Nedd4 Controls Animal Growth by Regulating IGF-I Signaling
Nedd4 (Neural precursor cell expressed developmentally down regulated 4 - OMIM 602278, chromosome 15q) is a cytoplasmic ubiquitin ligase that regulates protein movement and structure thereby its function or directs a protein into ubiquitin-proteasomal degradative pathway. Cao et al demonstrated that Nedd4 is essential for transduction of intracellular signals initiated by insulin and insulin-like growth factor (IGF)-I and the localization of the insulin receptor (IR, OMIM 147670, chromosome 19p13.2) and the IGF-I receptor (IGF1R, OMIM 147370, chromosome 15q25-q26) to the cell plasma membrane. Nedd4 does not bind to IR or IGF1R directly, but links to an adaptor protein, Grb10 (Growth factor receptor-bound protein10, OMIM 601523, chromosome 7p12-p11.2), which in turn is bound by IR and IGF1R. Grb10 inhibits movement of these receptors to their localization sites in the plasma membrane and thereby impairs function of IR and IGF1R. This effect is opposed by the binding of Nedd4 to Grb10. Cao and colleagues generated Nedd4 knockout (KO) mice. Nedd4-/- mice died during gestation or shortly after birth due to immature lung development and aeration (Figure); their linear growth and weight were severely impaired by embryonic day 12.5. Heterozygous Nedd4-/+ mice were also small at birth and through post-natal age 3 months (the end of the study period). In vitro, the proliferation of Nedd4-/- fibroblasts was impaired relative to that of wild-type fibroblasts due to decreased progression through the cell cycle at phases Go and G1º IGF-I and insulin mediated intracellular signaling was substantially reduced in Nedd4-/- and Nedd4+/- fibroblasts and could be restored by expression of Nedd4 in these cells. However, in Nedd4-/- fibroblasts, the expression and translation of IR and IGF1R were normal, but the receptors did not reach the cell surface, an abnormality that could also be reversed by expression of Nedd4 in these cells. Further studies demonstrated that the amount of Grb10 was increased in Nedd4-/- fibroblasts and that “knockdown” of Grb10 by small interfering RNA (siRNA) restored insulin and IGF-I signaling in Nedd4-/- fibroblasts. The investigators concluded that Nedd4 positively regulates IGF-I and insulin signaling by enhancing the movement of their receptors to the cell surface. Nedd4 does so by dis-inhibiting the inhibitory effect of Grb10 on this process—perhaps by controlling the rate of degradation of Grb10 itself through the ubiquitin-proteasomal system.
Cao XR, Lill NL, Boase N, et al. Nedd4 controls animal growth by regulating IGF-1 signaling. Sci Signal. 2008;1:ra5. [DOI:10.1126/scisignal.1160940]
Nedd4–/– mice die immediately after birth, and Nedd4+/– and Nedd4–/– mice exhibit intrauterine growth retardation. No mice homozygous for disruption of the Nedd4 gene were found 2 or 3 weeks after birth. Ratios of heterozygotes and homozygous mutants were thus assessed at earlier time points: (A) 12.5 dpc, (B and C) 18.5 dpc, and (D) immediately after birth. Both heterozygotes and homozygous mutants showed signs of intrauterine growth retardation as early as 12.5 dpc (A) and at late gestation [18.5 dpc (B) and (C)]. At the time of birth [postnatal day 1 (D)], the body weights among three genotypes differed significantly: Nedd4–/– body weight averaged 64 to 68% lower relative to that of wild-type littermates; heterozygote body weight averaged about 15 to 20% reduction in body weight relative to that of wild-type littermates. In (C) and (D), the numbers of animals used for the analyses are shown in parentheses; the body weight was significantly different between groups of mice, with P values indicated.
Reprinted with permission Cao XR, et al. Sci Signal. 2008;1: ra5. Copyright © AAAS 2008. All rights reserved.
This study has identified another intracellular signal transduction site (Nedd4-Grb10) to examine when a patient with severe growth retardation due to insensitivity to IGF-I and an intact IGF1R is encountered. A polymorphic variant or mutation in either one of these proteins might also account for impaired intrauterine growth in some small-for-gestational age neonates.
Allen W. Root, MD