Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lamellar granules are sphingolipid-enriched organelles, probably intimately related to the tubulo-vesicular elements of the trans-Golgi network, that deliver the precursors of stratum corneum barrier lipids to the extracellular compartment. Caveolins are cholesterol-binding scaffolding proteins that facilitate the assembly of cholesterol- and sphingolipid-enriched membrane domains known as caveolae. Similarities in the composition of lamellar granules and caveolae suggest that caveolins could be involved in lamellar granule assembly, trafficking, and/or function. In order to explore this relationship, we have examined the expression of caveolins in epidermis, keratinocyte cultures, and an isolated lamellar granule fraction using immunolabeling, immunoblotting, and northern blotting. Several antibodies show immunolocalization of caveolin-1 in the basal layer of human epidermis, with a decline in the suprabasal layers and a reemergence of expression at the stratum granulosum/stratum corneum junction. Two of three caveolin-2 antibodies show little basal staining, but strong signal throughout the rest of the epidermis, whereas a third shows a pattern like caveolin-1. An antibody against caveolin-3 shows a strong signal at the stratum granulosum/stratum corneum interface. Caveolins partially colocalize with glucocerebrosidase, an enzyme known to be critical for remodeling of extruded lamellar granule contents, with AE17, a previously described lamellar-granule-associated antibody, and with glucosylceramides, a major lipid component of lamellar granules. Caveolin-1 protein is present in undifferentiated low-calcium-grown keratinocyte cultures, decreases upon induction of differentiation, and then rises to levels above those seen in undifferentiated cultures, consistent with the immunofluorescence findings. Caveolin-1 mRNA expression parallels that of the protein. Caveolin-2 mRNA and protein expression were unchanged over the course of culture differentiation. Keratinocyte caveolin-1 mRNA expression is not induced by an increase in medium calcium level and is markedly reduced by phorbol-ester-mediated protein kinase C induction. Caveolin-1 is enriched in an isolated lamellar granule fraction that is also enriched, as we have previously described, in lysosomal acid lipase and glucocerebrosidase, and localizes to structures consistent with lamellar granules on immunoelectron microscopy. The differentiation-dependent expression of caveolin-1, the colocalization of caveolins with putative lamellar-granule-associated antigens, their enrichment in isolated lamellar granules, and their presence in lamellar-granule-like structures on immunoelectron microscopy, along with their known structural role in the assembly of glycosphingolipid- and cholesterol-enriched domains in other cell types, suggest that caveolins may play a role in lamellar granule assembly, trafficking, and/or function.
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PMID:Caveolin expression and localization in human keratinocytes suggest a role in lamellar granule biogenesis. 1264 44

Activation of protein kinase C (PKC) promotes the salvage pathway of ceramide formation, and acid sphingomyelinase has been implicated, in part, in providing substrate for this pathway (Zeidan, Y. H., and Hannun, Y. A. (2007) J. Biol. Chem. 282, 11549-11561). In the present study, we examined whether acid beta-glucosidase 1 (GBA1), which hydrolyzes glucosylceramide to form lysosomal ceramide, was involved in PKC-regulated formation of ceramide from recycled sphingosine. Glucosylceramide levels declined after treatment of MCF-7 cells with a potent PKC activator, phorbol 12-myristate 13-acetate (PMA). Silencing GBA1 by small interfering RNAs significantly attenuated acid glucocerebrosidase activity and decreased PMA-induced formation of ceramide by 50%. Silencing GBA1 blocked PMA-induced degradation of glucosylceramide and generation of sphingosine, the source for ceramide biosynthesis. Reciprocally, forced expression of GBA1 increased ceramide levels. These observations indicate that GBA1 activation can generate the source (sphingosine) for PMA-induced formation of ceramide through the salvage pathway. Next, the role of PKCdelta, a direct effector of PMA, in the formation of ceramide was determined. By attenuating expression of PKCdelta, cells failed to trigger PMA-induced alterations in levels of ceramide, sphingomyelin, and glucosylceramide. Thus, PKCdelta activation is suggested to stimulate the degradation of both sphingomyelin and glucosylceramide leading to the salvage pathway of ceramide formation. Collectively, GBA1 is identified as a novel source of regulated formation of ceramide, and PKCdelta is an upstream regulator of this pathway.
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PMID:Involvement of acid beta-glucosidase 1 in the salvage pathway of ceramide formation. 1927 11

In nonneuronopathic type 1 Gaucher disease (GD1), mutations in the glucocerebrosidase gene (GBA1) gene result in glucocerebrosidase deficiency and the accumulation of its substrate, glucocerebroside (GL-1), in the lysosomes of mononuclear phagocytes. This prevailing macrophage-centric view, however, does not explain emerging aspects of the disease, including malignancy, autoimmune disease, Parkinson disease, and osteoporosis. We conditionally deleted the GBA1 gene in hematopoietic and mesenchymal cell lineages using an Mx1 promoter. Although this mouse fully recapitulated human GD1, cytokine measurements, microarray analysis, and cellular immunophenotyping together revealed widespread dysfunction not only of macrophages, but also of thymic T cells, dendritic cells, and osteoblasts. The severe osteoporosis was caused by a defect in osteoblastic bone formation arising from an inhibitory effect of the accumulated lipids LysoGL-1 and GL-1 on protein kinase C. This study provides direct evidence for the involvement in GD1 of multiple cell lineages, suggesting that cells other than macrophages may be worthwhile therapeutic targets.
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PMID:Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage. 2096 79