Diacylglycerol Signaling

68 I. Mérida et al.
Different lines of evidence suggest that prevention of apoptosis is due to the
participation of DGKa in NF-kB activation. The exact mechanisms linking DGKa
activity and NFkB activation remain undefined, but the lack of effect of a kinase dead
enzyme suggests a role depending either on DAG generation and/or lack of PA.
The specific role of DGKa and not other type I enzymes suggest a role for this
particular isoform in the prevention of apoptosis. The recent characterization of
the regulation of DGKa by Src-dependent phosphorylation (Baldanzi et al. 2008)
suggests that the regulation of DGKa by Src kinases could be important for the
NF-KB activation and prevention of apoptosis. A role for c-Src as positive regulator
of TNF-a-mediated NF-kB activation was recently reported in endothelial cells
(Itoh et al. 2005). Thus, the association/activation of DGK with c-Src may be critical
for the activation of DGKa leading to the prevention of apoptosis. The blockade of
NF-kB activity in several cancer cells is related to the suppression of carcinogenesis
and metastasis, suggesting that the manipulation of DGKa activity could be of
interest in the treatment of other malignancies.
Studies in the anaplastic large cell lymphoma (ALCL) Karpas also reveal high
constitutive DGKa activity (Bacchiocchi et al. 2005). Pharmacological inhibition
of DGKa impairs the growth rate of NPM/ALK cells as well as the EGF-dependent
growth of cells expressing a chimeric EGFR/ALK receptor, identifying DGKa as
a possible therapeutic target in the treatment of ALCL lymphomas.
The function of DGKa as a positive regulator of cell proliferation was first
described in T cell lines showing that the low levels of DGKa activity in activated
T cells appear to be required for IL-2-mediated G1-S transition (Flores et al. 1999).
The inhibitory properties of the DGKa inhibitor R59459 in IL-2-dependent proliferation
of the lymphocyte cell line CTLL-2 were similar to those of rapamycin,
implying that both drugs act on the same pathway. Accordingly, rapamycin has
been proposed to inhibit mTOR by blocking PA-dependent activation of this protein
(Foster 2009). A role for DGKa as a positive modulator of cell cycle progression and
migration are not specific of T lymphocytes and has also been described for other
tyrosine kinase receptors. Experiments in endothelial cells demonstrated that
activation of DGKa in response to activation of tyrosine kinase receptors vascular
endothelial growth factor (VEGF) receptor-2 is required for ligand-induced
chemotaxis, proliferation and angiogenesis (Baldanzi et al. 2004). A similar role for
DGKa is required for HGF-induced cell motility and proliferation in endothelial
and epithelial cells (Cutrupi et al. 2000). The requirement for DGKa in the correct
transduction of VEGF and HGF receptor-dependent signals appears to be a direct
consequence of the interaction between DGKa and Src family kinases. The DGKa
carboxy-terminus can bind Src kinases, and in this case, there are two nonmutually
exclusive options. DGKa protein can act as a scaffold, maintaining the tyrosine
kinases in an appropriate conformation for activation, or DGKa might either generate
or metabolize a lipid needed to inhibit a phosphatase activity. Attenuation of
DGKa expression and/or function by different mechanisms has been shown to
impair both HGF and v-Src-induced cell scatter and migration, further demonstrating
a connection between Src kinases, DGKa and HGF-mediated signals. DGKa inhibition
results in uncoupling the downregulation of E-cadherin-mediated intercellular