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Science 6 February 1987:
Vol. 235. no. 4789, pp. 670 - 674
DOI: 10.1126/science.3101176
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Articles

Science, Vol 235, Issue 4789, 670-674
Copyright © 1987 by American Association for the Advancement of Science

articles

Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses

YA Hannun and RM Bell

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.


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