PMID:10734107

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
edit table

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

References

See Help:References for how to manage references in GONUTS.