalling might itself involve the Rho system. Pullikuth and Catlin (2010)
showed ERK functions through the agency of p190A Rho-GAP in activating fibronec-
tin-mediated focal adhesion and spreading of cells. The expressions of E-cadherin and
fibronectin are closely linked in EMT. For, EMT induced by TGF-β is associated with
increased fibronectin expression and loss of E-cadherin (Doherty et al., 2006) and
E-cadherin is known to inhibit fibronectin expression (Solanas et al., 2008).
DLC1 induced enhancement of E-cadherin suppresses the migratory ability of
cells. The suppressor function of DLCs is due to their Rho-GAP activity negatively
regulating RhoA, RhoB, RhoC and to a limited extent cdc42 (Healy et al., 2008;
Tripathi et al., 2013). In NSCLC cells, E-cadherin expression has been linked with
a reduction in the activity of Rho family proteins, RhoA and Cdc42. Reduction in
RhoA required DLC1 and p190 Rho-GAP and was associated with an increase in a
membrane-associated p190 Rho-GAP/p120 Ras-GAP complex in which p190 Rho-
GAP is activated by binding to p120 Ras-GAP. Extracellular signals seem to elicit
responses from Rho GTPases in the form of actin cytoskeletal rearrangements and
p190 Rho-GAP regulates Rho which mediates cell adhesive interactions.
Tensin appears to have some bearing on DLC function. As one might recall
that tensin binds to actin filaments via a PTB (phosphotyrosine-binding) domain
to the cytoplasmic tail of integrins thus establishing a link between integrin recep-
tors and the actin cytoskeleton (Lo, 2004), which might thus influence cell motility.
Besides, loss of tensin has been suggested to lead to tumorigenesis (Martuszewska
et al., 2009). Both DLC1 and DLC3 bind to human tensin1, the binding being medi-
ated by the SH2 (Src homology 2) and PTB domains of tensin proteins and specific
sequences of the DLC protein. DLC1 is said to compete with other cytoskeleton
modulators such as integrins for binding to tensin (Qian et al., 2007b). This has
raised the possibility that DLC1 might have recourse to a mode of function inde-
pendent of its Rho function. Equally DLCs might be recruited to membrane recep-
tors in this way to alter cell motility. Stress fibres play an important role in cell
adhesion and motility by constant modulation of the actin cytoskeleton and we know
that DLC overexpression leads to the dis-assembly of stress fibres (Kim et al., 2007).
DLC Expression in Metastatic Spread
There is much evidence that loss of expression of the DLC genes whether experi-
mentally contrived or occurring naturally does affect cell migration and metasta-
ses
in vivo
tumour models. However we have only a limited amount of information
about how this expression relates to the aggressive behaviour of human tumours
and whether the degree of expression of either DLC gene might offer information
about the potential for metastasis. Ullmannova and Popescu (2006) investigated the
expression of DLC genes in many human tumours and noticed reduced expression in
between 60% and 90% of tumour specimens. They were underexpressed in samples
of primary ductal breast cancers from patients with regional lymph node metastases.
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