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Analysis of SCAP N-glycosylation and Trafficking in Human Cells
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Ras/mitogen-activated protein kinase (MAPK) signaling modulates protein stability and cell surface expression of

Peta Wood1, Vishwaroop Mulay, Masoud Darabi

  • 1Faculty of Pharmacy, University of Sydney, Sydney, New South Wales 2006, Australia.

The Journal of Biological Chemistry
|April 29, 2011
PubMed

Insights

Mitogen-activated protein kinase (MAPK) Erk1/2 signaling impacts cholesterol export. Mek1/2 inhibition enhances PPARα-dependent degradation of scavenger receptor class BI (SR-BI) in liver cells.

Area of Science:

  • Cellular biology
  • Molecular biology
  • Biochemistry

Background:

  • Mitogen-activated protein kinase (MAPK) Erk1/2 signaling pathways regulate various cellular processes.
  • Nuclear receptors, such as peroxisome proliferator activator receptors (PPARs), play crucial roles in cholesterol homeostasis.
  • Scavenger receptor class BI (SR-BI) is a key mediator of reverse cholesterol transport.

Purpose of the Study:

  • To investigate the role of the Ras-Raf-Mek-Erk1/2 signaling cascade in regulating reverse cholesterol transport.
  • To determine if Mek1/2 signaling affects scavenger receptor class BI (SR-BI) expression and activity.
  • To elucidate the impact of Mek1/2 inhibition on SR-BI levels and cholesterol efflux.

Main Methods:

  • Utilized Chinese hamster ovary (CHO) and human embryonic kidney (HEK293) cells for experiments.
  • Employed Mek1/2 inhibitors and ectopic expression of signaling components (H-Ras, Mek1).
  • Assessed SR-BI protein expression, activity, cholesterol efflux, and degradation pathways (proteasomal and lysosomal).

Main Results:

  • Mek1/2 inhibition reduced PPARα-inducible SR-BI expression and activity, decreasing cholesterol efflux onto HDL.
  • Constitutively active H-Ras and Mek1 increased SR-BI levels and cholesterol efflux, correlating with PPARα phosphorylation.
  • Mek1/2 inhibition promoted SR-BI degradation via proteasomal pathways in hepatocytes, reducing HDL uptake.

Conclusions:

  • The Ras-Raf-Mek-Erk1/2 signaling cascade modulates SR-BI levels and function.
  • Mek1/2 activity is essential for maintaining SR-BI expression and facilitating cholesterol efflux.
  • Mek1/2 inhibition leads to enhanced PPARα-dependent SR-BI degradation in hepatocytes, impacting cholesterol transport.

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