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 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.
Cao
Xiao R
XR
Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Lill
Nancy L
NL
Boase
Natasha
N
Shi
Peijun P
PP
Croucher
David R
DR
Shan
Hongbo
H
Qu
Jing
J
Sweezer
Eileen M
EM
Place
Trenton
T
Kirby
Patricia A
PA
Daly
Roger J
RJ
Kumar
Sharad
S
Yang
Baoli
B
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D056827:Endosomal Sorting Complexes Required for Transport; D051383:GRB10 Adaptor Protein / Q000378:metabolism; D007328:Insulin / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D000075702:Nedd4 Ubiquitin Protein Ligases; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
D056827:Endosomal Sorting Complexes Required for Transport; D007328:Insulin; D051383:GRB10 Adaptor Protein; D007334:Insulin-Like Growth Factor I; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D017526:Receptor, IGF Type 1