GPCRs Signaling Directly Through Src-Family Kinases

A wide range of extracellular signals are transduced by G protein–coupled receptors (GPCRs). When activated by ligands, GPCRs can activate associated heterotrimeric guanine nucleotide–binding proteins (G proteins), which in turn act on various effectors. Increasing evidence indicates that GPCRs also signal independently of heterotrimeric G proteins. Several GPCRs directly interact with Src-family kinases. Here, we discuss the evidence for direct interaction and activation of Src-family kinases by GPCRs and data that suggest that agonist dosage provides a mechanism by which GPCRs can switch between G protein–dependent and G protein–independent signaling.