IRS Serine Phosphorylation and Insulin Sensitivity?

This is part of my last year in science series. Click here for the rationale.

Insulin signalling passes through a cascade of signaling proteins starting with the recruitment of the Insulin Receptor Substrate (IRS) to the Insulin Receptor.  Insulin resistance, or impaired insulin signaling is a hallmark of obesity and diabetes.  One of the ways in which was thought to happen was through phosphorylation of Serine 307 on IRS, a phosphorylation event which has been proposed to be inhibitory to insulin signaling.  As an example, it has been proposed that inflammation (via JNK or IKKbeta), overnutrition (via S6K) or several other factors can lead to the phosphorylation of this protein.  Since several of these factors correlate with reduced insulin signaling, and the ablation of these factors leads to both increased insulin signaling and reduced serine phosphorylation, the obvious hypothesis was that serine phosphorylation of IRS is causative of insulin signaling.

Correlation does not equal causation, so in order to test this hypothesis in vivo, Morris White's group at Harvard Medical School generated knockin mice, in which Serine 307 of IRS1 is mutated to an alanine (and is therefore unable to be phosphorylated).  The idea would be that these mice would be unable to phosphorylated IRS1 on Serine 307, and therefore would be resistant to the deleterious effects of this phosphorylation.  This serine to alanine knockin model is considered the gold standard for translating an observational protein phosphorylation site into an in vivo phenotype.  Unfortunately for the prevailing hypothesis, the opposite was true.

The paper, from Copps et al. published in January of 2010 show that on a normal diet S307A mice showed modest reductions in insulin sensitivity, and increased fasted insulin levels.  Both of these effects were amplified by high fat diet, and were associated with a reduction in weight gain, in contradiction to the previous hypothesis, that these effects would be ameliorated.  Mechanistically, when on a high fat diet (or coupled with liver specific IRS2 knockout) the S307A mouse had decreased tyrosine phosphorylation of IRS, but no effect of the downstream insulin targets Akt and S6K. Therefore it is unclear exactly how the insulin intolerance is propagated into effects on glucose homeostasis.

In the past year this article has been cited 10 times (according to Google Scholar), mostly in review articles, but the major upshot here, is that the models which showed effects on IRS Serine 307 phosphorylation and insulin resistance, and concluded that insulin resistance was mediated by increased phosphorylation may need re-interpretation.  IRS is phosphorylated on several other sites, so the general hypothesis that serine phosphorylation of IRS causes insulin resistance could still be true, but that again might need to wait until such a knockin model can be generated.  This work also points out the risks of correlating phenotypes with incompletely characterized phosphorylation sites.



Copps KD, Hancer NJ, Opare-Ado L, Qiu W, Walsh C, & White MF (2010). Irs1 serine 307 promotes insulin sensitivity in mice. Cell metabolism, 11 (1), 84-92 PMID: 20074531 DOI

Inositol Phosphates and Insulin Signaling

When most people think of the role of inositols in Akt signaling, they immediately think about the role of PIP3 in the PDK1-Akt signaling axis.  A recent paper published in Cell by Solomon Snyder's group at John's Hopkins highlights the role of soluble inositol phosphates in insulin signaling.

Soluble Inositol Phosphates

Inositol is best known as a lipid head group, that can be phosphorylated to form 8 potential phosphorylated phosphatidylinositols. These membrane bound signaling lipids have many important roles in cell biology, including in signal transduction. In addition to these 8 membrane bound lipids, the inositol headgroup can be solubilized from the lipid tails by phospholipases.  This leads to the important second messenger IP3, which can then be further phosphorylated to yield IP4, IP5 and IP6.  Adding even more to the complexity, these rings can be pyrophosphorylated to yield even more species including IP7 and IP8 among others. The functions of these phosphorylated inositol rings are largely unknown.

Role of IP7 in Akt Activation

The IP6-Kinase 1 phosphorylates IP6 to form IP7 (pyrophospho-IP5). The current paper, Chakraborty et al. (2010), describes insulin signaling in cells in which IP6 is knocked out. As expected, IP7 concentrations are reduced in these cells, but the major finding is that Akt phosphorylation and activation is increased. The proposed mechanism for this effect is that IP7 acts as an endogenous, physiological inhibitor of Akt, likely by competitively inhibiting the ability of PIP3 to bind to the same site in its PH domain. Once IP7 is reduced, this inhibition is released, and Akt can be activated more easily.

Consistent with hyperactivation of Akt, these knockout mice exhibit increased insulin sensitivity and a reduction in diet-induced obesity. Akt and its downstream targets are known to be major mediators of insulin signaling, and so increased insulin signaling through the Akt pathway leads to increased glucose disposal and a resistance to diet-induced weight gain, insulin resistance, hyperinsulinemia and hyperglycemia. These data are consistent with a role of IP7 as a negative regulator of insulin signaling and the authors propose that IP6K1 may be a novel potential therapeutic target to improve insulin sensitivity.



Chakraborty, A., Koldobskiy, M., Bello, N., Maxwell, M., Potter, J., Juluri, K., Maag, D., Kim, S., Huang, A., & Dailey, M. (2010). Inositol Pyrophosphates Inhibit Akt Signaling, Thereby Regulating Insulin Sensitivity and Weight Gain Cell, 143 (6), 897-910 DOI: 10.1016/j.cell.2010.11.032