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Vol. 273, Issue 2, 685-688, January 9, 1998
From the Howard Hughes Medical Institute, Departments of Medicine
and Biochemistry, Duke University Medical Center, Durham, North
Carolina 27710
The classical paradigm for G protein-coupled
receptor (GPCR) signal transduction involves the
agonist-dependent interaction of GPCRs with heterotrimeric G
proteins at the plasma membrane and the subsequent generation, by
membrane-localized effectors, of soluble second messengers or ion
currents. Termination of GPCR signals follows G protein-coupled
receptor kinase (GRK)- and 
-arrestin-mediated receptor uncoupling
and internalization. Here we show that these paradigms are inadequate
to account for GPCR-mediated, Ras-dependent activation of
the mitogen-activated protein (MAP) kinases Erk1 and -2. In HEK293
cells expressing dominant suppressor mutants of -arrestin or
dynamin, 2-adrenergic receptor-mediated activation of MAP kinase is inhibited. The inhibitors of receptor internalization specifically blocked Raf-mediated activation of MEK. Plasma
membrane-delimited steps in the GPCR-mediated activation of the MAP
kinase pathway, such as tyrosine phosphorylation of Shc and Raf kinase
activation by Ras, are unaffected by inhibitors of receptor
internalization. Thus, GRKs and -arrestins, which uncouple GPCRs and
target them for internalization, function as essential elements in the
GPCR-mediated MAP kinase signaling cascade.
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