Affinage

NCBP2

Nuclear cap-binding protein subunit 2 · UniProt P52298

Length
156 aa
Mass
18.0 kDa
Annotated
2026-06-10
20 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NCBP2 (CBP20) is the small, cap-binding subunit of the nuclear cap-binding complex (CBC), where it directly contacts the m7G cap of RNA Pol II transcripts through its RNA recognition motif (RRM) while heterodimerizing with the large subunit CBP80 (PMID:21326824). Conserved cap-recognition residues in the cap-binding pocket are essential for function: in yeast, cap binding by the ortholog Cbc2 is required for splicing of MER3 pre-mRNA and thereby for meiosis, as an intronless MER3 cDNA rescues the cap-binding-defective mutant (PMID:23002122). As the CBC small subunit, NCBP2/Cbc2 acts at the earliest steps of spliceosome assembly, forming part of the splicing commitment complex (PMID:8682299), and persists on newly exported transcripts as part of an mRNP that includes CBP80, PABP2, eIF4G, Upf2, and Upf3 to direct the pioneer round of translation that licenses nonsense-mediated decay before CBC is replaced by eIF4E (PMID:11551508). An alternatively spliced isoform (CBP20S) lacking most of the RRM cannot bind CBP80 or the cap yet retains general mRNA binding and accumulates at transcription sites and nucleolar caps (PMID:21326824). Through its cap-reader activity NCBP2 influences specific transcripts and downstream programs: it stabilizes LIPG mRNA via direct m7G-cap binding to drive lipid-droplet accumulation in colorectal cancer (PMID:41872454) and enhances translation of c-JUN to activate MEK/ERK signaling in pancreatic cancer (PMID:38001714), and its depletion reduces viability, induces apoptosis, and causes G1-S cell cycle arrest (PMID:40887503). NCBP2 also acts upstream of apoptotic pathways during neurodevelopment, interacting with other 3q29-deletion genes to modulate apoptosis and brain morphology in a manner rescued by apoptosis inhibitors (PMID:32053595).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1996 High

    Established that the CBP20 ortholog is a functional CBC subunit acting at the entry point of spliceosome assembly, defining the complex's role in pre-mRNA splicing rather than merely cap protection.

    Evidence Synthetic-lethal genetic screen with U1 snRNA mutations and splicing assays in delta-MUD13 yeast extracts

    PMID:8682299

    Open questions at the time
    • Did not define the cap-binding residues or RRM contribution
    • Commitment-complex role demonstrated in yeast, not human cells
  2. 2001 High

    Showed CBP20 persists on exported mRNA in a defined mRNP and marks the pioneer round of translation that enables NMD, distinguishing CBC-bound from eIF4E-bound translation.

    Evidence Reciprocal immunopurification of CBP80/eIF4E mRNPs with co-purifying NMD factors; translation inhibitors to block NMD in human cells

    PMID:11551508

    Open questions at the time
    • Did not isolate the specific contribution of NCBP2 versus CBP80
    • Mechanism of CBC-to-eIF4E exchange not resolved
  3. 2010 Medium

    Mapped cap and CBP80 binding to the RRM and revealed an RRM-deficient isoform, separating cap-reading from general mRNA association and localization.

    Evidence Splice-variant characterization, cap- and CBP80-binding assays, and live-cell imaging upon transcription inhibition

    PMID:21326824

    Open questions at the time
    • Functional role of the CBP20S isoform not established
    • Single-lab study without structural confirmation
  4. 2012 High

    Identified the specific cap-binding-pocket residues and linked cap recognition to a defined biological output (meiotic splicing of MER3), proving cap reading is functionally essential.

    Evidence Alanine-scanning mutagenesis, genetic epistasis, and intronless-MER3 cDNA rescue in yeast

    PMID:23002122

    Open questions at the time
    • Demonstrated for a single transcript in yeast meiosis
    • Generality of intron-specific dependence in humans unaddressed
  5. 2020 Medium

    Placed NCBP2 upstream of apoptotic pathways in neurodevelopment and within the 3q29 deletion gene network, linking cap-binding machinery to organismal phenotypes.

