Nedd4 controls animal growth by regulating IGF-1 signaling

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 sig...

Full description

Saved in:
Bibliographic Details
Published in:Science signaling Vol. 1; no. 38; p. ra5
Main Authors: Cao, Xiao R, Lill, Nancy L, Boase, Natasha, Shi, Peijun P, Croucher, David R, Shan, Hongbo, Qu, Jing, Sweezer, Eileen M, Place, Trenton, Kirby, Patricia A, Daly, Roger J, Kumar, Sharad, Yang, Baoli
Format: Journal Article
Language:English
Published: United States 23.09.2008
Subjects:
Animals
Cell Membrane - metabolism
Cells, Cultured
Endosomal Sorting Complexes Required for Transport
GRB10 Adaptor Protein - metabolism
Insulin - physiology
Insulin-Like Growth Factor I - physiology
Mice
Mice, Mutant Strains
Nedd4 Ubiquitin Protein Ligases
Phosphorylation
Receptor, IGF Type 1 - metabolism
Signal Transduction
Ubiquitin-Protein Ligases - physiology
ISSN:1937-9145, 1937-9145
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1937-9145
1937-9145
DOI:10.1126/scisignal.1160940