The Npc1 mutation causes an altered expression of caveolin-1, annexin II and protein kinases and phosphorylation of caveolin-1 and annexin II in murine livers
Copyright policy )The Npc1 mutation causes an altered expression of caveolin-1, annexin II and protein kinases and phosphorylation of caveolin-1 and annexin II in murine livers
We have previously demonstrated (1) an increased expression of caveolin-1 in murine heterozygous and homozygous Niemann-Pick type C (NPC) livers, and (2) an increased concentration of unesterified cholesterol in a detergent insoluble caveolae-enriched fraction from homozygous livers. To define further the relationship between caveolin-1 function and the cholesterol trafficking defect in NPC, we examined the expression and distribution of additional caveolar and signal transduction proteins. The expression of annexin II was significantly increased in homozygous liver homogenates and the Triton X-100 insoluble floating fraction (TIFF). Phosphoamino acid analysis of caveolin-1 and annexin II from the homozygous TIFF demonstrated an increase in serine and tyrosine phosphorylation, respectively. To determine the basis for increased phosphorylation of these proteins, the expression and distribution of several protein kinases was examined. The expression of PKCalpha, PKCzeta and pp60-src (protein kinases) were significantly increased in both heterozygous and homozygous liver homogenates, while PKCdelta was increased only in homozygous livers. Of the protein kinases analyzed, only CK IIalpha was significantly enriched in the heterozygous TIFF. Finally, the concentration of diacylglycerol in the homozygous TIFF was significantly increased and this elevation may modulate PKC distribution and function. These results provide additional evidence for involvement of a caveolin-1 containing cellular fraction in the pathophysiology of NPC and also suggest that the Npc1 gene product may directly or indirectly, regulate the expression and distribution of signaling molecules.
- University of Arizona United States
Male, Octoxynol, Caveolin 1, In Vitro Techniques, Caveolins, Annexin II, Diglycerides, Mice, Protein kinase A, Caveolin-1, Protein kinase C, pp60-src, Niemann-Pick C1 Protein, Animals, Phosphorylation, Niemann-Pick type C, Molecular Biology, Annexin A2, Phospholipids, Niemann-Pick Diseases, Mice, Inbred BALB C, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Disease Models, Animal, Cholesterol, Liver, Casein kinase IIα, Molecular Medicine, Female
Male, Octoxynol, Caveolin 1, In Vitro Techniques, Caveolins, Annexin II, Diglycerides, Mice, Protein kinase A, Caveolin-1, Protein kinase C, pp60-src, Niemann-Pick C1 Protein, Animals, Phosphorylation, Niemann-Pick type C, Molecular Biology, Annexin A2, Phospholipids, Niemann-Pick Diseases, Mice, Inbred BALB C, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Disease Models, Animal, Cholesterol, Liver, Casein kinase IIα, Molecular Medicine, Female
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