Regulation of diacylglycerol kinase α by phosphoinositide 3-kinase lipid products

Diacylglycerol kinase alpha (DAGKalpha), like all type I DAGKs, has calcium regulatory motifs that act as negative regulators of enzyme activity and localization. Accordingly, DAGKalpha is activated by phospholipase C-coupled receptors in a calcium-dependent manner. One of the first functions attributed to DAGKalpha in lymphocytes was that of regulating interleukin 2-induced cell cycle entry. Interleukin-2 nonetheless exerts its action in the absence of cytosolic calcium increase. We have studied alternative receptor-derived signals to explain calcium-independent DAGKalpha activation, and show that DAGKalpha is stimulated by Src-like kinase-dependent phosphoinositide 3 kinase (PI3K) activation in lymphocytes. Our results demonstrate that, in vivo, the increase in cellular levels of PI3K products is sufficient to induce DAGKalpha activation, allowing DAGKalpha relocation to the intact lymphocyte plasma membrane. This activation is isoform-specific, because other type I DAGKs are not subject to this type of regulation. These studies are the first to describe a pathway in which, in the absence of receptorregulated calcium increase, DAGKalpha activation and membrane localization is a direct consequence of PI3K activation.