β-Arrestins are cytosolic proteins that bind to activated and phosphorylated G-protein-coupled receptors [7MSRs (seven-membrane-spanning receptors)] and uncouple them from G-protein-mediated second messenger signalling pathways. The binding of β-arrestins to 7MSRs also leads to new signals via activation of MAPKs (mitogen-activated protein kinases) such as JNK3 (c-Jun N-terminal kinase 3), ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 MAPKs. By binding to endocytic proteins [clathrin, AP2 (adapter protein 2), NSF (N-ethylmaleimide-sensitive fusion protein) and ARF6 (ADP-ribosylation factor 6)], β-arrestins also serve as adapters to link the receptors to the cellular trafficking machinery. Agonist-promoted ubiquitination of β-arrestins is a prerequisite for their role in receptor internalization, as well as a determinant of the differing trafficking patterns of distinct classes of receptors. Recently, β-arrestins have also been implicated as playing novel roles in cellular chemotaxis and apoptosis. By virtue of their ability to bind, in a stimulus-dependent fashion, to 7MSRs as well as to different classes of cellular proteins, β-arrestins serve as versatile adapter proteins that regulate the signalling and trafficking of the receptors.
Abbreviations used: AP, adapter protein; β2AR, β2-adrenergic receptor; βARK, β-adrenergic receptor kinase; ARF, ADP-ribosylation factor; ARNO, ARF nucleotide binding site opener; ASK, apoptosis signal-regulating kinase; AT1AR, AT1A angiotensin receptor; Dvl, Dishevelled; ERK, extracellular-signal-regulated kinase; Fz4, Frizzled 4; GAP, GTPase-activating protein; GDS, GDP dissociation stimulator; GEF, guanine nucleotide exchange factor; GFP, green fluorescent protein; GPCR, G-protein-coupled receptor; GRK, G-protein-coupled receptor kinase; IGF, insulin-like growth factor; JNK, c-Jun N-terminal kinase; JIP, Jnk-interacting protein; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; MAPKKK, MAPKK kinase; MEK, MAPK/ERK kinase; 7MSR, seven-membrane-spanning receptor; NSF, N-ethylmaleimide-sensitive fusion protein; PAR, proteinase-activated receptor; PDE, phosphodiesterase; PH domain, pleckstrin homology domain; PKA, protein kinase A; PKC, protein kinase C; RGS, regulators of G-protein signalling; RH domain, RGS homology domain; SAPK, stress-activated protein kinase; SDF, stromal cell-derived factor; SH3 domain, Src homology 3 domain; siRNA, small interfering RNA; Ub, ubiquitin; V2R, V2 vasopressin receptor.