Review
Feature Review
Emerging paradigms of β-arrestin-dependent seven transmembrane receptor signaling

https://doi.org/10.1016/j.tibs.2011.06.003Get rights and content

β-Arrestins, originally discovered to desensitize activated seven transmembrane receptors (7TMRs; also known as G-protein-coupled receptors, GPCRs), are now well established mediators of receptor endocytosis, ubiquitylation and G protein-independent signaling. Recent global analyses of β-arrestin interactions and β-arrestin-dependent phosphorylation events have uncovered several previously unanticipated roles of β-arrestins in a range of cellular signaling events. These findings strongly suggest that the functional roles of β-arrestins are much broader than currently understood. Biophysical studies aimed at understanding multiple active conformations of the 7TMRs and the β-arrestins have begun to unravel the mechanistic basis for the diverse functional capabilities of β-arrestins in cellular signaling.

Section snippets

The seven transmembrane receptor (7TMR) superfamily

7TMRs, also referred to as G-protein-coupled receptors (GPCRs), are integral membrane proteins which constitute the largest class of cell surface receptors in the human genome with approximately 800 different members [1]. These receptors bind to a diverse array of ligands which include hormones, peptides, neurotransmitters and lipids [2]. Upon activation, they initiate a range of intracellular signaling pathways to elicit appropriate cellular responses [3]. As 7TMR signaling crucially regulates

β-Arrestins and G-protein-coupled receptor kinases (GRKs): a universal desensitization mechanism

7TMR desensitization is essentially a two-step process (Figure 1b). In the first step, agonist-occupied receptors are phosphorylated by GRKs, primarily in the carboxyl terminus of the receptors, but also in the intracellular loops [8]. GRKs are a family (GRK1–GRK7) of serine/threonine kinases [7]. Whereas GRK1 and GRK7 expression is confined to the retina, GRK4 also has limited cellular distribution with highest expression in the testes [9]. The other GRKs are widely expressed and phosphorylate

Expanding horizons: novel connections and novel regulatory roles of β-arrestins for 7TMRs

Following the discovery of the role of β-arrestins in 7TMR desensitization, additional studies found that β-arrestins also interact with and serve as adaptors for several key components of the endocytotic machinery to promote receptor internalization (Figure 1c) [19]. These proteins include clathrin heavy chain [20], β2 adaptin of the adaptin proteins AP2 complex [21], the small G protein ADP-ribosylation factor 6 (ARF6) [22] and the N-ethylmaleimide-sensitive fusion protein [23].

Roles of β-arrestin and GRKs in 7TMR signaling: changing the paradigm

A somewhat surprising, but also one of the most interesting, finding in the area of 7TMRs was the observation that β-arrestins can scaffold the tyrosine kinase c-Src to agonist-activated β2AR, eventually leading to activation of extracellular signal-regulated kinase (ERK1/2) [44] (Figure 1c). This finding not only provided the first hint that β-arrestins could function as signaling molecules but it has subsequently led to the discovery of the new field of G protein-independent,

Zooming in: the concept of biased agonism

The finding that β-arrestins can mediate G protein-independent cellular signaling downstream of 7TMRs subsequently led to the discovery that the two signaling arms are pharmacologically separable [58]. In other words, it is possible to identify or design ligands which can selectively trigger either G protein-dependent or β-arrestin-dependent signaling. Such ligands, which can selectively trigger one or the other signaling arm, are termed ‘biased agonists’ and this phenomenon of selective

Going global: ‘omics’ on β-arrestins

As the list of signaling pathways that β-arrestins can regulate in response to activation of 7TMRs has grown, so too has the application of global approaches to obtain a more comprehensive view of β-arrestin-dependent signaling and regulatory events in cells. Notably, two mass spectrometry (MS)-based systems biology approaches have aimed to provide novel insights into β-arrestin-dependent signaling in an unbiased manner. These approaches essentially utilize recent advances of MS to first,

Functional diversity of β-arrestins and the issue of specificity

As mentioned earlier, there are approximately 800 genes encoding 7TMRs in the human genome. Although the basic architecture of seven transmembrane bundles is highly conserved, there is relatively little sequence similarity among the primary sequences of the receptors. Despite this, the central paradigms of G protein- and β-arrestin-dependent signaling holds true for most receptors examined to date. This obviously raises the question of how the specificity of signaling is determined and tightly

Mechanistic basis of biased signaling

The fact that G protein-dependent and β-arrestin-dependent signaling pathways are pharmacologically separable (i.e. that it is possible to design ligands which can selectively trigger one or the other pathway) argues for the existence of multiple active receptor conformations. In this conceptual framework, one could envisage that an unbiased ligand induces a conformation which is capable of coupling to both arms of downstream signaling. However, a distinct conformation of the receptor is

The bar code hypothesis

Conformational differences at the receptor level must be recognized by immediate downstream effectors such as GRKs and β-arrestins to initiate specific sets of functional responses. For several different receptors, depletion of either GRK2/3 or GRK5/6 exert clearly distinguishable effects on receptor regulation and signaling 88, 89. GRK2/3 appears to be responsible for bulk phosphorylation of the receptor and their depletion negatively affects receptor internalization and β-arrestin recruitment

Concluding remarks and future perspectives

As systems biology approaches become more routine with advances at technological and bioinformatics levels, the number of large data sets describing global views of the functional capabilities of β-arrestins in the context of either specific receptors or specific stimuli should accumulate rapidly. This will hopefully result in construction of system-wide signaling networks and uncover many new avenues for future investigation. However, the direct demonstration and functional analysis of these

Acknowledgments

We thank Drs. Seungkirl Ahn, Jeffrey Kovacs and Tanya Daigle for critical reading of the manuscript. R.J.L. is an investigator with the Howard Hughes Medical Institute (HHMI). We acknowledge grant support from the National Institutes of Health (HL16037 and HL70631). We thank Donna Addison and Quivetta Lennon for excellent administrative assistance.

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