The phosphatidylinositol (PI)-5-phosphate 4-kinase type II enzyme controls insulin signaling by regulating PI-3,4,5-trisphosphate degradation.

Carricaburu V, Lamia KA, Lo E, Favereaux L, Payrastre B, Cantley LC, Rameh LE
Proc Natl Acad Sci U S A. 2003 100 (17): 9867-72

PMID: 12897244 · PMCID: PMC187868 · DOI:10.1073/pnas.1734038100

Phosphatidylinositol-5-phosphate (PI-5-P) is a newly identified phosphoinositide with characteristics of a signaling lipid but no known cellular function. PI-5-P levels are controlled by the type II PI-5-P 4-kinases (PIP4K IIs), a family of kinases that converts PI-5-P into phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2). The PI-5-P pathway is an alternative route for PI-4,5-P2 synthesis as the bulk of this lipid is generated by the canonical pathway in which phosphatidylinositol-4-phosphate (PI-4-P) is the intermediate. Here we examined the effect of activation of the PI-5-P pathway on phosphoinositide 3-kinase (PI3K) signaling by expressing PIP4K II beta in cells that lack this enzyme. Although PIP4K II generates PI-4,5-P2, a substrate for PI3K, expression of this enzyme reduced rather than increased phosphatidylinositol-3,4,5-trisphosphate (PI-3,4,5-P3) levels in cells stimulated with insulin or cells expressing activated PI3K. This reduction in PI-3,4,5-P3 levels resulted in decreased activation of the downstream protein kinase, Akt/PKB. Consistent with these results, expression of IpgD, a bacterial phosphatase that converts PI-4,5-P2 to PI-5-P, resulted in Akt activation, and this effect was partially reversed by PIP4K II beta. PIP4K II beta expression did not impair insulin-dependent association of PI3K with insulin receptor substrate 1 (IRS1) but abbreviated Akt activation, indicating that PIP4K II regulates PI-3,4,5-P3 degradation rather than synthesis. These data support a model in which the PI-5-P pathway controls insulin signaling that leads to Akt activation by regulating a PI-3,4,5-P3 phosphatase.

MeSH Terms (21)

Animals Bacterial Proteins CHO Cells COS Cells Cricetinae Down-Regulation Humans Insulin Models, Biological Phosphatidylinositol 3-Kinases Phosphatidylinositol Phosphates Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases (Alcohol Group Acceptor) Protein-Serine-Threonine Kinases Proto-Oncogene Proteins Proto-Oncogene Proteins c-akt Receptor, Insulin Recombinant Proteins Shigella flexneri Signal Transduction

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