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

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Ceramide kinase (CERK) converts ceramide (Cer) to ceramide-1-phosphate(C1P), which has recently emerged as a new bioactive molecule capable of regulatingdiverse cellular functions. The N-terminus of the CERK protein encompasses asequence motif known as a pleckstrin homology (PH) domain. Although the PH domainwas previously demonstrated to be an important domain for the subcellular localizationof CERK, the precise properties of this domain remained unclear. In this study, wereveal that the PH domain of CERK exhibits high affinity for phosphatidylinositol (4,5)bisphosphate (PI(4,5)P2)[0], among other lipids. Furthermore, in COS7 cells, GFPfusedCERK translocated rapidly from the cytoplasm to the plasma membrane inresponse to hyper-osmotic stress, which is known to increase the intracellular PI(4,5)P2levels, whereas a PH-domain deletion mutant did not. Additionally, in[32P]orthophosphate-labeled COS7 cells, the translocation of CERK to the plasmamembrane induced a 2.8 fold increase in C1P levels. The study presented here providesinsight into the crucial role of the CERK[0]-PH domain in plasma membrane targeting,through its binding to PI(4,5)P2, and subsequent induction of C1P production in thevicinity of the membrane
Elsevierの論文
2006-04-07