IRSProtein Signaling in Growth Nutrition and Longevity

The disruption of IRS-proteins in mice and flies reveals their role of coordinating multiple biological processes, including growth, nutrition, and fertility. The framework relating IRS-proteins to these biological processes might be easier to establish in Drosophila, because fewer signaling protein are involved. Deletion of Chico, the Drosophila IRS-protein, causes female sterility as well as reduced somatic growth and increased lipid storage [55]. Moreover, specific mutations of the binding sites for the Drosophila PI 3-kinase adapter p60 completely abrogates Chico function in growth control; however, mutating the consensus binding site in Chico for Grb2/Drk, which regulates the ras cascade, does not interfere with growth [28]. The important role of the PI 3-kinase cascade is further supported by the finding that growth is restored in Chico mutants by reducing the level of the PTEN ortholog, confirming that the PI 3-kinase cascade is a critical pathway for growth regulation [28].

In mice, the PI 3-kinase ^ PKB cascade also regulates growth, but the control appears to be parsed between IRS1 and IRS2. Mice lacking IRS1 are about 50% smaller, where IRS2-/- mice are nearly normal size; however, mice lacking alleles of each gene reveal a role for IRS2 in growth (Fig. 4). Growth curves based on daily weights from birth to 30 days

Figure 3 Phosphorylation of IRS1 or IRS2 and activation of PI 3-kinase in mouse liver. Wild-type mice, or mice retaining expression of IRS2 (IRS1-/- mice) or IRS1 (IRS2-/- mice) were stimulated with insulin as previously described [56]. Both IRS1 and IRS2 are tyrosine phosphorylated during insulin stimulation; however, the activation of the PI 3-kinase is distinctly different. In IRS2-/- liver, IRS1 barely mediates insulin-stimulated activation of the PI3K because the basal activity is relatively high. By contrast, in Irs1-/- livers, Irs2 strongly promotes insulin-stimulated activation of the PI 3-kinase because the basal activity is relatively low. This difference has been detected in 6-week-old mice when the circulating insulin levels are approximately equivalent.

Figure 3 Phosphorylation of IRS1 or IRS2 and activation of PI 3-kinase in mouse liver. Wild-type mice, or mice retaining expression of IRS2 (IRS1-/- mice) or IRS1 (IRS2-/- mice) were stimulated with insulin as previously described [56]. Both IRS1 and IRS2 are tyrosine phosphorylated during insulin stimulation; however, the activation of the PI 3-kinase is distinctly different. In IRS2-/- liver, IRS1 barely mediates insulin-stimulated activation of the PI3K because the basal activity is relatively high. By contrast, in Irs1-/- livers, Irs2 strongly promotes insulin-stimulated activation of the PI 3-kinase because the basal activity is relatively low. This difference has been detected in 6-week-old mice when the circulating insulin levels are approximately equivalent.

Figure 4 Growth characteristics of progeny of IRS1+/-xIRS2+/- intercross; mean weights ± SEM of mice of the various genotypes on a C57Bl/6 x 129SV background at 30 days of age. Data are from 170 liters with a total of at least 4 animals per genotype [98].

of age reveal that Irs1+/ mice, Irs2+/ , and IRS2 / mice are normal compared to controls [56]. Compound heterozygous mice (IRS1+/-x IRS2+/-) weigh 25% less than wild-type animals, whereas IRS1+/-x IRS2+/- mice were of similar size to IRS1-/- animals (Fig. 4). By contrast, IRS1-/-x IRS2+/-are nearly 75% smaller than normal throughout their life. IRS1-/-xIRS2+/- mice are among the smallest viable mice that have been generated from a variety of knockout strategies aimed at components of growth factor signaling pathways and demonstrate that a single copy of IRS-2 is sufficient to allow viability of very small mice, but only for a year. It is important to emphasize that owing to multiple system failure in Irs1-/-x Irs2+/- mice, longevity is markedly reduced. The popular conclusion based on work with invertebrates that partial inhibition of insulin and IGF signaling extends life span must be applied to mammalian system with caution [57]; however, application of this hypothesis to specific tissues might be another story.

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