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PMID: 12773382 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

A cholesterol-regulated PP2A/HePTP complex with dual specificity ERK1/2 phosphatase activity.

The EMBO journal ·Vol. 22 ·No. 11 ·2003-06-02 ·Pages 2658-67

Wang PY, Liu P, Weng J, Sontag E, Anderson RG

Abstract

The acute depletion of membrane cholesterol causes the concentration of pERK1/2 in caveola/raft lipid domains and the cytosol of human fibroblasts to dramatically increase. This increase could be caused by either the activation of MEK-1 or the inhibition of a pERK phosphatase. Here we describe the isolation of a high molecular weight ( approximately 440 kDa), cholesterol-regulated pERK phosphatase that dephosphorylates both the phosphotyrosine and the phosphothreonine residues in the activation loop of the enzyme. The dual activity in the complex appears to be due to the combined activities of the serine/threonine phosphatase PP2A and the tyrosine phosphatase HePTP. Acute depletion of cholesterol causes the disassembly of the complex and a concomitant loss of the dual specificity pERK phosphatase activity. The existence of a cholesterol-regulated HePTP/PP2A activity provides a molecular explanation for why ERK activity is sensitive to membrane cholesterol levels, and raises the possibility that ERK plays a role in regulating the traffic of cholesterol to caveolae/rafts and other membranes.

MeSH Terms
Biological Transport, Active Cells, Cultured Cholesterol/metabolism HeLa Cells Humans Intracellular Signaling Peptides and Proteins Macromolecular Substances Membrane Microdomains/metabolism Mitogen-Activated Protein Kinase 1/chemistry,metabolism Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases/chemistry,metabolism Phosphoprotein Phosphatases/chemistry,metabolism Phosphorylation Protein Tyrosine Phosphatase, Non-Receptor Type 6 Protein Tyrosine Phosphatases/chemistry,metabolism Protein Tyrosine Phosphatases, Non-Receptor Recombinant Proteins/chemistry,metabolism Transfection
Chemicals
Intracellular Signaling Peptides and Proteins Macromolecular Substances Recombinant Proteins Cholesterol Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases Phosphoprotein Phosphatases PTPN6 protein, human PTPN7 protein, human Protein Tyrosine Phosphatase, Non-Receptor Type 6 Protein Tyrosine Phosphatases Protein Tyrosine Phosphatases, Non-Receptor
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Wang Ping-Yuan
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9039, USA.
Liu Pingsheng
Weng Jian
Sontag Estelle
Anderson Richard G W
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdg255
Published
2003-06-02
Pages
2658-67
Language
English
Region
England
NLM ID
8208664
PMCID
PMC156752
Subset
IM
Grants
NIA NIH HHS · R56 AG018883 · United States
NHLBI NIH HHS · P01 HL020948 · United States
NIA NIH HHS · R01 AG018883 · United States
NIA NIH HHS · AG 18883 · United States
NIGMS NIH HHS · GM 52016 · United States
NHLBI NIH HHS · HL 20948 · United States
NIGMS NIH HHS · R01 GM052016 · United States
External Links
PubMed source DOI: 10.1093/emboj/cdg255 PMC Full Text View journal details
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