Diacylglycerol Kinase δ and Protein Kinase Cα Modulate Epidermal Growth Factor Receptor Abundance and Degradation through Ubiquitin-specific Protease 8

Many human epithelial cancers are characterized by abnormal activation of the epidermal growth factor receptor (EGFR), which is often caused by its excessive expression in tumor cells. The abundance of EGFR is modulated, in part, by its ubiquitination, which targets it for degradation. The components responsible for adding ubiquitin to EGFR are well characterized, but this is a reversible process, and the mechanisms that modulate the removal of ubiquitin from the EGFR are not well known. We found that de-ubiquitination of EGFR was regulated by diacylglycerol kinase delta (DGK delta), a lipid kinase that terminates diacylglycerol signaling. In DGK delta-deficient cells, ubiquitination of EGFR was enhanced, which attenuated the steady-state levels of EGFR and promoted its ligand-induced degradation. These effects were not caused by changes in the ubiquitinating apparatus, but instead were due to reduced expression of the deubiquitinase, ubiquitin-specific protease 8 (USP8). Depletion of protein kinase C alpha (PKC alpha), a target of diacylglycerol, rescued the levels of USP8 and normalized EGFR degradation in DGK delta-deficient cells. Moreover, the effects of PKC alpha were caused by its inhibition of Akt, which stabilizes USP8. Our data indicate a novel mechanism where DGK delta and PKC delta modulate the levels of ubiquitinated EGFR through Akt and USP8.