Cell Biology IKK Targets PI3K

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

The phosphatidylinositol 3-kinases (PI3Ks), which are composed of a p110 catalytic subunit and a p85 regulatory subunit, generate phosphatidylinositol 3,4,5-triphosphate (PIP₃) at the plasma membrane, which triggers the recruitment of target proteins. Localization of PI3K to the plasma membrane where it is activated depends on interactions between its Src homology 2 (SH2) domains and phosphorylated tyrosine residues in receptors and adaptor proteins. Downstream of PI3K, the kinases Akt and mTOR regulate cell growth, stress responses, and autophagy. Noting that the inhibitor of NF-B (IB) kinase (IKK) is required, in an NF-B–independent manner, for the activation of autophagy in response to starvation (see commentary by Lamb), Comb et al. investigated the regulation of the PI3K-Akt pathway in cells deprived of nutrients. Experiments in wild-type and IKK-deficient mouse embryo fibroblasts (MEFs) showed that IKK was required for starvation-induced feedback inhibition of Akt activity. Western blotting analysis showed that Ser⁶⁹⁰ of the p85α regulatory subunit of PI3K was phosphorylated in wild-type MEFs in response to starvation, which was blocked by an IKK-specific inhibitor. Phosphorylation of Ser⁶⁹⁰ (which is located within an SH2 domain) by IKK interfered with the interactions between the p85 subunit and tyrosine-phosphorylated proteins and disrupted membrane localization of PI3K. Loss of amino acids, rather than loss of serum or glucose, resulted in the activation of IKK in MEFs, and, specifically, loss of the amino acid leucine triggered IKK-dependent phosphorylation and inhibition of PI3K in MEFs. Together, these data suggest that IKK inhibits PI3K-Akt signaling in response to nutrient starvation by preventing the recruitment of PI3K to the plasma membrane, thus inhibiting its activation.

W. C. Comb, J. E. Hutti, P. Cogswell, L. C. Cantley, A. S. Baldwin, p85α SH2 domain phosphorylation by IKK promotes feedback inhibition of PI3K and Akt in response to cellular starvation. Mol. Cell 45, 719–730 (2012). [PubMed]

R. F. Lamb, Negative feedback loops: Nutrient starvation employs a new tr(IKK) to inhibit PI3K. Mol. Cell 45, 705–706 (2012). [PubMed]

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