Arrestins as adaptors for ubiquitination in endocytosis and sorting

Endocytosis is the process by which cells internalize portions of their cell membrane along with embedded proteins. These membrane proteins can be recycled back to the plasma membrane from the endosomal compartments to be reused or, alternatively, follow a degradative pathway to the lysosomes. Seven transmembrane receptors (7TMRs) are a well‐studied class of resident plasma‐membrane proteins that have been extensively characterized in terms of their downregulation and removal from the cell surface. The cytoplasmic tails of activated receptors can be phosphorylated, thereby creating binding sites for the arrestin proteins—so‐named because they physically preclude the interaction of receptors with G‐proteins, thereby arresting further signalling from these receptors. Arrestin proteins also promote the internalization of receptors by acting as adaptors for the endocytic proteins clathrin and AP2 (Lefkowitz et al , 2006). Humans have been presumed to have four ‘true’ arrestins, two photoreceptor‐specific visual arrestins and two ubiquitous β‐arrestins, so‐called because they were discovered as β2‐adrenergic‐receptor‐binding proteins. The arrestin family of adaptor proteins has recently expanded, and the new arrestin‐related proteins are no longer limited to the 7TMRs, but are now known to couple to other transmembrane proteins for internalization.Membrane proteins are often observed to be ubiquitinated during arrestin‐mediated internalization. Monoubiquitination of yeast cell‐surface receptors is now recognized as an internalization signal, whereas ubiquitination of mammalian 7TMRs and growth factor receptors has been shown to function as a lysosomal sorting signal (Haglund et al , 2003). Interestingly, β‐arrestins have been shown to function as adaptors in the process of receptor ubiquitination—as in the case of the β2‐adrenergic receptor—and are themselves ubiquitinated. Ubiquitination of arrestin is important for its stable binding to activated receptors; thus, slower deubiquitination of arrestin correlates with stable receptor association (Shenoy, 2007). Two studies have recently identified a family of arrestin‐like proteins that have a similar role in the endocytosis …