Diacylglycerol Signaling

7 Regulation and Function of Protein Kinase D Signaling
fundamental biological processes, including cell proliferation, survival, polarity,
migration and differentiation, membrane trafficking, inflammation and cancer.
7.3.1 PKD in the Regulation of Cell Proliferation
PKD can be activated by multiple growth-promoting GPCR agonists acting through
Gq, Gi and G 12 in a variety of cell types, suggesting that PKD functions in mediating
mitogenic signaling (Rozengurt et al. 2005). Indeed, overexpression of either
PKD or PKD2 strikingly potentiates the stimulation of DNA synthesis and cell
proliferation induced by Gq-coupled receptor agonists in Swiss 3T3 cells (Zhukova
et al. 2001a; Sinnett-Smith et al. 2004; Sinnett-Smith et al. 2007). In contrast, overexpression
of PKD mutants lacking catalytic activity, failed to promote any
enhancement of GPCR-induced mitogenesis. These results indicate that PKD activation
plays a critical role in GPCR mitogenic signaling.
A key pathway involved in mitogenic signaling induced by GPCRs is the extracellular-regulated
protein kinase (ERK) cascade (Johnson and Lapadat 2002;
Rozengurt 1998; Meloche and Pouyssegur 2007). The duration and intensity of
ERK pathway activation are of critical importance for determining specific biological
outcomes, including proliferation, differentiation and transformation (Marshall
1995; Pouyssegur and Lenormand 2003). ERK signal duration is sensed by the
cells through the protein products of immediate early genes, including c-Fos
(Murphy et al. 2002; Murphy et al. 2004). When ERK activation is transient, its
activity declines before the c-Fos protein accumulates and c-Fos is degraded rapidly.
However, when ERK signaling is sustained, c-Fos is phosphorylated by ERK
and RSK and its stability is dramatically increased, thereby leading to its accumulation
(Sinnett-Smith et al. 2004; Murphy et al. 2002; Murphy et al. 2004).
PKD alters the relative activities of the JNK and ERK pathways, attenuating
JNK activation and c-Jun phosphorylation in response to EGF receptor activation
(Bagowski et al. 1999; Hurd and Rozengurt 2001) while stimulating the ERK
pathway (Sinnett-Smith et al. 2004; Brandlin et al. 2002; Wang et al. 2002; Hurd
et al. 2002). For example, the stimulatory effect of PKD on GPCR-induced cell
proliferation (Zhukova et al. 2001a) has been linked to its ability to increase the
duration of the MEK/ERK/RSK pathway leading to accumulation of immediate
gene products, including c-Fos, that stimulate cell cycle progression (Sinnett-
Smith et al. 2004).
Although the immediate downstream targets of the PKDs necessary for the
transmission of its mitogenic signal have not been fully identified, putative substrates
are beginning to emerge. Recently, a number of scaffolding proteins and endogenous
inhibitors have been implicated in the regulation of the intensity and duration of
the ERK pathway (Kolch 2005). Modeling of the ERK pathway indicates that
scaffolds regulate the intensity of pathway activation, whereas inhibitors modulate
its duration in response to stimuli (Ebisuya et al. 2005). The activity and
subcellular localization of these proteins are also regulated by phosphorylation,
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