A Broader Role for β-Arrestins

Abstract

β-Arrestins are multifunctional proteins that desensitize heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors and help link such receptors to cellular signaling pathways, as well as promote endocytosis of the receptors. In two reports, Chen et al. (see the Perspective by Spiegel) show that β-arrestins are even more versatile than previously thought. β-arrestin 2 is required to promote internalization of Frizzled proteins (the cell surface receptors for Wnt glycoproteins). In this role, β-arrestins do not bind directly to receptors, as they do with G protein-coupled receptors. Rather, β-arrestin 2 binds to a protein called disheveled (Dvl) that is recruited to activated Frizzled receptor proteins in the cell membrane. Once Dvl brings β-arrestin to Frizzled receptor protein complexes, the receptors are recruited into clathrin-coated pits for internalization. β-arrestins also promote internalization of a completely different type of receptor, the transforming growth factor-β receptor type III. In this case, β-arrestin binds to a receptor subunit that is phosphorylated by another receptor subunit. W. Chen, D. ten Berge, J. Brown, S. Ahn, L. A. Hu, W. E. Miller, M. G. Caron, L. S. Barak, R. Nusse, R. J. Lefkowitz, Dishevelled 2 recruits β-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4. Science 301 , 1391-1394 (2003). [Abstract] [Full Text] W. Chen, K. C. Kirkbride, T. How, C. D. Nelson, J. Mo, J. P. Frederick, X.-F. Wang, R. J. Lefkowitz, G. C. Blobe, β-Arrestin 2 mediates endocytosis of type III TGF-β receptor and down-regulation of its signaling. Science 301 , 1394-1397 (2003). [Abstract] [Full Text] A. Spiegel, ß-Arrestin--Not just for G protein-coupled receptors. Science 301 , 1338-1339 (2003). [Summary] [Full Text]