Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses.

Lysosphingolipids potently and reversibly inhibited protein kinase C activity and binding of phorbol dibutyrate in vitro and in human platelets. As with activation of protein kinase C by phosphatidylserine and sn-1,2-diacylglycerol, inhibition was subject to surface dilution. Accordingly, inhibition in mixed micelle assays was dependent on the molar percentage of lysosphingolipids rather than the bulk concentration. Lysosphingolipids inhibited protein kinase C activity at molar percentages similar to those required for activation by phosphatidylserine and sn-1,2-diacylglycerol. Since lysosphingolipids accumulate in Krabbe's disease, Gaucher's disease, and other sphingolipidoses, the hypothesis that lysosphingolipid inhibition of protein kinase C represents the missing functional link between the accumulation of sphingolipids and the pathogenesis of these disorders appears to unify existing data. The accumulation of lysosphingolipids would cause progressive dysfunction of signal transduction mechanisms vital for neural transmission, differentiation, development, and proliferation and would eventually lead to cell death.

[1]  Y. Hannun,et al.  Inhibition of phorbol ester-dependent differentiation of human promyelocytic leukemic (HL-60) cells by sphinganine and other long-chain bases. , 1986, The Journal of biological chemistry.

[2]  Y. Hannun,et al.  Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets. , 1986, The Journal of biological chemistry.

[3]  A. Merrill,et al.  Inhibition of the oxidative burst in human neutrophils by sphingoid long-chain bases. Role of protein kinase C in activation of the burst. , 1986, The Journal of biological chemistry.

[4]  Y. Hannun,et al.  Phorbol ester binding and activation of protein kinase C on triton X-100 mixed micelles containing phosphatidylserine. , 1986, The Journal of biological chemistry.

[5]  W. R. Bishop,et al.  Quantitative measurement of sn-1,2-diacylglycerols present in platelets, hepatocytes, and ras- and sis-transformed normal rat kidney cells. , 1986, The Journal of biological chemistry.

[6]  Y. Hannun,et al.  Protein kinase C activation in mixed micelles. Mechanistic implications of phospholipid, diacylglycerol, and calcium interdependencies. , 1986, The Journal of biological chemistry.

[7]  G. Mazzei,et al.  Immunological quantitation of phospholipid/Ca2+-dependent protein kinase and its fragments. Tissue levels, subcellular distribution, and ontogenetic changes in brain and heart. , 1986, The Journal of biological chemistry.

[8]  S. Burgess,et al.  Phorbol ester receptors and protein kinase C in primary neuronal cultures: development and stimulation of endogenous phosphorylation , 1986, The Journal of cell biology.

[9]  P. Cuatrecasas,et al.  Interaction of protein kinase C with membranes is regulated by Ca2+, phorbol esters, and ATP. , 1985, The Journal of biological chemistry.

[10]  Y. Hannun,et al.  Activation of protein kinase C by Triton X-100 mixed micelles containing diacylglycerol and phosphatidylserine. , 1985, The Journal of biological chemistry.

[11]  R. Desnick,et al.  Glycosphingolipid studies of visceral tissues and brain from type 1 Gaucher disease variants , 1985, Clinical genetics.

[12]  J. Wood,et al.  Polyclonal antibodies to phospholipid/Ca2+-dependent protein kinase and immunocytochemical localization of the enzyme in rat brain. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[13]  H. Egge,et al.  Synthesis of lysogangliosides. , 1985, Biochemistry.

[14]  Y. Nishizuka Turnover of inositol phospholipids and signal transduction. , 1984, Science.

[15]  H. Igisu,et al.  Analysis of galactosylsphingosine (psychosine) in the brain. , 1984, Journal of lipid research.

[16]  W. Shearer,et al.  Enhanced N-acylation of palmitic acid in sphingomyelin of antibody-stimulated L cells. , 1984, Biochemical and biophysical research communications.

[17]  M. Berridge Inositol trisphosphate and diacylglycerol as second messengers. , 1984, The Biochemical journal.

[18]  H. Igisu,et al.  Progressive accumulation of toxic metabolite in a genetic leukodystrophy. , 1984, Science.

[19]  Y. Nishizuka The role of protein kinase C in cell surface signal transduction and tumour promotion , 1984, Nature.

[20]  A. Merrill Characterization of serine palmitoyltransferase activity in Chinese hamster ovary cells. , 1983, Biochimica et biophysica acta.

[21]  S. Snyder,et al.  Phorbol ester receptors: autoradiographic identification in the developing rat. , 1983, Science.

[22]  J. Månsson,et al.  The occurrence of psychosine and other glycolipids in spleen and liver from the three major types of Gaucher's disease. , 1982, Biochimica et biophysica acta.

[23]  L. Svennerholm,et al.  Accumulation of Glucosylceramide and Glucosylsphingosine (Psychosine) in Cerebrum and Cerebellum in Infantile and Juvenile Gaucher Disease , 1982, Journal of neurochemistry.

[24]  L. Svennerholm,et al.  CHEMICAL PATHOLOGY OF KRABBE'S DISEASE , 1975, Acta paediatrica Scandinavica.

[25]  J. Kanfer,et al.  Isolation and characterization of glucosylsphingosine from Gaucher's spleen. , 1974, Journal of lipid research.

[26]  Y. Eto,et al.  Sulfogalactosylsphingosine sulfatase. Characteristics of the enzyme and its deficiency in metachromatic leukodystrophy in human cultured skin fibroblasts. , 1974, The Journal of biological chemistry.

[27]  K. Suzuki,et al.  GALACTOSYLSPHINGOSINE GALACTOSYL HYDROLASE IN RAT BRAIN: PROBABLE IDENTITY WITH GALACTOSYLCERAMIDE GALACTOSYL HYDROLASE 1 , 1974, Journal of neurochemistry.

[28]  K. Suzuki,et al.  Globoid cell leukodystrophy: additional deficiency of psychosine galactosidase. , 1972, Biochemical and biophysical research communications.

[29]  P. Mandel,et al.  ENZYMIC SYNTHESIS OF PSYCHOSINE SULPHATE , 1972, Journal of neurochemistry.

[30]  G. McKhann,et al.  Characterization of cerebroside sulfotransferase from rat brain. , 1971, The Journal of biological chemistry.

[31]  J. Hildebrand,et al.  BIOSYNTHESIS OF LACTOSYLCERAMIDE BY RAT BRAIN PREPARATIONS AND COMPARISON WITH THE FORMATION OF GANGLIOSIDE GM1 AND PSYCHOSINE DURING DEVELOPMENT , 1970, Journal of neurochemistry.

[32]  H. Barra,et al.  Sulfation of glycosphingolipids and related carbohydrates by brain preparations from young rats. , 1968, The Journal of biological chemistry.

[33]  C. Sweeley,et al.  Chemistry and metabolism of sphingolipids. 3-Oxo derivatives of N-acetylsphingosine and N-acetyldihydrosphingosine. , 1966, Journal of the American Chemical Society.

[34]  J. Månsson,et al.  Krabbe disease: a galactosylsphingosine (psychosine) lipidosis. , 1980, Journal of lipid research.

[35]  L. Svennerholm,et al.  Chemical pathology of Krabbe disease: the occurrence of psychosine and other neutral sphingoglycolipids. , 1976, Advances in experimental medicine and biology.

[36]  E. P. Kennedy,et al.  The enzymatic synthesis of psychosine. , 1960, The Journal of biological chemistry.