PAFAH1B3

PAFAH1B3 is a catalytic subunit of the heterotrimeric platelet-activating factor acetylhydrolase 1B complex that hydrolyzes signaling lipids and, through this enzymatic activity, controls intracellular levels of platelet-activating factor (PAF) (PMID:24954006, PMID:29853524). It assembles into the PAF-AH1B complex via a C-terminal region required for binding the LIS1 regulatory subunit (PMID:11285245). PAFAH1B3 catalytic activity is functionally essential during oocyte meiosis: the protein localizes to the meiotic spindle at metaphase I and II, and selective enzymatic inhibition or antibody microinjection arrests cells at metaphase I with defective spindle morphology and failed first polar body extrusion (PMID:30008286). Through its control of PAF/PAFR signaling, PAFAH1B3 supports cell survival, and its loss sensitizes BCR-ABL1 leukemia cells to dasatinib in a PAFR-dependent manner (PMID:29853524). In multiple cancer and fibrotic contexts PAFAH1B3 drives proliferation, migration, and invasion: it cooperates with E2F8 to promote VEGFA transcription in gastric cancer (PMID:42140448), and it binds SMAD7 to block SMAD7–TβR1 association, reducing TβR1 ubiquitination and sustaining TGF-β signaling to promote hepatic stellate cell activation and liver fibrosis (PMID:39906692). PAFAH1B3 expression is negatively regulated by KLF9, which binds its promoter and represses transcription (PMID:38649699).

1. 2001 Medium

   Established how PAFAH1B3 is incorporated into the PAF-AH1B complex by mapping the LIS1-binding determinant to its C-terminal region.

   Evidence Characterization of a PAFAH1B3-CLK2 fusion translocation and interaction assays showing a 136-aa N-terminal truncation lost LIS1 binding

   PMID:11285245

   Open questions at the time

   • Structural basis of the C-terminal LIS1 interface not resolved
   • Functional consequence of the fusion protein not established
   • Catalytic activity of the truncated protein not assessed
2. 2014 Medium

   Linked PAFAH1B3 enzymatic activity to cancer metabolism by showing its loss elevates tumor-suppressing signaling lipids.

   Evidence Metabolomic profiling combined with PAFAH1B3 loss-of-function in breast cancer cell lines

   PMID:24954006

   Open questions at the time

   • Specific lipid substrates not definitively assigned
   • Downstream signaling consequences of altered lipids not mapped
   • Single-lab cell-line evidence
3. 2018 Medium

   Connected PAFAH1B3 lipid-hydrolase activity to a survival pathway by showing it controls intracellular PAF and that its loss sensitizes leukemia cells to TKI via PAF/PAFR signaling.

   Evidence In vivo/in vitro RNAi screens, KO and overexpression cell lines, and PAFR antagonist rescue in a BCR-ABL1 BCP-ALL mouse model

   PMID:29853524

   Open questions at the time

   • Only partial reversal by PAFR antagonism indicates additional effectors
   • Mechanism linking PAF levels to TKI sensitivity not fully resolved
4. 2018 High

   Demonstrated a catalysis-dependent cellular role for PAFAH1B3 in meiosis by localizing it to the meiotic spindle and showing enzymatic inhibition arrests metaphase I.

   Evidence Cross-species immunolocalization (bovine, murine, human oocytes) with selective inhibitor P11 and antibody microinjection scoring spindle morphology and polar body extrusion

   PMID:30008286

   Open questions at the time

   • Lipid substrate(s) acted on at the spindle not identified
   • Molecular link between PAF hydrolysis and microtubule organization unknown
5. 2021 Low

   Began to map proliferative downstream effectors of PAFAH1B3 in osteosarcoma.

   Evidence siRNA knockdown, xenograft growth, ChIP, and proliferation/apoptosis assays linking PAFAH1B3 to EIF4EBP1, MYC, PTGS2, and RPS6KB1

   PMID:34136395

   Open questions at the time

   • Mechanism only partially characterized with limited orthogonal validation
   • Direct vs. indirect regulation of the named genes not distinguished
   • No biochemical link to PAFAH1B3 enzymatic activity
6. 2024 Medium

   Identified an upstream transcriptional repressor by showing KLF9 directly binds the PAFAH1B3 promoter to suppress its expression.

   Evidence ChIP, dual-luciferase reporter, and KLF9/PAFAH1B3 co-overexpression rescue in pancreatic cancer cells with in vitro and in vivo assays

   PMID:38649699

   Open questions at the time

   • Only partial rescue indicates additional KLF9 targets
   • Regulation in non-pancreatic contexts not tested
7. 2024 Medium

   Defined a non-canonical scaffold function whereby PAFAH1B3 sustains TGF-β signaling by sequestering SMAD7 to stabilize TβR1.

   Evidence Co-IP of PAFAH1B3 with SMAD7, TβR1 ubiquitination/degradation assays, Pafah1b3 KO CCl4 fibrosis model, and pharmacological inhibition with 3-IN-P11

   PMID:39906692

   Open questions at the time

   • Whether SMAD7 binding requires catalytic activity is unclear
   • Reciprocal validation and structural detail of the SMAD7 interface lacking
8. 2026 Medium

   Placed VEGFA downstream of PAFAH1B3 via cooperation with E2F8 to drive gastric cancer proliferation and migration.

   Evidence Transcriptomic profiling of knockdown cells, VEGFA rescue experiment, functional assays, and xenograft models

   PMID:42140448

   Open questions at the time

   • Direct physical interaction between PAFAH1B3 and E2F8 not established
   • Link to lipid-hydrolase activity not defined

• How PAFAH1B3's lipid-hydrolase activity mechanistically connects its diverse roles — meiotic spindle assembly, PAF/PAFR survival signaling, and its scaffold/transcriptional effects in cancer and fibrosis — remains unresolved.
• Whether catalytic vs. scaffold functions are separable is untested
• No structural model of the active site or partner interfaces
• Direct lipid substrate identities across contexts not defined