Psychiatry related information on CERK

• Systematic mutation analysis of KIAA0767 and KIAA1646 in chromosome 22q-linked periodic catatonia [1].

High impact information on CERK

• We finally identified a novel gene encoding a ceramide kinase (CERKL), which encompassed 13 exons [2].
• Cells transfected with hCERK showed a higher liquid crystalline order than control cells with stimulation, conditions that are favorable for the promotion of membrane fusion at the sites of phagocytosis [3].
• Utilizing an antibody against hCERK, we observed that CERK translocates during activation from the cytosol to a lipid raft fraction [3].
• Ceramide kinase (CERK) catalyzes the conversion of ceramide to ceramide 1-phosphate (C1P) and is known to be activated by calcium [4].
• We studied the RBL-2H3 cell line, a widely used model for mast cells, and found that CERK and C1P are required for activation of the degranulation process in mast cells [4].

Biological context of CERK

• Ceramide is a key player governing cell fate, and its conversion to ceramide-1-phosphate by ceramide kinase (CERK) is emerging as an important mean to regulate apoptosis and inflammatory processes [5].
• In addition, methylation of the secondary hydroxyl group drastically decreased the phosphorylation by CERK [6].
• Methylation of the primary hydroxyl group resulted in a loss of activity, confirming that CERK produces ceramide-1-phosphate versus ceramide-3-phosphate [6].
• In this study, we investigated the substrate specificity of CERK using baculovirus-expressed human CERK (6 x His) and a newly designed assay based on mixed micelles of Triton X-100 [6].
• Since itscloning, in 2002, CERK has been the subject of an explosion of publications concerning various signal transduction pathways [7].

Anatomical context of CERK

• Furthermore, in COS7 cells, GFP-fused CERK translocated rapidly from the cytoplasm to the plasma membrane in response to hyper-osmotic stress, which is known to increase the intracellular PI(4,5)P(2) levels, whereas a PH domain deletion mutant did not [8].
• Moreover, to our knowledge, this is the first report demonstrating that inhibition of CERK suppresses IgE/antigen-induced mast cell degranulation [9].
• Northern blot analysis revealed that hCERK mRNA expression was high in the brain, heart, skeletal muscle, kidney, and liver [10].
• Upon analysis of EGFP-tagged proteins, CERK was found associated with the Golgi complex [11].
• Conversely, 1,2-diacylglycerol does not serve as substrate for the neutrophil ceramide kinase [12].

Associations of CERK with chemical compounds

• Together, these results indicate a very high specificity for substrate recognition by CERK, explaining the use of ceramide and not sphingosine or diacylglycerol as substrates [6].
• Lastly, the sphingoid chain was also required for substrate recognition by CERK [6].
• Replacing this residue with a neutral alanine or isoleucine, caused a dramatic decrease in CERK activity to 1% and 29%, respectively, compared to CERK, but had no effect on substrate affinity [13].
• In this study, we reveal that the PH domain of CERK exhibits high affinity for phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)), among other lipids [8].
• Finally, we show that K1 affects neither IgE/antigen-induced global tyrosine phosphorylation nor subsequent Ca(2+) elevation, suggesting a specificity for CERK-mediated signals [9].

Regulatory relationships of CERK

• In vitro kinase assays demonstrated that K1 effectively inhibits CERK without inhibiting sphingosine kinase and diacylglycerol kinase [9].

Other interactions of CERK

• Surprisingly, various ceramides, known substrates for CERK, were not phosphorylated by CERKL in vitro [5].
• Further SPHK superfamily members, namely ceramide kinase and a "SPHK-like" protein, failed to phosphorylate sphingosine and FTY720 [14].
• The interaction between the pleckstrin homology domain of ceramide kinase and phosphatidylinositol 4,5-bisphosphate regulates the plasma membrane targeting and ceramide 1-phosphate levels [8].
• Ceramide is converted into ceramide 1-phosphate by ceramide kinase and we have measured levels of this metabolite to clarify the effect of TNF alpha on sphingomyelinase activity in neutrophils [15].
• RESULTS: The mutation scan revealed 24 single nucleotide polymorphisms, among them two rare codon variants (KIAA0767: S159I; KIAA1646: V338G) [1].

Analytical, diagnostic and therapeutic context of CERK

• Using site-directed mutagenesis, we have further determined that Leu10 in the PH domain has an important role in CERK activity [13].
• Ceramide kinase, a novel lipid kinase. Molecular cloning and functional characterization [10].
• Moreover, this high specificity eliminates the need for analysis of the lipid product by thin-layer chromatography since ceramide-1-phosphate is the only radiolabeled lipid in organic solvent extracts of ceramide kinase reactions [16].

References