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

Citation
Ws. Garver et al., 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, BBA-MOL BAS, 1453(2), 1999, pp. 193-206
Citations number
61
Categorie Soggetti
Medical Research General Topics
Journal title
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
ISSN journal
09254439 → ACNP
Volume
1453
Issue
2
Year of publication
1999
Pages
193 - 206
Database
ISI
SICI code
0925-4439(19990224)1453:2<193:TNMCAA>2.0.ZU;2-J
Abstract
We have previously demonstrated (I) an increased expression of caveolin-1 i n murine heterozygous and homozygous Niemann-Pick type C (NPC) livers, and (2) an increased concentration of unesterified cholesterol in a detergent i nsoluble caveolae-enriched fraction from homozygous livers. To define furth er the relationship between caveolin-1 function and the cholesterol traffic king defect in NPC, we examined the expression and distribution of addition al 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 cav eolin-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 distrib ution of several protein kinases was examined. The expression of PKC alpha, PKC zeta and pp60-src (protein kinases) were significantly increased in bo th heterozygous and homozygous liver homogenates, while PKC delta was incre ased only in homozygous livers. Of the protein kinases analyzed, only CK II alpha was significantly enriched in the heterozygous TIFF. Finally, the co ncentration of diacylglycerol in the homozygous TIFF was significantly incr eased and this elevation may modulate PKC distribution and function. These results provide additional evidence for involvement of a caveolin-1 contain ing cellular fraction in the pathophysiology of NPC and also suggest that t he Npc1 gene product may directly or indirectly, regulate the expression an d distribution of signaling molecules. (C) 1999 Elsevier Science B.V. All r ights reserved.