Actin cytoskeleton remodeling defines a distinct cellular function for adhesion G protein-coupled receptors ADGRL/latrophilins 1, 2 and 3.

Latrophilins represent a subgroup of the adhesion G protein-coupled receptor family, which bind to actin-associated scaffolding proteins. They are expressed in various tissues, suggesting that they might participate in biological processes that are ubiquitous. Here we focus on actin cytoskeleton dynamics to explore the role of latrophilins in mammalian cells. Individual overexpression of each latrophilin isoform comparably increased cell volume while modifying the net profile of F-actin-dependent cell extensions, as evaluated by confocal microscopy analysis. Latrophilin deletion mutants evidenced that direct coupling to the intracellular machinery was a requirement for modulating cell extensions. The association between latrophilins and the actin cytoskeleton was detected by co-immunoprecipitation assays and corroborated with immunocytochemistry analysis. Consistent with the destabilization of F-actin structures, latrophilin isoforms constitutively induced a prominent increase in the activity of actin-depolymerizing factor, cofilin. Intercellular adhesion events stabilized by heterophilic Teneurin-4 trans-interactions disrupted latrophilin colocalization with F-actin and led to an isoform-specific rescue of cell extensions. Thus, we find that the actin cytoskeleton machinery constitutes an important component of constitutive as well as ligand-induced signaling for latrophilins.This article has an associated First Person interview with the first author of the paper.