Subcellular localization of ceramide kinase and ceramide kinase-like protein requires interplay of their Pleckstrin Homology domain-containing N-terminal regions together with C-terminal domains

Rovina, Philipp; Schanzer, Andrea; Gräf, Christine; Mechtcheriakova, Diana; Jaritz, Markus; Bornancin, Frédéric

doi:10.1016/j.bbalip.2009.05.009

Cited by 34 publications

(35 citation statements)

References 28 publications

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“…One possibility is that ACD5 is needed in various cell compartments for different biological processes. The highly conserved CXXCXXXC motif in all ceramide kinases is important for enzyme activity and function in plants (Bi et al, 2011) and animals (Lidome et al, 2008); this motif also affects enzyme localization in animal cells (Lidome et al, 2008;Rovina et al, 2009). It is possible that under different stress conditions, ceramide kinase can translocate from one compartment to another, as has been documented in animal cells (Van Overloop et al, 2006;Rovina et al, 2009).…”

Section: Ceramide Kinase Activity and Localization Reflects Its Functionmentioning

confidence: 99%

Loss of Ceramide Kinase in Arabidopsis Impairs Defenses and Promotes Ceramide Accumulation and Mitochondrial H₂O₂ Bursts

Liu

et al. 2014

Plant Cell

146

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Arabidopsis thaliana plants that lack ceramide kinase, encoded by ACCELERATED CELL DEATH5 (ACD5), display spontaneous programmed cell death late in development and accumulate substrates of ACD5. Here, we compared ceramide accumulation kinetics, defense responses, ultrastructural features, and sites of reactive oxygen species (ROS) production in wild-type and acd5 plants during development and/or Botrytis cinerea infection. Quantitative sphingolipid profiling indicated that ceramide accumulation in acd5 paralleled the appearance of spontaneous cell death, and it was accompanied by autophagy and mitochondrial ROS accumulation. Plants lacking ACD5 differed significantly from the wild type in their responses to B. cinerea, showing earlier and higher increases in ceramides, greater disease, smaller cell wall appositions (papillae), reduced callose deposition and apoplastic ROS, and increased mitochondrial ROS. Together, these data show that ceramide kinase greatly affects sphingolipid metabolism and the site of ROS accumulation during development and infection, which likely explains the developmental and infection-related cell death phenotypes. The acd5 plants also showed an early defect in restricting B. cinerea germination and growth, which occurred prior to the onset of cell death. This early defect in B. cinerea restriction in acd5 points to a role for ceramide phosphate and/or the balance of ceramides in mediating early antifungal responses that are independent of cell death.

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Section: Ceramide Kinase Activity and Localization Reflects Its Functionmentioning

confidence: 99%

Loss of Ceramide Kinase in Arabidopsis Impairs Defenses and Promotes Ceramide Accumulation and Mitochondrial H₂O₂ Bursts

Liu

et al. 2014

Plant Cell

146

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“…Based on the presence of nuclear import and export signals in the CerK sequence, both nuclear and cytoplasmic localizations were suggested [15]. Moreover, in COS-1 cells transfected with green fluorescence protein (GFP)-tagged CerK the enzyme was shown to localize in the cytoplasm, the nucleus and the nucleolus [15]. Further investigations are therefore warranted to reconcile the subcellular localization of CerK with the putative site of C1P activity and its link to cell cycle regulation.…”

Section: Discussionmentioning

confidence: 99%

“…The enzyme shows sequence homology to diacylglycerol kinase and sphingosine kinase, and contains a N-terminal myristoylation site and a pleckstrin homology domain, which both seem to be indispensable for membrane association. The enzyme is localized at various subcellular sites including Golgi, cytoplasm and nucleus [14,15]. Since the N-terminal sequence of CerK contains a nuclear import signal and the C-terminal sequence contains a nuclear export signal [15], it was speculated that nucleocytoplasmic shuttling of CerK occurs and that CerK is active both inside and outside of the nucleus.…”

Section: Introductionmentioning

confidence: 99%

Ceramide Kinase Contributes to Proliferation but not to Prostaglandin E<sub>2</sub> Formation in Renal Mesangial Cells and Fibroblasts

Pastukhov

Schwalm

Römer

et al. 2014

Cell Physiol Biochem

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Background/Aims: Ceramide kinase (CerK) catalyzes the generation of the sphingolipid ceramide-1-phosphate (C1P) which regulates various cellular functions including cell growth and death, and inflammation. Here, we used a novel catalytic inhibitor of CerK, NVP-231, and CerK knockout cells to investigate the contribution of CerK to proliferation and inflammation in renal mesangial cells and fibroblasts. Methods: Cells were treated with NVP-231 and [³H]-thymidine incorporation into DNA, [³H]-arachidonic acid release, prostaglandin E₂ (PGE₂) synthesis, cell cycle distribution, and apoptosis were determined. Results: Treatment of rat mesangial cells and mouse renal fibroblasts with NVP-231 decreased DNA synthesis, but not of agonist-stimulated arachidonic acid release or PGE₂ synthesis. Similarly, proliferation but not arachidonic acid release or PGE₂ synthesis was reduced in CERK knockout renal fibroblasts. The anti-proliferative effect of NVP-231 on mesangial cells was due to M phase arrest as determined using the mitosis markers phospho-histone H3, cdc2 and polo-like kinase-1, and induction of apoptosis. Moreover, loss of CerK sensitized cells towards stress-induced apoptosis. Conclusions: Our data demonstrate that CerK induces proliferation but not PGE₂ formation of renal mesangial cells and fibroblasts, and suggest that targeted CerK inhibition has potential for treating mesangioproliferative kidney diseases.

