Protein kinase D signaling in cancer: A friend or foe?

Abstract

Protein kinase D is a family of evolutionarily conserved serine/threonine kinases that belongs to the Ca⁺⁺/Calmodulin-dependent kinase superfamily. Signal transduction pathways mediated by PKD can be triggered by a variety of stimuli including G protein-coupled receptor agonists, growth factors, hormones, and cellular stresses. The regulatory mechanisms and physiological roles of PKD have been well documented including cell proliferation, survival, migration, angiogenesis, regulation of gene expression, and protein/membrane trafficking. However, its precise roles in disease progression, especially in cancer, remain elusive. A plethora of studies documented the cell- and tissue-specific expressions and functions of PKD in various cancer-associated biological processes, while the causes of the differential effects of PKD have not been thoroughly investigated. In this review, we have discussed the structural-functional properties, activation mechanisms, signaling pathways and physiological functions of PKD in the context of human cancer. Additionally, we have provided a comprehensive review of the reported tumor promoting or tumor suppressive functions of PKD in several major cancer types and discussed the discrepancies that have been raised on PKD as a major regulator of malignant transformation.

Keywords: Cancer; Function; PKD; Regulation; Signaling mechanisms; Structure.

Figure 1

Diagram of protein kinase D structure. The structure of PKD contains an N-terminal regulatory domain which consists of cysteine-rich Zn-finger like motifs (CIa and CIb), a plekstrin homology (PH) domain and a Cterminal catalytic domain, which are shared by all three isoforms. However, PKD3 lacks C-terminal PDZ binding (PB) domain as it is present in both PKD1 and PKD2. The serine residues shown in the catalytic domain represent the conserved activation loop amino acids phosphorylated by the members of the c/nPKCs, which leads to PKD activation. Note: Phosphorylation sites are numbered based on the murine PKD isoforms.

Figure 2

Major signaling pathways and biological functions of PKD. Several extracellular stimuli activate phospholipase C (PLC) which catalyzes the formation of diacylglycerol (DAG). DAG recruits PKD and PKC to the plasma membrane inducing the activation of PKC which then further phosphorylates PKD at two serine (Ser^744,748) residues resulting in the activation of PKD. PKD can also be activated by PKC-independent pathways and the activity of PKD can be sustained through autophosphorylation at Ser⁷⁴⁸ residue (dashed line). Activated PKD regulates an array of cancer-associated functions including cell proliferation, migration, survival, regulation of gene transcription, protein/vesicle trafficking and secretion through several major signaling pathways.

Figure 3

Tumor-specific roles of PKD isoforms in several major cancer types. Benign cells transform into neoplasm such as carcinoma of prostate, breast, pancreas, skin and gastric. Three isoforms of PKD, namely PKD1, PKD2 and PKD3 either promote (solid arrow) or inhibit (bar-headed solid line) cancer progression in highly tumor-specific manner.