Upon their discovery, β-arrestins 1 and 2 were named for their capacity to sterically hinder the G protein coupling of agonist-activated seven-transmembrane receptors, ultimately resulting in receptor desensitization. Surprisingly, recent evidence shows that β-arrestins can also function to activate signaling cascades independently of G protein activation. By serving as multiprotein scaffolds, the β-arrestins bring elements of specific signaling pathways into close proximity. β-Arrestin regulation has been demonstrated for an everincreasing number of signaling molecules, including the mitogenactivated protein kinases ERK, JNK, and p38 as well as Akt, PI3 kinase, and RhoA. In addition, investigators are discovering new roles for β-arrestins in nuclear functions. Here, we review the signaling capacities of these versatile adapter molecules and discuss the possible implications for cellular processes such as chemotaxis and apoptosis.

(maximum stimulation Ϸ50% of wild type). This G protein-independent activation of mitogen-activated protein kinase is abolished by depletion of cellular ␤-arrestin 2 but is unaffected by the PKC inhibitor Ro-31-8425. In parallel, stimulation of the wild-type angiotensin type 1A receptor with Ang II robustly stimulates ERK1͞2 activation with Ϸ60% of the response blocked by the PKC inhibitor (G protein dependent) and the rest of the response blocked by depletion of cellular ␤-arrestin 2 by small interfering RNA (␤-arrestin dependent). These findings imply the existence of independent G protein-and ␤-arrestin 2-mediated pathways leading to ERK1͞2 activation and the existence of distinct ''active'' conformations of a seven-membrane-spanning receptor coupled to each.