Diacylglycerol Signaling

22 PKCd as a Target for Chemotherapeutic Drugs
Therefore, understanding the different parameters that affect PKCd function is
essential for the design of PKCd inhibitors that can selectively target specific PKC
functions.
22.4.1.1 Phosphorylation of PKCd on Tyrosine Residues
One of the earliest events that are common to many apoptotic stimuli that affect
PKCd is its phosphorylation of specific tyrosine residues (Brodie and Blumberg
2003). Indeed, PKCd undergoes tyrosine phosphorylation in response to diverse
stimuli (Brodie et al. 1998; Denning et al. 1993; Kronfeld et al. 2000; Li et al. 1996;
Lu et al. 2007a; Steinberg, 2004). It was recently found that etoposide induced
phosphorylation of PKCd on tyrosines 64 and 187 in the regulatory domain, and
this phosphorylation was essential for the cleavage of PKCd by caspase 3 and for
the apoptotic effect of PKCd (Blass et al. 2002; Lomonaco et al. 2008). In addition,
H 2 O 2 induced phosphorylation of PKCd on multiple phosphorylation sites (Konishi
et al. 2001; Lu et al. 2007a), cisplatin induced phosphorylation of tyrosine 332 and
this phosphorylation was essential for the cleavage of PKCd (Lu et al. 2007b).
In contrast, infection of the cells with SV induced phosphorylation of PKCd on
tyrosines 52, 64, and 155 and this phosphorylation was essential for the antiapoptotic
effect of PKCd (Zrachia et al. 2002). Similarly, TRAIL induced phosphorylation
of PKCd on tyrosine 155 that was essential for the translocation of PKCd to the ER
(Okhrimenko et al. 2005).
Although tyrosine phosphorylation of PKCd is common to many apoptotic
stimuli, its role in the antiapoptotic function of this kinase is still not completely
understood. A number of tyrosine kinases have been implicated in the phosphorylation
of PKCd. c-Abl is one of the important tyrosine kinases that is activated by
apoptotic stimuli and phosphorylates PKCd in response to DNA damage and oxidative
stress (Steinberg 2004; Sun et al. 2000). c-Abl is a ubiquitously expressed
kinase that can localize to the nucleus, ER, and mitochondria and plays a role in
cell apoptosis in a p53- and p73-dependent manner (Deng et al. 2004). c-Abl and
PKCd interact in response to oxidative and genotoxic stresses (Sun et al. 2000). It
was proposed that c-Abl associates with PKCd via the SH3 domain and that following
radiation it phosphorylates PKCd on tyrosine residues and mediates its
nuclear translocation (Yuan et al. 1998). c-Abl also phosphorylates PKCd in
response to oxidative stress on tyrosine 311 in glioma cells (Lu et al. 2007a). The
association of PKCd and c-Abl is important for the activation of the latter since
the inhibition of PKCd by overexpression of its regulatory domain decreased the
activity of c-Abl (Sun et al. 2000). Similarly, cells treated with cisplatin and methylglyoxal
increased the association of these two kinases and the activity of c-Abl
(Godbout et al. 2002).
Src kinases also play an important role in the phosphorylation of PKCd (Joseloff
et al. 2002; Rybin et al. 2007; Song et al. 1998). Src phosphorylates PKCd in
glioma cells on tyrosine 332 in response to PMA and cisplatin (Lu et al. 2007b) and
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