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“…Many of the proteins containing PH domains are involved in intracellular signal cascades and cytoskeletal remodelling [25][26][27] . Any genetic defects in the PH domain-containing proteins are possibly associated with various cancers and other serious human diseases, including retinal degenerative diseases 28,29 . The aim of the current study is to determine the presence of a single nucleotide polymorphism (SNP) deposit and uncover new genetic factors contributing to DR development in a well-classified Taiwanese population.…”

Section: Introductionmentioning

confidence: 99%

Association of the PLEKHO2 and PLEKHH1 gene polymorphisms with type 2 diabetic retinopathy in a Taiwanese population

et al. 2012

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Diabetic retinopathy (DR) is a chronic retinal disorder, in which the retinal microvasculature is gradually altered, ultimately leading to blindness. Previous observations on clinical variations of the onset and severity of DR in various patients and populations suggest that genetic polymorphisms contribute to DR development. The present study was undertaken in an attempt to uncover new genetic factors contributing to the development of DR in a Taiwanese population. A well-defined Taiwanese population comprising persons with type 2 diabetes mellitus (T2DM) (n = 749) was recruited for this study. We conducted a genome-wide association study in an independent set of 174 patients with DR and 575 without DR, using Illumina HumanHap550-Duo BeadChip. Eleven single nucleotide polymorphisms (SNPs) with the most significant test statistics (p 1 × 10 −5 ) were selected from one of the models. Of the selected SNPs, rs832882 (G/A) (p = 2.29 × 10 −6 ; odds ratio (OR) = 1.49; 95% confidence interval (CI) = 1.11-2.00) and rs3742872 (G/A) (P = 1.19 × 10 −15 ; OR = 1.95; 95% CI = 1.02-3.72), both identified as having the most significant association with DR, are located in the intronic region of the gene encoding the pleckstrin homology (PH) domain-containing proteins family O member 2 (PLEKHO2) and family H member 1 (PLEKHH1), respectively. Functional prediction analysis strengthened the likelihood of participation of PLEKHO2 and PLEKHH1 in the development of DR. The current findings suggest that the rs832882 and rs3742872 polymorphisms may be harbouring retinopathy susceptibility in a Taiwanese population, and implicate the pathological role of PH domain-containing proteins in DR development.

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Subcellular localization of ceramide kinase and ceramide kinase-like protein requires interplay of their Pleckstrin Homology domain-containing N-terminal regions together with C-terminal domains

Cited by 34 publications

References 28 publications

Loss of Ceramide Kinase in Arabidopsis Impairs Defenses and Promotes Ceramide Accumulation and Mitochondrial H₂O₂ Bursts

Loss of Ceramide Kinase in Arabidopsis Impairs Defenses and Promotes Ceramide Accumulation and Mitochondrial H₂O₂ Bursts

Ceramide Kinase Contributes to Proliferation but not to Prostaglandin E<sub>2</sub> Formation in Renal Mesangial Cells and Fibroblasts

Association of the PLEKHO2 and PLEKHH1 gene polymorphisms with type 2 diabetic retinopathy in a Taiwanese population

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Subcellular localization of ceramide kinase and ceramide kinase-like protein requires interplay of their Pleckstrin Homology domain-containing N-terminal regions together with C-terminal domains

Cited by 34 publications

References 28 publications

Loss of Ceramide Kinase in Arabidopsis Impairs Defenses and Promotes Ceramide Accumulation and Mitochondrial H2O2 Bursts

Loss of Ceramide Kinase in Arabidopsis Impairs Defenses and Promotes Ceramide Accumulation and Mitochondrial H2O2 Bursts

Ceramide Kinase Contributes to Proliferation but not to Prostaglandin E<sub>2</sub> Formation in Renal Mesangial Cells and Fibroblasts

Association of the PLEKHO2 and PLEKHH1 gene polymorphisms with type 2 diabetic retinopathy in a Taiwanese population

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Loss of Ceramide Kinase in Arabidopsis Impairs Defenses and Promotes Ceramide Accumulation and Mitochondrial H₂O₂ Bursts

Loss of Ceramide Kinase in Arabidopsis Impairs Defenses and Promotes Ceramide Accumulation and Mitochondrial H₂O₂ Bursts