Arrestin scaffolding and activation of MAPK cascades

The vertebrate arrestins comprise a family of four protein isoforms that play an essential role in regulating G protein–coupled receptor (GPCR) signaling. The arrestins were discovered for orchestrating receptor desensitization and internalization. However, arrestins play an important role as multifunctional adaptor proteins, and signal initiation is one of their key functions. Arrestin-dependent signaling can initiate numerous cellular responses through coupling to distinct effectors. One of the best-studied arrestin-dependent signaling processes is the scaffolding and activation of mitogen-activated protein kinase (MAPK) cascades. Indeed, arrestins regulate all three canonical MAPK families: the extracellular signal–regulated kinases, ERK1/2; the c-Jun N-terminal kinases, JNK1/2/3; and p38. Here, we summarize the current literature on how arrestin scaffolds and facilitates activation of MAPK cascades and provide a perspective on structural and molecular work.