beta-Arrestin- mediated ADP-ribosylation factor 6 activation and beta 2-adrenergic receptor endocytosis.
beta-Arrestins are multifunctional adaptor proteins known to regulate internalization of agonist-stimulated G protein- coupled receptors by linking them to endocytic proteins such as clathrin and AP-2. Here we describe a previously unappreciated mechanism by which beta-arrestin orchestrates the process of receptor endocytosis through the activation of ADP-ribosylation factor 6 (ARF6), a small GTP-binding protein. Involvement of ARF6 in the endocytic process is demonstrated by the ability of GTP-binding defective and GTP hydrolysis-deficient mutants to inhibit internalization of the beta(2)-adrenergic 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 stimulation of the receptor, beta-arrestin also interacts with the GDP-liganded form of ARF6, thereby facilitating ARNO- promoted GTP loading and activation of the G protein. Thus, the agonist-driven formation of a complex including beta-arrestin, ARNO, and ARF6 provides a molecular mechanism that explains how the agonist- stimulated receptor recruits a small G protein necessary for the endocytic process and controls its activation.[1]References
- beta-Arrestin-mediated ADP-ribosylation factor 6 activation and beta 2-adrenergic receptor endocytosis. Claing, A., Chen, W., Miller, W.E., Vitale, N., Moss, J., Premont, R.T., Lefkowitz, R.J. J. Biol. Chem. (2001) [Pubmed]
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