    Evidence Tissue-specific RNAi and pairwise epistasis in Drosophila and Xenopus with apoptosis-inhibitor rescue

    PMID:32053595

    Open questions at the time
    • Molecular mechanism connecting NCBP2 cap-binding to apoptosis not defined
    • Relevance to human 3q29 phenotypes inferred from orthologs
  6. 2023 Medium

    Connected NCBP2 cap-reader activity to oncogenic signaling by showing it enhances c-JUN translation to activate MEK/ERK in pancreatic cancer.

    Evidence Knockdown/overexpression cell lines, xenografts, and pathway western blots

    PMID:38001714

    Open questions at the time
    • Direct cap-dependence of c-JUN translation not biochemically isolated
    • Single-lab, one tumor type
  7. 2025 Medium

    Quantified the consequence of NCBP2 loss as a cell-cycle and survival defect, framing it as a candidate dependency in cancer cells.

    Evidence Knockdown, viability/cell-cycle assays, and RNA sequencing in cancer cells

    PMID:40887503

    Open questions at the time
    • Causal transcripts driving G1-S arrest not identified
    • Specificity versus general CBC disruption unresolved
  8. 2026 Medium

    Demonstrated transcript-selective regulation by NCBP2 — direct m7G-cap binding stabilizing LIPG mRNA to drive lipid metabolism and tumor progression.

    Evidence Knockdown/overexpression in CRC, direct RNA-protein binding to m7G cap, mRNA stability and lipid-droplet measurements, in vivo models

    PMID:41872454

    Open questions at the time
    • How NCBP2 confers selectivity for LIPG over other capped mRNAs is unclear
    • Single-lab study
  9. 2026 Low

    Proposed NCBP2-controlled alternative splicing of KIF23 and a KIF23-PGAM5 mitophagy axis, with FBXW8 as an E3 ligase degrading NCBP2.

    Evidence Proliferation/migration assays, alternative-splicing analysis, and a FBXW8 ubiquitination assay (single lab)

    PMID:41874817

    Open questions at the time
    • Splicing and ubiquitination claims have limited mechanistic validation
    • FBXW8-NCBP2 interaction not independently confirmed
    • Mitophagy link is correlative

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NCBP2 achieves transcript selectivity for stabilization, splicing, and translational control while serving as a general cap reader, and how its turnover is regulated, remain unresolved.
  • No structural model explaining selective target recognition
  • Regulatory inputs controlling CBC versus eIF4E exchange in humans undefined
  • FBXW8-mediated degradation needs independent confirmation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4
Localization
GO:0005634 nucleus 1 GO:0005730 nucleolus 1
Pathway
R-HSA-8953854 Metabolism of RNA 3
Partners
EIF4G1FBXW8NCBP1PABPN1UPF2UPF3
Complex memberships
nuclear cap-binding complex (CBC)

