Diacylglycerol Signaling

4 Diacylglycerol Signaling
4.3 DAG Receptors and Oncogenesis
Since the early identification of the PKCs as intracellular receptor for the tumor
promoting phorbol esters (Kikkawa et al. 1983), the role of DAG in the context of
oncogenesis has been extensively investigated. After several years of intensive
research, it is now generally accepted that each of the ten existing PKC isoforms
contribute differently to cancer development and progression. Among the multiple
PKC family members, several isoforms have tissue specific and even opposite role in
tumor initiation. An example is PKCd, proposed as an antiproliferative molecule
in animal models of skin cancer (Reddig et al. 1999), whereas other authors report
a role for this isoform in the survival of breast and lung cancer (Clark et al. 2003;
McCracken et al. 2003; Grossoni et al. 2007). PKCa has been reported as a mediator
of cell proliferation in head and neck cancer cell lines and also a predictive biomarker
for disease free survival in head and neck cancer patients (Cohen et al. 2009).
From the initial studies, PKCe emerged as a protein with clear oncogenic properties
(Cacace et al. 1993). PKCe overexpression is associated with oncogenesis
from multiple organ sites, including breast, lung, prostate and head and neck (Bae
et al. 2007; Cornford et al. 1999; Martinez-Gimeno et al. 1995; Pan et al. 2005).
Albeit the exact etiology of PKCe overexpression remains to be fully elucidated, it
is clear that this isoform is emerging through the literature as an important biomarker
and potential drug target for many cancer types (Gorin and Pan 2009).
The characterization of nonkinase receptors for DAG has further extended the
possible mechanisms by which this lipid second messenger can exert its functions.
The characterization of a family of exchange factors for Ras family GTPases
containing a conserved C1 domain directly couples elevation of DAG membrane
levels with Ras activation. These proteins are designated RasGRP (Ras guanine
releasing proteins) or CalDAG-GEF (calcium and DAG regulated guanine nucleotide
exchange factors). The high expression of RasGRP family members in
hematopoietic and nervous system suggest the existence of tissue specificity for
DAG-mediated Ras activation. RasGRP2/CalDAG-GEF 1, which primarily targets
Rap1 and Rap2 and is related to the regulation of integrin-mediated adhesion, has
also been identified as a leukemogenic protooncogene in a murine model (Dupuy
et al. 2001). A role for CalDAG-GEF1 as an oncogene in human hematologic
malignancies has not been demonstrated, but the human RasGRP2 locus has been
found to be differentially expressed in lymphoma cells of patients, where the disease
progressed from low-grade follicular lymphoma to aggressive diffuse large cell
lymphoma (Martinez-Climent et al. 2003).
A third family of DAG receptors is represented by the chimaerins, a family of
GTPase-activating protein (GAPs) also regulated by DAG. Mammalian genomes
contain two chimaerin loci, each of which produces at least two splice variants: a
full length transcript (a2 and b2-chimaerin respectively) and a truncated transcript
(a1 and b1-) that lacks the N-terminal SH2 domain (Hall et al. 2001). Recent studies
have implicated b2-chimaerin as a tumor suppressor. Levels of this protein are
reduced in multiple types of cancer, including breast tumors and malignant gliomas
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