Diacylglycerol Signaling

3 Phorbol Esters and Diacylglycerol: The PKC Activators
DAG
PKCs PKDs RasGRPs Chimaerins MRCK Munc13s DGKs
cPKCs nPKCs
α, βI, βII,γ ε, η, θ, δ
PKD1
PKD2
PKD3
RasGRP1
RasGRP3
RasGRP4
Alpha1
Alpha2
Beta 1
Beta 2
Alpha
Beta
Gamma
Munc13-1
Munc13-2
Munc13-3
An additional six families of signaling proteins are now known (Fig. 3.1). The PKD
isoforms (PKD1, 2, 3) are kinases with distinct specificity from that of the PKCs
(Wang 2006). The chimaerins (a1, a2, b1, b2) are GTPase activating proteins for
Rac (Yang and Kazanietz 2007). The RasGRP family members (RasGRP1, 3, and
4 are DAG/phorbol ester responsive) are guanyl nucleotide exchange factors for
various members of the Ras and Rap families (Stone 2006). The MRCK isoforms
(a, b, g) are effectors of the Rho family member Cdc42 (Leung et al. 1998; Choi
et al. 2008). The Munc-13 isoforms (Munc13-1, -2, -3) promote priming for vesicle
fusion (Silinsky and Searl 2003). Finally, several of the DAG kinase isoforms
respond to DAG/phorbol ester as a regulator of their enzymatic function, which is
to convert DAG to phosphatidic acid, abrogating signaling (Topham 2006). Multiple
additional protein families have been described with modified C1 domains, termed
“atypical” domains, which do not bind phorbol ester (Hurley et al. 1997).
The existence of more than 20 different transducing proteins for DAG/phorbol
ester provides for extensive branching of signaling pathways downstream of the
ligand binding. How can cells choose which branches will be utilized? Can ligands
differentiate between these different targets and their distal pathways? Do C1
domains represent viable therapeutic targets? Here, great opportunity is afforded by
the multiple layers of regulatory complexity impacting these proteins.
3.2 Early Insights into the Opportunities Provided
by C1 Domain Ligands
DGKβ DGKγ
Fig. 3.1 Multiplicity of families of signaling proteins with C1 domains which recognize diacylglycerol
and phorbol esters
The early findings with the phorbol esters, predating the demonstration of their
receptor or the discovery of PKC, had already yielded important insights into the
potential of this class of molecules. First, it was clear that these compounds were
highly potent, with cellular actions in the low nanomolar range (Blumberg 1980,
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