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PMID:10734107

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Citation

Maudsley, S, Pierce, KL, Zamah, AM, Miller, WE, Ahn, S, Daaka, Y, Lefkowitz, RJ and Luttrell, LM (2000) The beta(2)-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor. J. Biol. Chem. 275:9572-80

Abstract

Many G protein-coupled receptors (GPCRs) activate MAP kinases by stimulating tyrosine kinase signaling cascades. In some systems, GPCRs stimulate tyrosine phosphorylation by inducing the "transactivation" of a receptor tyrosine kinase (RTK). The mechanisms underlying GPCR-induced RTK transactivation have not been clearly defined. Here we report that GPCR activation mimics growth factor-mediated stimulation of the epidermal growth factor receptor (EGFR) with respect to many facets of RTK function. beta(2)-Adrenergic receptor (beta(2)AR) stimulation of COS-7 cells induces EGFR dimerization, tyrosine autophosphorylation, and EGFR internalization. Coincident with EGFR transactivation, isoproterenol exposure induces the formation of a multireceptor complex containing both the beta(2)AR and the "transactivated" EGFR. beta(2)AR-mediated EGFR phosphorylation and subsequent beta(2)AR stimulation of extracellular signal-regulated kinase (ERK) 1/2 are sensitive to selective inhibitors of both EGFR and Src kinases, indicating that both kinases are required for EGFR transactivation. beta(2)AR-dependent signaling to ERK1/2, like direct EGF stimulation of ERK1/2 activity, is sensitive to inhibitors of clathrin-mediated endocytosis, suggesting that signaling downstream of both the EGF-activated and the GPCR-transactivated EGFRs requires a productive engagement of the complex with the cellular endocytic machinery. Thus, RTK transactivation is revealed to be a process involving both association of receptors of distinct classes and the interaction of the transactivated RTK with the cells endocytic machinery.

Links

PubMed

Keywords

Animals; COS Cells; Clathrin/physiology; Endocytosis/physiology; Enzyme Activation/physiology; Ligands; Mitogen-Activated Protein Kinases/metabolism; Phosphorylation; Protein Binding; Receptor, Epidermal Growth Factor/genetics; Receptor, Epidermal Growth Factor/metabolism; Receptors, Adrenergic, beta-2/metabolism; Receptors, Adrenergic, beta-2/physiology; Transcriptional Activation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ADRB2

involved_in

GO:0007171: activation of transmembrane receptor protein tyrosine kinase activity

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ADRB2

located_in

GO:0005768: endosome

ECO:0000304: author statement supported by traceable reference used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SRC

involved_in

GO:0007165: signal transduction

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:EGFR_original

GO:0007173: epidermal growth factor receptor signaling pathway

TAS: Traceable Author Statement: :

P


HUMAN:EGFR_original

GO:0007173: epidermal growth factor receptor signaling pathway

TAS: Traceable Author Statement:

P


HUMAN:SRC

involved_in

GO:0007165: signal transduction

ECO:0000304: author statement supported by traceable reference used in manual assertion


P

Seeded From UniProt

complete


See also

References

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