Ras/Mitogen-activated Protein Kinase (MAPK) Signaling Modulates Protein Stability and Cell Surface Expression of Scavenger Receptor SR-BI*
| Autor: | Carlos Enrich, Albert Pol, Masoud Darabi, Gilles Lambert, Peta Wood, Joerg Heeren, Kerry-Anne Rye, Thomas Grewal, Karen Cecilia Chan, Vishwaroop Mulay |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
MAPK/ERK pathway
Proteasome Endopeptidase Complex MAP Kinase Signaling System MAP Kinase Kinase 2 MAP Kinase Kinase 1 CHO Cells Biology Biochemistry Cricetulus Cricetinae Animals Humans PPAR alpha Scavenger receptor Kinase activity Enzyme Inhibitors Phosphorylation Liver X receptor Protein kinase A Molecular Biology Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Protein Stability Chinese hamster ovary cell Reverse cholesterol transport Cell Biology Scavenger Receptors Class B Molecular biology Cell biology HEK293 Cells Gene Expression Regulation Hepatocytes ras Proteins raf Kinases Signal transduction Lysosomes Signal Transduction |
| Popis: | The mitogen-activated protein kinase (MAPK) Erk1/2 has been implicated to modulate the activity of nuclear receptors, including peroxisome proliferator activator receptors (PPARs) and liver X receptor, to alter the ability of cells to export cholesterol. Here, we investigated if the Ras-Raf-Mek-Erk1/2 signaling cascade could affect reverse cholesterol transport via modulation of scavenger receptor class BI (SR-BI) levels. We demonstrate that in Chinese hamster ovary (CHO) and human embryonic kidney (HEK293) cells, Mek1/2 inhibition reduces PPARα-inducible SR-BI protein expression and activity, as judged by reduced efflux onto high density lipoprotein (HDL). Ectopic expression of constitutively active H-Ras and Mek1 increases SR-BI protein levels, which correlates with elevated PPARα Ser-21 phosphorylation and increased cholesterol efflux. In contrast, SR-BI levels are insensitive to Mek1/2 inhibitors in PPARα-depleted cells. Most strikingly, Mek1/2 inhibition promotes SR-BI degradation in SR-BI-overexpressing CHO cells and human HuH7 hepatocytes, which is associated with reduced uptake of radiolabeled and 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyane-labeled HDL. Loss of Mek1/2 kinase activity reduces SR-BI expression in the presence of bafilomycin, an inhibitor of lysosomal degradation, indicating down-regulation of SR-BI via proteasomal pathways. In conclusion, Mek1/2 inhibition enhances the PPARα-dependent degradation of SR-BI in hepatocytes. |
| Databáze: | OpenAIRE |
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