LAGE3

LAGE3 is a component of the EKC/KEOPS complex implicated in threonylcarbamoylation of adenosine at position 37 in tRNAs, and it functions as a pro-tumorigenic factor across multiple cancer contexts (PMID:38653358). In hepatocellular carcinoma, LAGE3 is required for VEGFA mRNA stability, and its elevated expression increases VEGFA secretion and angiogenesis (PMID:38653358); it further drives proliferation, migration, invasion, and apoptosis resistance through activation of the JNK and ERK signaling pathways, as pharmacological ERK or JNK inhibition reverses LAGE3-induced malignant phenotypes (PMID:34837962). In non-small cell lung cancer, LAGE3 promotes metastasis and stemness via AKT/PI3K signaling, with its knockdown suppressing the stemness factors Nanog, SOX2, and OCT4 and reducing tumor growth in vivo (PMID:37473499). LAGE3 also physically interacts with the orf virus immunomodulatory protein ORFV024 (PMID:29605601). Beyond these signaling and interaction findings, the biochemical mechanism by which LAGE3 stabilizes VEGFA mRNA or engages upstream kinase activation has not been characterized in the available corpus.

1. 2018 Medium

   Establishing a physical binding partner for LAGE3 provided the first direct interaction-level evidence for the protein, linking it to viral immunomodulation.

   Evidence Yeast two-hybrid screen, His-tag pull-down, and co-immunoprecipitation with confocal microscopy identifying orf virus ORFV024 as a binding partner

   PMID:29605601

   Open questions at the time

   • Functional consequence of the LAGE3-ORFV024 interaction for host immunity is undefined
   • No mapping of the interaction interface or binding domain
   • Relevance to endogenous LAGE3 cellular function unclear
2. 2021 Medium

   Placed LAGE3 within defined kinase cascades by showing it activates JNK and ERK to drive HCC malignant phenotypes, moving from correlation toward mechanism.

   Evidence siRNA knockdown and overexpression in Hep3B and SK-HEP1 cells, xenograft model, phospho-JNK/ERK western blots, and inhibitor (SCH772984, SP600125) rescue

   PMID:34837962

   Open questions at the time

   • How LAGE3 connects to upstream JNK/ERK activation is unknown
   • No structural or biochemical basis for pathway engagement
   • Single lab, no orthogonal genetic rescue
3. 2023 Medium

   Extended LAGE3's oncogenic role beyond liver cancer to NSCLC and to a distinct pathway, implicating AKT/PI3K in metastasis and stemness control.

   Evidence siRNA knockdown in A549 and H1975 cells, xenograft nude mouse model, western blotting of AKT/PI3K components and stemness markers Nanog/SOX2/OCT4

   PMID:37473499

   Open questions at the time

   • No rescue or mutagenesis to confirm causality
   • Mechanistic link between LAGE3 and AKT/PI3K activation unresolved
   • Whether different pathways in HCC vs NSCLC reflect tissue context is untested
4. 2024 Medium

   Connected LAGE3's EKC/KEOPS complex membership to a specific molecular output by showing it is required for VEGFA mRNA stability and angiogenesis.

   Evidence Knockdown/overexpression in HCC cell lines with western blot and mRNA stability assays

   PMID:38653358

   Open questions at the time

   • Direct biochemical mechanism linking LAGE3 or tRNA modification to VEGFA mRNA stability not defined
   • No orthogonal method or rescue reported
   • Whether tRNA threonylcarbamoylation activity underlies the mRNA effect is untested

• How LAGE3's role in the EKC/KEOPS tRNA-modification complex mechanistically gives rise to its diverse oncogenic signaling and mRNA-stabilizing activities remains unresolved.
• No structural model of LAGE3 within the EKC/KEOPS complex from the corpus
• No demonstration that catalytic tRNA modification activity is required for the cancer phenotypes
• Unifying mechanism across angiogenesis, JNK/ERK, and AKT/PI3K pathways not established