Figure 1. Multifaceted functions of β-arrestins.

Desensitization: Agonist-stimulation of 7TMRs leads to G protein coupling and activation, following which the receptors are rapidly phosphorylated by G protein-coupled receptor kinases (GRKs). Phosphorylated receptors present high affinity binding surfaces to recruit the cytosolic adaptors, β-arrestins. Steric binding by β-arrestin interferes with further G protein coupling leading to the desentization of G protein-dependent signaling. β-arrestins also scaffold the second messenger degrading enzymes (phosphodiesterase 4D, PDE4D that degrades cAMP and diacyl glycerol kinase or DAG-K that converts diacyl glycerol to phosphatidic acid).

Endocytosis: Agonist-stimulation promotes rapid internalization of cell-surface 7TMRs into clathrin-coated vesicles. This internalization is facilitated by β-arrestin binding, which has specific binding domains for clathrin and AP2 interactions. β-arrestin binding to other endocytic proteins is also required for efficient receptor internalization: N ethyl maleimide fusion protein, NSF and ADP ribosylation factor 6, Arf6. The interaction between β-arrestin and the E3 ubiquitin ligase Mdm2 (mouse double minute 2) promotes ubiquitination of β-arrestin, that facilitates robust binding of β-arrestin with both cargo (7TMR) as well as endocytic machinery (clathrin and AP2). Receptor internalization is followed by post-endocytic sorting of internalized receptors for recycling or lysosomal degradation.

Signaling: β-arrestin acquires an active conformation upon forming a complex with agonist-stimulated 7TMRs and scaffolds MAP kinase, MAP kinase kinase, and MAP kinase kinase kinase, leading to the robust activation of MAP kinase, and subsequently targets the activated kinase to distinct subcellular compartments. Such β-arrestin-dependent MAP Kinase activity has been shown to regulate cellular chemotaxis, apoptosis, cancer metastasis and protein translation.