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PMID: 19153083 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

MEK1 binds directly to betaarrestin1, influencing both its phosphorylation by ERK and the timing of its isoprenaline-stimulated internalization.

The Journal of biological chemistry ·Vol. 284 ·No. 17 ·2009-04-24 ·Pages 11425-35

Meng D, Lynch MJ, Huston E, Beyermann M, Eichhorst J, Adams DR, Klussmann E, Klusmann E, Houslay MD, Baillie GS

Abstract

betaArrestin is a multifunctional signal scaffold protein. Using SPOT immobilized peptide arrays, coupled with scanning alanine substitution and mutagenesis, we show that the MAPK kinase, MEK1, interacts directly with betaarrestin1. Asp(26) and Asp(29) in the N-terminal domain of betaarrestin1 are critical for its binding to MEK1, whereas Arg(47) and Arg(49) in the N-terminal domain of MEK1 are critical for its binding to betaarrestin1. Wild-type FLAG-tagged betaarrestin1 co-immunopurifies with MEK1 in HEKB2 cells, whereas the D26A/D29A mutant does not. ERK-dependent phosphorylation at Ser(412) was compromised in the D26A/D29A-betaarrestin1 mutant. A cell-permeable, 25-mer N-stearoylated betaarrestin1 peptide that encompassed the N-domain MEK1 binding site blocked betaarrestin1/MEK1 association in HEK cells and recapitulated the altered phenotype seen with the D26A/D29A-betaarrestin1 in compromising the ERK-dependent phosphorylation of betaarrestin1. In addition, the MEK disruptor peptide promoted the ability of betaarrestin1 to co-immunoprecipitate with endogenous c-Src and clathrin, facilitating the isoprenaline-stimulated internalization of the beta(2)-adrenergic receptor.

MeSH Terms
Adrenergic beta-Agonists/pharmacology Amino Acid Sequence Arginine/chemistry Arrestins/metabolism Aspartic Acid/chemistry Clathrin/metabolism Humans Isoproterenol/metabolism MAP Kinase Kinase 1/metabolism Models, Biological Molecular Sequence Data Phosphorylation Protein Structure, Tertiary Sequence Homology, Amino Acid beta-Arrestins src-Family Kinases/metabolism
Chemicals
Adrenergic beta-Agonists Arrestins Clathrin beta-Arrestins Aspartic Acid Arginine src-Family Kinases MAP Kinase Kinase 1 MAP2K1 protein, human Isoproterenol
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Meng Dong
Neuroscience and Molecular Pharmacology, Faculty of Biomedical and Life Sciences, Wolfson Building, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom.
Lynch Martin J
Huston Elaine
Beyermann Michael
Eichhorst Jenny
Adams David R
Klussmann Enno
Klusmann Enno
Houslay Miles D
Baillie George S
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M806395200
Published
2009-04-24
Epub
2009-00-19
Pages
11425-35
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2670148
Subset
IM
Grants
Medical Research Council · G0600765 · United Kingdom
Medical Research Council · G8604010 · United Kingdom
Medical Research Council · G0400053 · United Kingdom
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1074/jbc.M806395200 PMC Full Text View journal details
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