GPCR-dependent and -independent arrestin signaling

Biological activity of free arrestins is often overlooked. Based on available data, we compare arrestin-mediated signaling that requires and does not require binding to G-protein-coupled receptors (GPCRs). Receptor-bound arrestins activate ERK1/2, Src, and focal adhesion kinase (FAK). Yet, arrestin-3 regulation of Src family member Fgr does not appear to involve receptors. Free arrestin-3 facilitates the activation of JNK family kinases, preferentially binds E3 ubiquitin ligases Mdm2 and parkin, and facilitates parkin-dependent mitophagy. The binding of arrestins to microtubules and calmodulin and their function in focal adhesion disassembly and apoptosis also do not involve receptors. Biased GPCR ligands and the phosphorylation barcode can only affect receptor-dependent arrestin signaling. Thus, elucidation of receptor dependence or independence of arrestin functions has important scientific and therapeutic implications.