Diacylglycerol kinase δ regulates protein kinase C and epidermal growth factor receptor signaling

Diacylglycerol kinases (DGKs) phosphorylate diacylglycerol (DAG) to terminate its signaling. To study DGK delta, we disrupted its gene in mice and found that DGK delta deficiency reduced EGF receptor (EGFR) protein expression and activity. Similar to EGFR knockout mice, DGK delta-deficient pups were born with open eyelids and died shortly after birth. PKCs are activated by DAG and phosphorylate EGFR to reduce its expression and activity. We found DAG accumulation, increased threonine phosphorylation of EGFR, enhanced phosphorylation of other PKC substrates, and increased PKC autophosphorylation in DGK delta knockout cells, indicating that DGK delta regulates EGFR by modulating PKC signaling.