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
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
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.