Protein kinase D signaling: multiple biological functions in health and disease

Abstract

Protein kinase D (PKD) is an evolutionarily conserved protein kinase family with structural, enzymological, and regulatory properties different from the PKC family members. Signaling through PKD is induced by a remarkable number of stimuli, including G-protein-coupled receptor agonists and polypeptide growth factors. PKD1, the most studied member of the family, is increasingly implicated in the regulation of a complex array of fundamental biological processes, including signal transduction, cell proliferation and differentiation, membrane trafficking, secretion, immune regulation, cardiac hypertrophy and contraction, angiogenesis, and cancer. PKD mediates such a diverse array of normal and abnormal biological functions via dynamic changes in its spatial and temporal localization, combined with its distinct substrate specificity. Studies on PKD thus far indicate a striking diversity of both its signal generation and distribution and its potential for complex regulatory interactions with multiple downstream pathways, often regulating the subcellular localization of its targets.

Figure 1. PKDs activation by multiple stimuli

Hormones, growth factors, neurotransmitters, chemokines, bioactive lipids, proteases and oxidative stress induce PLC-mediated hydrolysis of phosphatidylinositol 4,5-biphosphate (PIP₂) to produce DAG at the plasma membrane, which in turn mediates the translocation of inactive PKDs from the cytosol to that cellular compartment. DAG also recruits, and simultaneously activates, novel PKCs to the plasma membrane which mediate transphosphorylation of PKD1 on Ser⁷⁴⁴ (in mouse PKD1). DAG and PKC-mediated transphosphorylation of PKD act synergistically to promote PKD catalytic activation and autophosphorylation on Ser⁷⁴⁸. The modular structure of PKD (mouse PKD1) is illustrated as an example of the PKD family. PKD1 is the most studied member of the family and its knockout induces embryonic lethality. Further details are provided in the text.

Figure 2. PKD signaling regulates multiple normal and abnormal biological processes

Active PKD phosphorylates a variety of cellular targets at specific sites thereby regulating its sub-cellular localization (as in Fig. 3) or activity (see Table 1 for examples of substrates and of the consensus sequence phosphorylated by PKD). Solid lines indicate direct phosphorylation of substrates (in light blue). Broken lines represent processes in which PKD is implicated but the sequence of molecular events has not been elucidated. Further details are in the text.

Figure 3. Schematic representation of the mechanism by which PKD modulates intracellular localization of its substrates

In many cases, the phosphorylation of PKD substrates induces binding of 14-3-3 proteins that sequester them to the cytosol, thereby preventing them from acting at the plasma membrane (e.g. RIN1, Par-1, DLC1) or at the nucleus (e.g. HDACS 5 and HDACS 7). An emerging theme is that PKD signaling regulates cell function by altering the sub-cellular localization of its substrates.