Phosphatidylinositol 5 phosphate 4-kinase regulates insulin sensitivity and PIP3 turnover in Drosophila.

Phosphatidylinositol-3,4,5-trisphosphate (PIP3) generation at the plasma membrane is a key event during activation of receptor tyrosine kinases such as the insulin receptor and is critical for normal growth and metabolism. The lipid kinases and phosphatases regulating PIP3 levels are described but mechanisms controlling their activity remain unclear. We report that in Drosophila, phosphatidylinositol 5 phosphate 4-kinase (PIP4K) function at the plasma membrane is required for normal PIP3 levels during insulin receptor activation. Depletion of PIP4K increases PIP3 levels and augments sensitivity to insulin through enhanced Class I phosphoinositide 3-kinase (PI3K) activity. Animals lacking PIP4K show enhanced insulin signalling dependent phenotypes in vivo and are resistant to the metabolic consequences of a high-sugar diet, highlighting the importance of PIP4K in normal metabolism and development. Thus, PIP4KS are key regulators of receptor tyrosine kinase signalling with implications for growth factor dependent processes including tumour growth, T-cell activation and metabolism.