Protein Kinase D

The protein kinase D (PKD) family of serine/threonine protein kinases contains three members; PKD1, PKD2 and PKD3. These enzymes occupy a unique position in the signal transduction pathway initiated by diacylglycerol (DAG) and protein kinase C (PKC). PKDs are direct targets of DAG, and also lie downstream of PKC in a novel signal transduction pathway that is implicated in a variety of biological processes.

Structurally, PKDs contain an N' terminal cysteine-rich domain (CRD), which binds phorbol esters with high affinity and has a role in mediating PKD translocation to the plasma membrane upon activation. The PH domains have an autoregulatory phosphorylation site (PKD1 and PKD2 only) and the catalytic domains have a high degree of homology to myosin light chain and calmodulin-dependent kinases.

In the inactivated state, PKD1 and PKD2 are localized mainly to the cytoplasm, whilst PKD3 is found both in the cytoplasm and nucleus. Kinase activity of these enzymes is repressed by their CRD and PH domains. PKDs are activated by a variety of stimuli including regulatory peptides, lysophosphatidic acid, thrombin, PDGF, IGF-1, oxidative stress, cholecystokinin, G_βγ, ATP and more. These stimuli produce a rapid generation of DAG, which induces CRD-mediated PKD translocation from the cytosol to the plasma membrane. Novel PKCs are also recruited to the plasma membrane in response to DAG generation. Novel PKCs are allosterically activated by DAG, and transphosphorylate PKDs. This stabilizes PKD in its active conformation. Activated PKD dissociates from the plasma membrane, translocates to the cytosol and subsequently to the nucleus.

PKDs have been implicated in fundamental physiological processes including signal transduction, membrane trafficking, and cell survival, migration, differentiation and proliferation. PKD upregulates the ERK and Ras signaling pathways, and suppresses the JNK signaling pathway. These enzymes regulate the budding of secretory vesicles from the trans-Golgi network and promote integrin recruitment to focal adhesions. In addition, PKDs have a role in regulating apoptosis and have functions in cell survival pathways induced by oxidative stress. They also have a role in immune regulation. Despite the plethora of physiological processes PKDs are involved in, only a few direct targets are known. These include kidins220, an integral membrane protein of neuroendocrine cells, c-Jun and RIN1, a protein that associates with Ras and 14.3.3 and activates the Ras-MEK-ERK pathway.

The human genes encoding PKD1, PKD2 and PKD3 have been localized to chromosomes 14q11, 19q13.2 and 2p21 respectively.

External sources of pharmacological information for Protein Kinase D :

• BJP Guide

Protein Kinase D Gene Data