A. Claing et al., beta-arrestin-mediated ADP-ribosylation factor 6 activation and beta(2)-adrenergic receptor endocytosis, J BIOL CHEM, 276(45), 2001, pp. 42509-42513
beta -Arrestins are multifunctional adaptor proteins known to regulate inte
rnalization of agonist-stimulated G protein-coupled receptors by linking th
em to endocytic proteins such as clathrin and AP-2. Here we describe a prev
iously unappreciated mechanism by which beta -arrestin orchestrates the pro
cess of receptor endocytosis through the activation of ADP-ribosylation fac
tor 6 (ARF6), a small GTP-binding protein. Involvement of ARF6 in the endoc
ytic process is demonstrated by the ability of GTP-binding defective and GT
P hydrolysis-deficient mutants to inhibit internalization of the beta (2)-a
drenergic receptor. The importance of regulation of ARF6 function is shown
by the ability of the ARF GTPase-activating protein GIT1 to inhibit and of
the ARF nucleotide exchange factor, ARNO, to enhance receptor endocytosis.
Endogenous beta -arrestin is found in complex with ARNO. Upon agonist stimu
lation of the receptor, beta -arrestin also interacts with the GDP-liganded
form of ARF6, thereby facilitating ARNO-promoted GTP loading and activatio
n of the G protein. Thus, the agonist-driven formation of a complex includi
ng beta -arrestin, ARNO, and ARF6 provides a molecular mechanism that expla
ins how the agonist-stimulated receptor recruits a small G protein necessar
y for the endocytic process and controls its activation.