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Sci. Signal., 23 September 2008
Vol. 1, Issue 38, p. ra5
[DOI: 10.1126/scisignal.1160940]


Nedd4 Controls Animal Growth by Regulating IGF-1 Signaling

Xiao R. Cao1*, Nancy L. Lill1*{dagger}, Natasha Boase2, Peijun P. Shi1, David R. Croucher3, Hongbo Shan1, Jing Qu1, Eileen M. Sweezer1, Trenton Place1, Patricia A. Kirby1, Roger J. Daly3, Sharad Kumar2,4{ddagger}, and Baoli Yang1{ddagger}

1 Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
2 Hanson Institute, Institute of Medical and Veterinary Science, Adelaide, SA 5000, Australia.
3 Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
4 Department of Medicine, University of Adelaide, Adelaide, SA 5005, Australia.

* These authors contributed equally to this work.

{dagger} Present address: Department of Pathology, Ohio State University, 1645 Neil Avenue, Columbus, OH 43210, USA.

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.

{ddagger} To whom correspondence should be addressed. E-mail: baoli-yang{at} (B.Y.) and sharad.kumar{at} (S.K.)

Citation: X. R. Cao, N. L. Lill, N. Boase, P. P. Shi, D. R. Croucher, H. Shan, J. Qu, E. M. Sweezer, T. Place, P. A. Kirby, R. J. Daly, S. Kumar, B. Yang, Nedd4 Controls Animal Growth by Regulating IGF-1 Signaling. Sci. Signal. 1, ra5 (2008).

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