G protein-coupled receptors (GPCRs) have emerged as key biological entities that regulate a plethora of physiological processes and participate in the onset and development of many diseases. Moreover, these receptors are important targets of almost 25% of the current therapeutic drugs in the market. Upon agonist binding, GPCRs activate a great number of signaling pathways, resulting in important cellular events like gene transcription, survival, proliferation and differentiation. In order to activate such events, GPCRs interact with a variety of scaffold and molecular entities, particularly with G proteins, but also with β-arrestins and the extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway, forming unique signaling modules. The aim of this review is to analyze the signaling features of the multi-protein complex GPCR-β-arrestin-ERK1/2, a unique signaling module that has received considerable attention from different research groups due to its molecular and physiological roles in diverse cellular contexts.
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