Inhibition of the insulin receptor tyrosine kinase by phosphatidic acid

The lipid second messenger, phosphatidic acid, inhibits the intrinsic tyrosine kinase activity of the insulin receptor in detergent-lipid mixed micelles or in reconstituted membranes. Enzymatic studies revealed that this lipid second messenger inhibits the catalytic activity of partially purified insulin receptor without affecting the affinity of the receptor for insulin. Selectivity in the protein-lipid interaction is suggested by the inability of several other acidic lipids to affect the kinase activity of the receptor and by the relative insensitivity of the inhibition to increasing ionic strength and, in some cases, micelle surface charge. Lysophosphatidic acid and phosphatidic acids with short acyl chains do not affect significantly the receptor's kinase activity, suggesting that hydrophobic interactions are involved in the inhibition. Thus, both a high affinity interaction of the insulin receptor with the phosphate headgroup and a stabilizing hydrophobic interaction with the acyl chains contribute to the inhibitory protein-lipid interaction. The selective sensitivity of the insulin receptor to phosphatidic acid suggests that the receptor-mediated generation of this lipid in the plasma membrane could negatively modulate insulin receptor function.