CCDC137

CCDC137 is a nucleolar protein that has emerged primarily as an oncogenic effector across multiple cancers, where it converges on AKT-axis signaling to drive proliferation and disease progression (PMID:37542342, PMID:38918619). As an RNA-binding protein, it binds a defined set of mRNAs (FOXM1, JTV1, LASP1, FLOT2) and, through interaction with the microprocessor protein DGCR8, promotes their cytoplasmic localization and elevated protein output, thereby activating AKT signaling in hepatocellular carcinoma (PMID:37542342). In a distinct nuclear function, CCDC137 binds the β-catenin negative regulator LZTS2 and recruits the E3 ligase β-TrCP to catalyze K48-linked polyubiquitination of LZTS2 at lysine 467 via its 1–75 domain, triggering AKT phosphorylation and β-catenin pathway activation (PMID:38918619). It also acts as a protein stabilizer, binding S100A6 to enhance its stability and engage PI3K/AKT signaling in acute myeloid leukemia (PMID:41964482). In normal biology, CCDC137 behaves as a nucleolar stress sensor: HIV Vpr and genotoxic insults activate an ATR-dependent nucleolar pathway that drives its degradation, accompanied by nucleolar protein redistribution and repressed ribosome biogenesis (PMID:40530693). Its transcription is itself driven by CDK12 through super-enhancer regulation in colorectal cancer (PMID:36254394).

1. 2022 Medium

   Established how CCDC137 expression is controlled, identifying it as a super-enhancer-associated oncogenic target of CDK12 transcriptional regulation.

   Evidence shRNA knockdown, selective CDK12 inhibitor (SR-4835), RNA-seq integrated with super-enhancer landscape, and in vivo metastasis assays in colorectal cancer

   PMID:36254394

   Open questions at the time

   • Does not address the molecular function of the CCDC137 protein itself
   • Mechanism by which CCDC137 supports survival/stemness downstream not defined here
2. 2023 Medium

   Defined CCDC137 as an RNA-binding protein that uses DGCR8 to redirect specific mRNAs to the cytoplasm, providing a mechanistic basis for its activation of AKT signaling.

   Evidence APOBEC1-mediated RNA profiling, Co-IP with DGCR8, mRNA localization assays, and in vitro/in vivo HCC models

   PMID:37542342

   Open questions at the time

   • Direct RNA-binding domain of CCDC137 not mapped
   • How DGCR8 is repurposed from microprocessor to mRNA-localization role mechanistically unresolved
   • Single lab
3. 2024 High

   Revealed a separate nuclear scaffolding function in which CCDC137 directs ubiquitin-mediated degradation of a β-catenin antagonist, linking it to β-catenin/AKT activation.

   Evidence Reciprocal Co-IP, site-specific (K467) ubiquitination mapping, domain deletion (1–75), and peptide disruption in HCC organoids and PDX models

   PMID:38918619

   Open questions at the time

   • How CCDC137 selects LZTS2 as substrate-presenting partner not defined
   • Relationship between this nuclear function and the RNA-binding function unclear
4. 2025 Medium

   Identified CCDC137 as a target of nucleolar stress in normal biology, degraded through an ATR-dependent pathway upon HIV Vpr expression or genotoxic insult.

   Evidence Vpr functional genetics, ATR pathway inhibition, nucleolar localization and ribosome biogenesis assays, comparison across Vpr variants

   PMID:40530693

   Open questions at the time

   • The E3 ligase mediating CCDC137 degradation not identified
   • Whether CCDC137 loss is cause or consequence of nucleolar disruption not resolved
   • Degradation uncoupled from G2/M arrest but functional consequence of loss unclear
5. 2026 Medium

   Extended the protein-stabilizing mode of CCDC137 to S100A6, connecting it to PI3K/AKT-driven proliferation in acute myeloid leukemia.

   Evidence Co-IP, protein stability assays, and proliferation/cell-cycle functional experiments

   PMID:41964482

   Open questions at the time

   • Mechanism of S100A6 stabilization (e.g. blocking degradation) not detailed
   • Whether interaction is direct not established

• It remains unknown how CCDC137's nucleolar localization and stress-sensor role mechanistically relate to its cytoplasmic oncogenic functions, and whether a single biochemical activity underlies its RNA-binding, ubiquitin-scaffolding, and protein-stabilizing roles.
• No structural model of CCDC137 or its functional domains beyond the 1–75 region
• No unifying biochemical activity defined across reported functions
• Lipid-metabolism (SCD) and AKT/mTOR roles rest on correlative single-lab data