Abstract

Arrestins are multifunctional adaptor proteins best known for their role in regulating G protein-coupled receptor signaling. Arrestins also regulate other types of receptors, including the insulin-like growth factor receptor (IGF-1R), although the mechanism by which this occurs is not well understood. In Caenorhabditis elegans, the IGF-1R ortholog DAF-2 regulates dauer formation, stress resistance, metabolism, and lifespan through a conserved signaling cascade. To further elucidate the role of arrestin in IGF-1R signaling, we employed an in vivo approach to investigate the role of ARR-1, the sole arrestin ortholog in C. elegans, on longevity. Here, we report that ARR-1 functions to positively regulate DAF-2 signaling in C. elegans. arr-1 mutant animals exhibit increased longevity and enhanced nuclear localization of DAF-16, an indication of decreased DAF-2 signaling, whereas animals overexpressing ARR-1 have decreased longevity. Genetic and biochemical analysis reveal that ARR-1 functions to regulate DAF-2 signaling via direct interaction with MPZ-1, a multi-PDZ domain-containing protein, via a C-terminal PDZ binding domain in ARR-1. Interestingly, ARR-1 and MPZ-1 are found in a complex with the phosphatase and tensin homolog (PTEN) ortholog DAF-18, which normally serves as a suppressor of DAF-2 signaling, suggesting that these three proteins work together to regulate DAF-2 signaling. Our results suggest that the ARR-1-MPZ-1-DAF-18 complex functions to regulate DAF-2 signaling in vivo and provide insight into a novel mechanism by which arrestin is able to regulate IGF-1R signaling and longevity.