Nedd4 Controls Animal Growth by Regulating IGF-1 Signaling

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 show that loss of Nedd4 results in reduced insulin-like growth factor 1 (IGF-1) and insulin signaling, delayed embryonic development, reduced growth and body weight, and neonatal lethality. In mouse embryonic fibroblasts, mitogenic activity was reduced, the abundance of the adaptor protein Grb10 was increased, and the IGF-1 receptor, which is normally present on the plasma membrane, was mislocalized. However, surface expression of IGF-1 receptor was restored in homozygous mutant mouse embryonic fibroblasts after knockdown of Grb10, and Nedd4 −/− lethality was rescued by maternal inheritance of a disrupted Grb10 allele. Thus, in vivo, Nedd4 appears to positively control IGF-1 and insulin signaling partly through the regulation of Grb10 function.

Anterograde Transport of Surfactant Protein C Proprotein to Distal Processing Compartments Requires PPDY-mediated Association with Nedd4 Ubiquitin Ligases

“…Transgenic mice homozygous for disruption of the NEDD4 gene are neonatal lethal (43). Although the lungs of the knockout mice are small, the phenotype of this model is dominated by defects in insulin-like growth factor-1 signaling (also Nedd4-dependent), which would preclude detection of ENaC trafficking/ functional defects, alterations in SP-C biosynthesis, or disruption of any other PY-dependent phenotype in type 2 cells.…”

“…Both Nedd4 and Nedd4-2 have been the subject of genetargeting strategies in mice in vivo (43,44). Transgenic mice homozygous for disruption of the NEDD4 gene are neonatal lethal (43).…”

Functional Interaction of Phosphatase and Tensin Homologue (PTEN) with the E3 Ligase NEDD4-1 during Neuronal Response to Zinc

“…Recently, NEDD4-1 (neural precursor cell expressed, developmentally down-regulated 4-1) was identified as the first ubiquitin ligase (E3) for PTEN that regulates PTEN degradation in multiple types of cancer cells (human bladder, gastric, and colorectal carcinomas) (30,31). It is intriguing to note that cellular PTEN is generally very stable, and gene knock-out of NEDD4-1 does not result in a further increase of PTEN stability in the several cell types tested (32,33). Therefore, it is possible that the enzymatic activity of NEDD4-1 toward PTEN is under tight control (34).…”

Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity

“…Nedd4 is expressed in a variety of tissues and regulates the trafficking and/or degradation of its substrate proteins 13,14 . IGF-IR is reported to be a putative Nedd4 substrate, but the effects of Nedd4 on IGF-IR are controversial 15,16 . Nedd4 knockout mice show fetal growth retardation and perinatal lethality 16 , indicating a crucial role for Nedd4 in embryonic growth.…”

“…IGF-IR is reported to be a putative Nedd4 substrate, but the effects of Nedd4 on IGF-IR are controversial 15,16 . Nedd4 knockout mice show fetal growth retardation and perinatal lethality 16 , indicating a crucial role for Nedd4 in embryonic growth. Nedd4 is overexpressed in several types of cancers and functions as an oncogenic protein [17][18][19][20][21] .…”