Disease relevance of PRKD2

• Protein kinase D2 mediates activation of nuclear factor kappaB by Bcr-Abl in Bcr-Abl+ human myeloid leukemia cells [1].
• The diagnosis of ADPKD is typically made using renal imaging despite the identification of mutations in PKD1 and PKD2 that account for virtually all cases [2].
• PKD2-linked ADPKD is supposed to be a milder form of the disease, its mean age of end-stage renal failure (ESRF) approximately 20 years later than PKD1 [3].
• Mutations of the human polycystic kidney disease 2 (PKD2) gene [4].

High impact information on PRKD2

• These include whether the patient has a germline mutation in the PKD1 or in the PKD2 gene, and the nature of the mutation [5].
• Inspection of the haplotypes of these individuals suggested the possibility of bilineal disease from independently segregating PKD1 and PKD2 mutations [6].
• Mutations in the PKD2 gene, on the long arm of chromosome 4, are expected to be responsible for approximately 15% of cases of ADPKD [7].
• Targeting PKD2 tyrosine phosphorylation, not its kinase activity, could be a novel therapeutic approach for the treatment of Bcr-Abl(+) myeloid leukemia [1].
• Caenorhabditis elegans polycystins LOV-1 and PKD-2 are expressed in the male-specific HOB neuron, and are necessary for sensation of the hermaphrodite vulva during mating [8].

Biological context of PRKD2

• In addition, we could identify the C-terminal Ser(876) residue as an in vivo phosphorylation site within PKD2 [9].
• Protein kinase D2 contributes to either IL-2 promoter regulation or induction of cell death upon TCR stimulation depending on its activity in Jurkat cells [10].
• However, when the C-terminal tail of PKD2 was added to its catalytic domain, the nuclear localization of the resulting protein was inhibited [11].
• Mice with targeted mutations of either the PKD1 or the PKD2 genes die during embryogenesis [12].
• Individuals with mutations in PKD1 or PKD2 have identical phenotypes, which present at a later age in PKD2 patients [12].

Anatomical context of PRKD2

• Cell stimulation with the G protein-coupled receptor agonist neurotensin induced a rapid and reversible plasma membrane translocation of PKD2 by a mechanism that requires PKC activity [13].
• Expression analysis localized LOV-1 and PKD-2 to the ends of sensory neurons in male tails and to the tips of CEM neurons in the head, consistent with functions as chemo- or mechanosensors [14].
• We have shown that this gene (pkd2) is essential for cellular viability, and is involved in cell growth and cell wall synthesis [15].

Associations of PRKD2 with chemical compounds

• Molecular cloning and characterization of the human protein kinase D2. A novel member of the protein kinase D family of serine threonine kinases [9].
• A mutant that mimicks tyrosine phosphorylation of PKD2 in the pleckstrin homology domain activates nuclear factor kappaB independently of its catalytic activity [1].
• Recently, we cloned a novel serine/threonine kinase termed protein kinase D2 (PKD2) [16].
• In LCLs obtained from subjects carrying PKD2 mutations (PKD2-LCLs) and showing reduced PC2 levels, intracellular Ca2+ concentrations evoked by platelet-activating factor (PAF), were significantly lower than in non-PKD-LCLs [17].
• In addition to characterizing PKD-2-mediated aggregation and mating behaviors, we found that polycystin-2 is an intracellular Ca(2+) release channel that is required for the normal pattern of Ca(2+) responses involving IP(3) and ryanodine receptor-mediated Ca(2+) release from intracellular stores [18].

Other interactions of PRKD2

• Intracellular redistribution of protein kinase D2 in response to G-protein-coupled receptor agonists [13].
• Proteomic analysis of isolated LBs identifies adipophilin and TIP47, various lipid-specific enzymes, cytoskeletal components, chaperones, Ras-related proteins, protein kinase D2, and other regulatory proteins [19].

Analytical, diagnostic and therapeutic context of PRKD2

• We screened 48 members of the NFL10 pedigree, by ultrasonography, and genotyped them, with informative markers, at both the PKD1 locus and the PKD2 locus [6].
• The cloning of PKD1 and PKD2 in recent years has provided the initial steps in defining the mechanisms underlying renal cyst formation in this condition, with the aim of defining pharmacological and genetic interventions that may ameliorate the diverse and often serious clinical manifestations of this disease [20].
• In 22 patients, a mutation in the PKD2 gene was defined: 18 of 46 patients from the elderly group and 4 of 40 patients from the control group [21].
• We analyzed all exons and intron-exon boundaries of the PKD2 gene by single-strand conformation polymorphism analysis and silver staining technique in 46 patients with ADPKD who reached ESRD after the age of 63 years or were not yet undergoing renal replacement therapy (RRT) by that age [21].

References