Phospholipase D stabilizes HDM2 through an mTORC2/SGK1 pathway

Abstract

Phosphatidic acid (PA), the primary metabolite of the phospholipase D (PLD)-mediated hydrolysis of phosphatidylcholine, has been shown to act as a tumor promoting second messenger in many cancer cell lines. A key target of PA is the mammalian target of rapamycin (mTOR), a serine–threonine kinase that has been widely implicated in cancer cell survival signals. In agreement with its ability to relay survival signals, it has been reported that both PLD and mTOR are required for the stabilization of the p53 E3 ubiquitin ligase human double minute 2 (HDM2) protein. Thus, by stabilizing HDM2, PLD and mTOR are able to counter the pro-apoptotic signaling mediated by p53 and promote survival. mTOR exists in at least two distinct complexes—mTORC1 and mTORC2—that are both dependent on PLD-generated PA. Although PLD and its metabolite PA are clearly implicated in the transduction of survival signals to mTOR, it is not yet apparent which of the two mTOR complexes is critical for the stabilization of HDM2. We report here that the PLD/mTOR-dependent stabilization of HDM2 involves mTORC2 and the AGC family kinase serum- and glucocorticoid-inducible kinase 1 (SGK1). This study reveals that mTORC2 is a critical target of PLD-mediated survival signals and identifies SGK1 as a downstream target of mTORC2 for the stabilization of HDM2.