Publications

Abstract

The ubiquitin ligase Nedd4 has been proposed to regulate a number of signaling pathways but its physiological role in mammals has not been characterized. Here we present an analysis of Nedd4 null mice to demonstrate that loss of Nedd4 results in reduced IGF-I and insulin signaling. Consistent with reduced IGF-I signaling, the Nedd4 -/- mice showed delayed embryonic development, reduced growth and body weight, and neonatal lethality. In mouse embryonic fibroblasts (MEFs), mitogenic activity was reduced and IGF-1R, which is normally presented on the plasma membrane, was mislocalized. However, surface expression of IGF-1R was restored in homozygous mutant MEFs following knock-down of Grb10, which encodes an adaptor protein, and Nedd4 -/- lethality was rescued by maternal inheritance of a disrupted Grb10 allele. Overall, these findings suggest that, in vivo, Nedd4 positively regulates IGF-I and insulin signaling through an interaction with Grb10.