PLAAT2

PLAAT2 (HRASLS2) is a Ca2+-independent cysteine-dependent thiol hydrolase that governs the biosynthesis of N-acylphosphatidylethanolamine (NAPE) precursors of bioactive N-acylethanolamines (PMID:19615464, PMID:30620559). As a purified recombinant enzyme it displays phospholipase A1/A2 activity (PLA1 predominating) on phosphatidylcholines and phosphatidylethanolamines and, critically, an N-acyltransferase activity that transfers an acyl chain from the sn-1 position of phosphatidylcholine onto phosphatidylethanolamine to generate N-acyl-PE (PMID:19615464, PMID:27245897, PMID:36152189). This catalytic output is operational in cells: PLAAT2 expression drives endogenous production of NAPEs and downstream NAEs including anandamide, an output abolished by selective α-ketoamide PLAAT-family inhibitors (PMID:22825852, PMID:32787138). Heterologous expression of human PLAAT2 in engineered bacteria confers resistance to diet-induced obesity in mice, confirming NAPE generation as its physiologically relevant activity in vivo (PMID:31203417). A C-terminal hydrophobic domain directs PLAAT2 to a granular perinuclear localization and is required for its suppression of RAS-GTP levels and cell growth (PMID:18163183). Beyond lipid metabolism, PLAAT2 acts as a context-dependent modulator of cancer cell signaling: it binds and stabilizes aspartate β-hydroxylase (ASPH) to promote growth and glycolysis in pancreatic cancer (PMID:40833600), whereas in gastric cancer it recruits the E3 ligase TRIM32 to ubiquitinate and degrade cMyc, thereby dampening MEK/ERK signaling and proliferation (PMID:41851102).

1. 2007 Medium

   Established the first cellular phenotype for PLAAT2 by linking it to RAS pathway suppression and identifying the protein domain responsible.

   Evidence RAS-GTP pulldown, colony formation, and localization of C-terminal truncation mutants in cancer cell lines

   PMID:18163183

   Open questions at the time

   • Mechanism connecting catalytic/lipid activity to RAS-GTP reduction not defined
   • Single lab, not independently replicated
   • Whether perinuclear localization is causally upstream of RAS suppression untested
2. 2009 High

   Defined the core enzymology of PLAAT2 as a Ca2+-independent phospholipase and N-acyltransferase, answering what biochemical reactions it catalyzes.

   Evidence In vitro enzyme assays with purified recombinant protein across multiple phospholipid substrates

   PMID:19615464

   Open questions at the time

   • Relative physiological weighting of PLA1 versus NAT activity in vivo unresolved
   • Active-site residues not directly mapped in this study
3. 2012 High

   Demonstrated that PLAAT2 enzymatic activity translates into NAPE and NAE production in living cells, bridging in vitro biochemistry to cellular lipid signaling.

   Evidence Metabolic labeling with [14C]ethanolamine plus LC-MS/MS in transient/stable expression systems and endogenous HeLa contribution

   PMID:22825852

   Open questions at the time

   • Endogenous knockout-level loss-of-function not assessed
   • Tissue-specific physiological NAE outputs not addressed
4. 2019 Medium

   Confirmed PLAAT2 is a cysteine-dependent thiol hydrolase and placed it firmly within the HRASLS cysteine-hydrolase family via chemical biology.

   Evidence Activity-based protein profiling with MB064 probe and competitive inhibition by α-ketoamide LEI110

   PMID:30620559

   Open questions at the time

   • Catalytic cysteine residue not individually mutated in this report
   • Endogenous physiological substrates in native tissue not enumerated
5. 2019 Medium

   Provided in vivo evidence that PLAAT2-driven NAPE production has a metabolic, anti-obesity consequence in a whole animal.

   Evidence Engineered E. coli Nissle 1917 expressing human PLAAT2 in a diet-induced obesity mouse model, benchmarked to plant NAPE synthase

   PMID:31203417

   Open questions at the time

   • Effect demonstrated via heterologous bacterial expression, not native mammalian PLAAT2
   • Mechanistic chain from NAPE to satiety not dissected here
6. 2020 Medium

   Pharmacologically tied PLAAT2 catalytic activity to cellular anandamide and NAE levels, establishing it as a controllable node in endocannabinoid-related lipid metabolism.

   Evidence ABPP with α-ketoamide inhibitor LEI-301 and NAE quantification in PLAAT2-overexpressing cells

   PMID:32787138

   Open questions at the time

   • Inhibitor selectivity across PLAAT family limits attribution to PLAAT2 alone
   • Endogenous-level contribution to anandamide pools not quantified
7. 2025 Medium

   Identified a non-catalytic protein-stabilizing function whereby PLAAT2 promotes pancreatic cancer growth and glycolysis through ASPH.

   Evidence Co-IP, protein stability assays, knockdown/overexpression epistasis rescue, glycolysis measurements, and xenograft in pancreatic cancer cells

   PMID:40833600

   Open questions at the time

   • Direct vs indirect nature of the PLAAT2-ASPH interaction not resolved
   • Whether enzymatic activity is required for ASPH stabilization unknown
   • Single lab, single study
8. 2026 Medium

   Revealed an opposing tumor-suppressive function in which PLAAT2 acts as a scaffold recruiting TRIM32 to degrade cMyc and restrain MEK/ERK signaling.

   Evidence IP-MS discovery, co-IP and ubiquitination assays, MEK/ERK western blots, knockdown/overexpression, and xenograft in gastric cancer cells

   PMID:41851102

   Open questions at the time

   • Reconciliation with the pro-tumor ASPH role (context dependence) not mechanistically explained
   • Role of catalytic activity in TRIM32 recruitment untested
   • Single lab, single study

• How PLAAT2's lipid-metabolic activity, RAS/MEK-ERK modulation, and context-dependent partner interactions (ASPH vs TRIM32-cMyc) are integrated into one coherent mechanism remains unresolved.
• No study links catalytic NAT/PLA activity to the protein-protein scaffolding functions
• Determinants of opposite cancer roles across tissues unknown
• No structural model of substrate or partner engagement