Diacylglycerol Signaling

5 Regulation of PKC by Protein–Protein Interactions in Cancer
KO cells (Brandman et al. 2007). These peptides are likely to represent regions in
the C2 domain that interact with conserved sequences in different PKC isozymes.
This more systematic approach of mapping the surface of the C2 domain also lead
to the identification of a number of potential peptide inhibitors of PKCe that are
derived from sites on the C2 domain unlikely to interact with the RACK. We predict
that these peptides represent sites in that domain that interact with select substrates
of each PKC isozyme. These may represent STICKs proposed by Jaken and Parker
(2000). Further characterization of these peptides and corresponding peptides from
other C2 domains is under way.
5.2.4 The V3 Region
The V3 region is the hinge region between the catalytic and regulatory domain. Upon
activation, a proteolytic site for a variety of proteases is exposed in that region, leading
to the separation of the regulatory domain from the catalytic domain and the
generation of constitutively active kinase fragments (Mochly-Rosen and Koshland
1987; Steinberg 2004). The generation of a catalytic fragment occurs also in cells and
has been suggested to be critical in processes such as long-term memory (Hernandez
et al. 2003) and apoptosis (Emoto et al. 1995). The V3 region is also critical in protein–protein
interaction. For example, it interacts with b1 integrin, an interaction that
regulates cell migration and chemotaxis (Ng et al. 1999; Parsons et al. 2002).
5.2.5 The C3/C4 Domain
These domains contain the ATP- and substrate-binding sites as well as the catalytic
domain of the enzyme. The location of the substrate-binding site was identified by
House and Kemp before the crystal structure of that domain was confirmed (House
and Kemp 1987). As with any enzyme, the interaction with the substrate is terminated
upon its phosphorylation and is thus likely to reflect the binding of the domain to the
PKC consensus phosphorylation motif in the substrate protein. Although this intermolecular
protein–protein interaction has not been studied in detail and selective
regulators of these interactions have not been identified, it may mediate, at least in part,
the interaction between PKC isozymes and their STICKs (Jaken and Parker 2000).
5.2.6 The V5 Region
The V5 region contains important posttranslational phosphorylation sites in PKC.
Studies by Newton and collaborators showed that a number of serines and threonines
in the V5 domain need to be phosphorylated to mature the enzyme; in the
un-phosphorylated state, the V5 region occupies the catalytic site of the enzyme
and prevents its activation by DAG (Newton 2003). As discussed above, the mature
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