Never a rest for arrestins

Published August 08 2016

The spectrum of beta-arrestin-mediated signaling. Beta-arrestins regulate a wide array of pathways downstream of GPCRs. PDEs, phosphodiesterases; EGFR, EGF receptor; PP2A, protein phosphatase 2A; TRP, transient receptor potential.

Much like actors, proteins can be underestimated and their complexity ignored once they’ve been pigeonholed into a role. Such was the case for the beta-arrestin family. Concisely named for their function, beta-arrestins were long thought to only have one purpose: to arrest G–protein–coupled receptor, or GPCR, signaling. But recent research has widened their range of roles and shown that this widely expressed protein family does much more than its name suggests.

In the recent Journal of Biological Chemistry minireview “The β-arrestins: multifunctional regulators of G protein-coupled receptors,” Jeffrey Smith and Sudarshan Rajagopal at Duke University Medical Center discuss beta-arrestins’ newly identified roles as hubs of complex cellular signaling.

After a GPCR is activated through ligand binding, the receptor adopts an “on” position and begins to signal to downstream pathways through G proteins. This signaling continues until the receptor is desensitized and removed from the membrane through the active transport process of endocytosis. To facilitate receptor endocytosis, active GPCRs first are phosphorylated by G–protein receptor kinases. Beta-arrestins then bind to the phosphorylated GPCRs and mitigate receptor signaling in two ways. First, beta-arrestin desensitizes the receptor by physically blocking it from activating more downstream effectors. Then beta-arrestin acts as a scaffold for the protein coat of clathrin, which drives the internalization of the receptor. Most GPCRs require beta-arrestins for internalization.

For many years, this curtailing of GPCR signaling was thought to be beta-arrestins’ sole role. But we now know that the beta-arrestins are more than adapters between phosphorylated receptors and clathrin. Over the past decade, beta-arrestins have been discovered to interact with many different types of proteins and consequently several different signaling pathways. For example, beta-arrestins can bind both ubiquitin ligases and deubiquitinating enzymes, thereby promoting ubiquitin signaling pathways, receptor degradation or receptor recycling. In fact, some ligands preferentially signal through beta-arrestin-related pathways, a process known as beta-arrestin biased agonism. Certain ligands specifically promote GPCR phosphorylation and beta-arrestin binding, regardless of G–protein activation. These ligands cause the receptor to select beta-arrestin-based signaling instead of conventional G–protein signaling. In this way, beta-arrestins greatly expand the world of GPCR signaling instead of diminishing it.

Compared with the hundreds of GPCRs in a cell, there are only two beta-arrestins in humans. So how are beta-arrestins able to choose which pathway to activate for a specific receptor? Smith and Rajagopal describe how beta-arrestins are able to act as interpreters for distinct patterns of receptor phosphorylation. Different ligands cause different phosphorylation patterns (barcodes) on the receptor. By “reading” this phosphorylation barcode, beta-arrestins then activate different downstream signaling pathways.

Many specifics about this barcode are not yet fully understood, but this unique role of beta-arrestins potentially positions them to play a major new role in the area of drug development. GPCRs already are widely targeted by various pharmaceuticals, and identifying new ligands or small molecules that can influence how beta-arrestins interact with receptors will be crucial for understanding signaling in disease states.

Caitlin Hanlon Caitlin Hanlon earned a BS from Ursinus College and a Ph.D. from the Department of Cell Biology at the Johns Hopkins School of Medicine.