Protein kinase D (PKD), the founding member of a new family of serine/threonine protein kinases and the subject of this minireview, occupies a unique position in the signal transduction pathways initiated by DAG and PKC. PKD not only is a direct DAG target but also lies downstream of PKCs in a novel signal transduction pathway implicated in the regulation of multiple fundamental biological processes.

Complementary DNA clones encoding human PKD (initially called atypical PKCμ) and PKD from mouse were identified by two different laboratories in 1994. Subsequently, two additional mammalian protein kinases have been identified that share extensive overall homology with PKD, termed PKD2 and PKCn/PKD3.

PKD Function

The multistep model of activation suggests that the PKDs are well positioned to regulate membrane, cytoplasmic and nuclear events. Indeed, it is emerging that the PKDs are implicated in the regulation of a remarkable array of fundamental biological processes, including cell proliferation, survival, polarity, migration and differentiation, membrane trafficking, inflammation and cancer.

PKD and Osteoblast Differentiation

Bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor beta (TGFβ) superfamily. BMPs bind to receptor complexes that stimulate multiple intracellular pathways, including the SMADS, leading to a wide range of biological effects in different tissues. In particular, they contribute to the formation of bone and connective tissues by inducing the differentiation of mesenchymal cells into bone-forming cells. Studies demonstrated that BMP-2 induces PKD activation through a PKC-independent pathway during osteoblast lineage progression and that PKD is required for the effects of BMP-2 on osteoblast differentiation.

More studies explored the mechanism of action of the BMP-2/PKD pathway. Runx is a master transcriptional regulator of skeletal biology that plays a critical role in bone cell growth and differentiation, as well as in the structural and functional integrity of skeletal tissue. Interestingly, HDAC7 associates and represses the activity of Runx2. Further studies demonstrated that BMP-2 induces export of HDAC7 from the nucleus in mesenchymal cells that require Crm1-mediated nuclear export and are associated with increased HDAC7 serine phosphorylation and 14-3-3 binding. PKD was shown to form a molecular complex with HDAC7 in a BMP2-enhanced manner, and a constitutively active form of PKD stimulated HDAC7 nuclear export. An important finding was that active PKD inhibited repression of Runx2-mediated transcription by HDAC7. Although other pathways may be involved, these results establish a mechanism by which BMP-2 signaling regulates Runx2 activity via PKD-dependent inhibition of HDAC7 transcriptional repression. The elucidation of the precise mechanism by which BMP-2 induces PKD activation requires further experimental work.

PKDs, is a key transcription factor that is activated by multiple receptors and regulates the expression of a wide variety of proteins that control innate and adaptive immunity. A number of studies indicate that PKD is a mediator of NF-κB induction in a variety of cells exposed to GPCR agonists or oxidative stress. In view of the increasing recognition of the interplay between inflammation and cancer development, a possible role of PKD in linking these processes is of importance. However, the precise molecular mechanisms remain incompletely understood.

Stimulation of human colonic epithelial NCM460 cells with the GPCR agonist and bioactive lipid lysophosphatidic acid (LPA) led to a rapid and striking activation of PKD2, the major isoform of the PKD family expressed by these cells. LPA induced a striking increase in the production of interleukin 8 (IL-8), a potent pro-inflammatory chemokine, and stimulated NF-kB activation. PKD2 gene silencing utilizing small interfering RNAs dramatically reduced LPAstimulated NF-κB promoter activity and IL-8 production. These results imply that PKD2 mediates LPA-stimulated IL-8 secretion in NCM460 cells through a NF-κB dependent pathway. PKD2 has also been implicated in mediating NF-κB activation by Bcr-Abl in myeloid leukemia cells.

NF-κB also plays a critical role in inflammatory and cell death responses during acute pancreatitis. Studies demonstrated that the PKC isoforms PKCδ and ε are key regulators of NF-κB activation induced by cholecystokinin-8 (CCK-8), an agonist that induces pancreatitis when administered to rodents at supramaximal doses. PKD has been shown to function as a key downstream target of PKCδ and PKCε in pancreatic acinar cells stimulated by CCK-8 or the cholinergic agonist carbachol (CCh). Furthermore, PKD was necessary for NF-κB activation induced by these GPCR agonists. The kinetics of PKD and NF-κB activation during rat pancreatitis showed that both PKD and NF-κB activation were early events during acute pancreatitis and that their time courses of response in vivo were similar. These results identify PKD as a novel early point of convergence in the signaling pathways mediating NF-κB activation in pancreatitis, a condition that predisposes to pancreatic cancer.

Since the original finding that oxidative stress induces PKD activation, partly via PKC-mediated activation loop phosphorylation and partly through Src-mediated PKD tyrosine phosphorylation, a number of reports confirmed that PKD is a sensor of oxidative stress. Recently, Tyr95 in PKD has been identified as a phosphorylation site that is regulated by oxidative stress and generates a binding motif for PKCδ. Oxidative stress-mediated PKCδ/PKD interaction results in PKD activation loop phosphorylation on Ser744 and Ser748 leading to catalytic activation. A number of studies have shown that PKD opposes the apoptotic effects of oxidative stress in a variety of cells.


Toker, A. (2010). Protein Kinase C in Cancer Signaling and Therapy: Introduction and Historical Perspective. In Protein Kinase C in Cancer Signaling and Therapy (pp. 3-8). Humana Press, Totowa, NJ.

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