MAT2B

MAT2B encodes the catalytically inactive regulatory β subunit of methionine adenosyltransferase II (MAT II), functioning both as a metabolic regulator of S-adenosylmethionine (SAM) biosynthesis and as a signaling scaffold that promotes cell growth and survival. MAT2B binds and stabilizes the catalytic subunit MAT2A in an NADP⁺-dependent manner, and this interaction is essential for SAM production, which in turn controls mRNA m6A methylation and downstream gene expression (PMID:39353892, PMID:11337507). Independent of its metabolic role, MAT2B assembles a GIT1–MEK1–ERK signaling complex that drives cyclin D1 expression and proliferation, and it directly interacts with AKT to activate PI3K/AKT signaling (PMID:23325601, PMID:26940012). MAT2B silencing in hepatocellular carcinoma cells inhibits growth and invasion through coordinate suppression of EGFR, ERK, STAT3, and AKT phosphorylation, and pharmacological targeting of MAT2B suppresses mTORC1 signaling and induces apoptosis (PMID:31493275, PMID:39293586).

1. 2001 High

   Identification of MAT2B as the gene encoding the regulatory β subunit of MAT II established that this non-catalytic subunit controls intracellular SAM levels, with its loss causing a 6–10-fold SAM increase.

   Evidence Promoter deletion/EMSA/ChIP analysis of the MAT2B locus in human cells

   PMID:11337507

   Open questions at the time

   • Mechanism by which MAT2B modulates MAT2A catalytic activity was unknown
   • No structural information on the MAT2A–MAT2B complex
   • Role of MAT2B beyond SAM metabolism was unexplored
2. 2008 Medium

   MAT2B knockdown in HCC cells revealed a pro-survival and pro-proliferative role through regulation of cyclin D1 and Bcl-xL/Bcl-xS, establishing MAT2B as functionally important in cancer cell growth.

   Evidence Lentiviral shRNA knockdown with proliferation, apoptosis, and western blot readouts in HCC cells

   PMID:18698677

   Open questions at the time

   • Whether growth effects were mediated through SAM changes or direct signaling was unresolved
   • No signaling pathway dissection performed
3. 2013 High

   Discovery that MAT2B scaffolds a GIT1–MEK1–ERK complex and directly binds MEK1 and ERK2 revealed a signaling function independent of its metabolic role, explaining its proliferative effects through cyclin D1 induction.

   Evidence Reciprocal co-IP, in vitro recombinant pull-down, proteomics, and orthotopic liver cancer model

   PMID:23325601

   Open questions at the time

   • Whether MAT2B's scaffold and metabolic functions are coordinated or independent was unclear
   • Structural basis of scaffold assembly not determined
4. 2016 Medium

   Demonstration that MAT2B directly interacts with AKT and promotes PI3K/AKT signaling extended its scaffold function beyond the ERK pathway, showing it activates multiple growth-promoting kinase cascades.

   Evidence Co-IP of MAT2B–AKT, PI3K inhibitor rescue, and overexpression/knockdown in porcine preadipocytes

   PMID:26940012

   Open questions at the time

   • Interaction validated in a single cell system
   • Binding domain on AKT not mapped
5. 2018 Medium

   Identification of miR-21-3p as a direct regulator of MAT2B mRNA established post-transcriptional control of MAT2B expression and linked MAT2B suppression to NF-κB-mediated inflammation and blood-brain barrier damage.

   Evidence 3′UTR luciferase reporter assay, miR-21-3p antagomir in vivo (TBI and MCAO models)

   PMID:29695199 PMID:31686458

   Open questions at the time

   • Whether MAT2B loss drives inflammation via SAM depletion or signaling scaffold disruption was not determined
   • Other miRNA regulators of MAT2B not yet systematically cataloged
6. 2019 Medium

   MAT2B silencing suppressed EGFR pathway phosphorylation (AKT, Src, FAK, STAT3, ERK), broadening the signaling network downstream of MAT2B to include EGFR-associated kinases in HCC migration and invasion.

   Evidence Phospho-kinase array, immunoblotting, zebrafish xenograft, and mouse lung metastasis model

   PMID:31493275

   Open questions at the time

   • Whether MAT2B directly binds EGFR pathway components or acts indirectly was not resolved
   • Mechanism connecting MAT2B to EGFR activation not established
7. 2019 Medium

   CircMAT2B, a circular RNA derived from the MAT2B locus, was shown to sponge miR-338-3p and de-repress PKM2, promoting glycolysis and HCC malignancy under hypoxia — a function distinct from the MAT2B protein.

   Evidence RNA pull-down, miRNA capture, luciferase reporter, RIP, FISH, in vivo xenograft under hypoxia

   PMID:31004447

   Open questions at the time

   • Relationship between circMAT2B and MAT2B protein expression not assessed
   • Whether circMAT2B biogenesis affects mRNA-derived MAT2B protein levels is unknown
8. 2022 Medium

   MAT2B was found to directly interact with the co-chaperone BAG3 in renal cell carcinoma, linking MAT2B to a CYTOR/miR-136-5p regulatory axis that controls proliferation and apoptosis.

   Evidence Co-IP of MAT2B–BAG3, dual luciferase, RNA pull-down, in vivo xenograft

   PMID:35597301

   Open questions at the time

   • Single Co-IP without reciprocal validation for the MAT2B–BAG3 interaction
   • Functional significance of the MAT2B–BAG3 complex beyond the RCC context is unknown
9. 2024 High

   The NADP⁺-dependent binding of MAT2B to MAT2A was shown to stabilize MAT2A protein levels and drive SAM synthesis, which regulates mRNA m6A modification; dietary NADP⁺ modulation (ketogenic diet) remodels this axis in liver tumors.

   Evidence Co-IP, NADP⁺ perturbation, m6A profiling, mRNA stability assays, in vivo ketogenic diet intervention, gene editing

   PMID:39353892

   Open questions at the time

   • NADP⁺ binding site on MAT2B not structurally defined
   • Full spectrum of m6A-regulated transcripts downstream of MAT2B–MAT2A not cataloged
10. 2024 Medium

    Pharmacological targeting of MAT2B by JX24120 demonstrated that direct MAT2B inhibition suppresses SAM synthesis and mTORC1 signaling, establishing MAT2B as a druggable target in endometrial cancer.

    Evidence Direct binding assay (Kd measurement), MAT2B KO rescue, PDO drug screening, in vivo xenograft

    PMID:39293586

    Open questions at the time

    • Co-crystal structure of inhibitor–MAT2B complex not available
    • Selectivity of JX24120 across MAT isoforms not fully characterized

• A structural understanding of the MAT2A–MAT2B complex with NADP⁺ and the molecular basis for MAT2B's dual scaffold (metabolic enzyme stabilization and kinase complex assembly) functions remain unresolved.
• No high-resolution structure of the MAT2A–MAT2B–NADP⁺ complex
• Whether the metabolic and signaling scaffold functions of MAT2B are structurally separable is unknown
• Relative contribution of SAM-dependent vs. SAM-independent signaling to MAT2B's oncogenic role is not quantified