Phospholipase D stabilizes HDM2 through an mTORC2/SGK1 pathway.

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Phosphatidic acid (PA) is a tumor-promoting second messenger derived from phosphatidylcholine hydrolysis by phospholipase D (PLD).
• PA activates the mammalian target of rapamycin (mTOR) kinase, which is crucial for cancer cell survival signals.
• Both PLD and mTOR are implicated in stabilizing the human double minute 2 (HDM2) protein, an E3 ubiquitin ligase that promotes cancer cell survival by targeting p53 for degradation.

Purpose of the Study:

• To elucidate the specific mTOR complex involved in PLD/mTOR-dependent stabilization of HDM2.
• To identify downstream targets of mTOR signaling in the context of HDM2 stabilization.
• To understand the role of mTORC2 in relaying PLD-mediated survival signals.

Main Methods:

• Investigated the role of mTORC1 and mTORC2 in HDM2 stabilization.
• Utilized cell-based assays to examine the interaction between PLD, PA, mTOR, and HDM2.
• Identified downstream effectors of mTORC2 in this pathway, including SGK1.

Main Results:

• The PLD/mTOR-dependent stabilization of HDM2 is mediated by mTORC2, not mTORC1.
• Serum- and glucocorticoid-inducible kinase 1 (SGK1) was identified as a critical downstream target of mTORC2 in this process.
• mTORC2 acts as a key mediator of PLD-generated survival signals leading to HDM2 stabilization.

Conclusions:

• mTORC2 is a critical component of the PLD signaling pathway that promotes cancer cell survival.
• SGK1 is a novel downstream target of mTORC2 involved in the stabilization of HDM2.
• Targeting the mTORC2/SGK1 axis may offer a therapeutic strategy for cancers dependent on this survival pathway.