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[beta]1 adrenergic receptor ([beta]1AR)‐epidermal growth factor receptor (EGFR) interaction regulates ERK cellular activity
Author(s) -
Tilley Douglas G.,
Rockman Howard A.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.723.1
Subject(s) - microbiology and biotechnology , mapk/erk pathway , transactivation , arrestin , hek 293 cells , epidermal growth factor receptor , signal transduction , g protein coupled receptor , epidermal growth factor , phosphorylation , cardioprotection , receptor , chemistry , stimulation , biology , medicine , endocrinology , biochemistry , transcription factor , ischemia , gene
Recently, we showed that β1AR stimulation mediates transactivation of the EGFR and induces ERK activation in a βarrestin‐dependent manner to confer cardioprotection. However, ERK activation is associated with increased cardiac growth and hypertrophy, frequently a detrimental process in the failing heart. Therefore, we hypothesized that the β1AR and EGFR form a βarrestin‐dependent signaling complex in which ERK may be differentially targeted within the cell. Here, via (A) confocal microscopy, (B) immunoprecipitation and (C) FRET‐based assays, we show the physical association between β1AR and EGFR in a HEK 293 cell‐based system that is regulated by agonist stimulation. The interaction between β1AR and EGFR and the stimulation‐induced recruitment of βarrestin to the receptor complex is dependent on G protein receptor‐coupled kinase (GRK) phosphorylation sites in the C‐terminal tail of β1AR. While both β1AR stimulation and EGF ligand induce EGFR activation, EGF ligand causes translocation of activated ERK to the nucleus, whereas β1AR‐activated ERK is restricted to the cytoplasm. These data reveal a new signaling paradigm in which a β 1 AR‐EGFR‐βarrestin complex acts to retain activated ERK in the cytoplasm, resulting in differential intracellular targeting of ERK signaling. Supported by the Heart and Stroke Foundation of Canada and the National Institutes of Health.