Ras/mitogen-activated protein kinase (MAPK) signaling modulates protein stability and cell surface expression of scavenger receptor SR-BI.
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Ras/mitogen-activated protein kinase (MAPK) signaling modulates protein stability and cell surface expression of scavenger receptor SR-BI. / Wood, Peta; Mulay, Vishwaroop; Darabi, Masoud; Chan, Karen Cecilia; Heeren, Jörg; Pol, Albert; Lambert, Gilles; Rye, Kerry-Anne; Enrich, Carlos; Grewal, Thomas.
in: J BIOL CHEM, Jahrgang 286, Nr. 26, 26, 2011, S. 23077-23092.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Ras/mitogen-activated protein kinase (MAPK) signaling modulates protein stability and cell surface expression of scavenger receptor SR-BI.
AU - Wood, Peta
AU - Mulay, Vishwaroop
AU - Darabi, Masoud
AU - Chan, Karen Cecilia
AU - Heeren, Jörg
AU - Pol, Albert
AU - Lambert, Gilles
AU - Rye, Kerry-Anne
AU - Enrich, Carlos
AU - Grewal, Thomas
PY - 2011
Y1 - 2011
N2 - 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 PPAR?-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 PPAR? Ser-21 phosphorylation and increased cholesterol efflux. In contrast, SR-BI levels are insensitive to Mek1/2 inhibitors in PPAR?-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 PPAR?-dependent degradation of SR-BI in hepatocytes.
AB - 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 PPAR?-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 PPAR? Ser-21 phosphorylation and increased cholesterol efflux. In contrast, SR-BI levels are insensitive to Mek1/2 inhibitors in PPAR?-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 PPAR?-dependent degradation of SR-BI in hepatocytes.
KW - Animals
KW - Humans
KW - CHO Cells
KW - Cricetinae
KW - Cricetulus
KW - HEK293 Cells
KW - Enzyme Inhibitors/pharmacology
KW - Gene Expression Regulation/drug effects/physiology
KW - Hepatocytes/metabolism
KW - Lysosomes/genetics/metabolism
KW - MAP Kinase Kinase 1/antagonists & inhibitors/genetics/metabolism
KW - MAP Kinase Kinase 2/antagonists & inhibitors/genetics/metabolism
KW - MAP Kinase Signaling System/drug effects/physiology
KW - Mitogen-Activated Protein Kinase 1/antagonists & inhibitors/genetics/metabolism
KW - Mitogen-Activated Protein Kinase 3/antagonists & inhibitors/genetics/metabolism
KW - PPAR alpha/genetics/metabolism
KW - Phosphorylation/drug effects/physiology
KW - Proteasome Endopeptidase Complex/genetics/metabolism
KW - Protein Stability/drug effects
KW - Scavenger Receptors, Class B/biosynthesis/genetics
KW - raf Kinases/antagonists & inhibitors/genetics/metabolism
KW - ras Proteins/genetics/metabolism
KW - Animals
KW - Humans
KW - CHO Cells
KW - Cricetinae
KW - Cricetulus
KW - HEK293 Cells
KW - Enzyme Inhibitors/pharmacology
KW - Gene Expression Regulation/drug effects/physiology
KW - Hepatocytes/metabolism
KW - Lysosomes/genetics/metabolism
KW - MAP Kinase Kinase 1/antagonists & inhibitors/genetics/metabolism
KW - MAP Kinase Kinase 2/antagonists & inhibitors/genetics/metabolism
KW - MAP Kinase Signaling System/drug effects/physiology
KW - Mitogen-Activated Protein Kinase 1/antagonists & inhibitors/genetics/metabolism
KW - Mitogen-Activated Protein Kinase 3/antagonists & inhibitors/genetics/metabolism
KW - PPAR alpha/genetics/metabolism
KW - Phosphorylation/drug effects/physiology
KW - Proteasome Endopeptidase Complex/genetics/metabolism
KW - Protein Stability/drug effects
KW - Scavenger Receptors, Class B/biosynthesis/genetics
KW - raf Kinases/antagonists & inhibitors/genetics/metabolism
KW - ras Proteins/genetics/metabolism
M3 - SCORING: Journal article
VL - 286
SP - 23077
EP - 23092
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 26
M1 - 26
ER -