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 CBP20 (NCBP2) is a component of the NMD-susceptible mRNP complex that also contains CBP80, PABP2, eIF4G, Upf2, and Upf3, and is present on mRNAs undergoing a 'pioneer' round of translation before CBP80-CBP20 are replaced by eIF4E. Immunopurification of RNP with antibody to CBP80 or eIF4E, followed by identification of co-purifying components; NMD blocked by cycloheximide or suppressor tRNA Cell High 11551508
1996 Yeast Mud13p/Cbc2 (ortholog of CBP20/NCBP2) is a component of the splicing commitment complex and is required for early steps of spliceosome assembly, functioning as the small cap-binding subunit of the nuclear cap-binding complex (CBC). Genetic screen for synthetic lethality with U1 snRNA mutations; characterization of splicing in delta-MUD13 yeast strains and extracts; biochemical identification of Mud13p as yeast CBC small subunit Genes & development High 8682299
2012 Yeast Cbc2 (CBP20/NCBP2 ortholog) binds the m7G cap via specific residues in its cap-binding pocket (Y24, F91, D120, D122, R129, R133), and cap recognition by Cbc2 is essential for meiosis through splicing of MER3 pre-mRNA; an intronless MER3 cDNA fully rescues the sporulation defect of cbc2-NΔ42. Alanine scanning and N-terminal deletion mutagenesis; genetic interaction screens (synthetic lethality with spliceosome assembly factors); RNA analysis of pre-mRNA splicing in meiosis; rescue with intronless MER3 cDNA RNA (New York, N.Y.) High 23002122
2010 Full-length CBP20 (NCBP2) binds CBP80 and the m7G cap via its RNA recognition motif (RRM); an alternatively spliced isoform CBP20S lacking most of the RRM fails to bind CBP80 or the m7G cap but retains mRNA binding and localizes to active transcription sites and nucleolar caps upon transcription inhibition. Characterization of alternative splice variant; cap-binding and CBP80-binding assays; live-cell imaging and localization upon transcription inhibition Nucleus (Austin, Tex.) Medium 21326824
2020 NCBP2 (via its Drosophila ortholog Cbp20 and Xenopus ortholog ncbp2) genetically interacts with other 3q29 deletion region genes to enhance apoptosis, disrupt cellular organization, and impair brain morphology; these defects are rescued by overexpression of apoptosis inhibitors Diap1 and xiap, placing NCBP2 upstream of apoptotic pathways during neurodevelopment. Tissue-specific RNAi knockdown in Drosophila melanogaster and Xenopus laevis; quantitative phenotypic assays for apoptosis and brain morphology; pairwise knockdown epistasis screen; rescue by apoptosis inhibitor overexpression PLoS genetics Medium 32053595
2023 NCBP2 promotes pancreatic ductal adenocarcinoma progression by enhancing translation of c-JUN, which activates MEK/ERK signaling; NCBP2 knockdown inhibits PDAC cell proliferation and NCBP2 overexpression promotes growth in vitro and in vivo. Stable NCBP2 knockdown and overexpression cell lines; in vitro proliferation assays; in vivo xenograft models; western blot for c-JUN and MEK/ERK pathway components Cancers Medium 38001714
2026 NCBP2 stabilizes LIPG mRNA via direct binding to the m7G motif in the 5'-cap structure of LIPG mRNA, increasing LIPG expression and promoting lipid droplet accumulation in colorectal cancer cells, driving CRC proliferation, migration, and invasion. NCBP2 overexpression and knockdown in CRC cell lines and in vivo models; direct RNA-protein binding assay to m7G cap structure; measurement of LIPG mRNA stability and lipid droplet accumulation; in vivo tumor models Communications biology Medium 41872454
2026 NCBP2 regulates alternative splicing of KIF23 to promote cervical cancer progression; NCBP2 also regulates mitophagy via the KIF23-PGAM5 axis; FBXW8 ubiquitinates and degrades NCBP2, inhibiting overactivation of mitophagy. CCK-8, EdU, Transwell assays; RT-qPCR and western blot; bioinformatics screening; alternative splicing analysis of KIF23; ubiquitination assay for FBXW8-mediated NCBP2 degradation Applied biochemistry and biotechnology Low 41874817
2025 NCBP2 knockdown leads to reduced cancer cell viability, apoptosis induction, and G1-S cell cycle arrest; RNA sequencing confirmed downregulation of cell-cycle-related pathways upon CBP20 depletion in cancer cells. NCBP2 knockdown; cell viability assays; cell cycle analysis; RNA sequencing Experimental & molecular medicine Medium 40887503

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20. Cell 491 11551508
2018 Simultaneous CRISPR/Cas9-mediated editing of cassava eIF4E isoforms nCBP-1 and nCBP-2 reduces cassava brown streak disease symptom severity and incidence. Plant biotechnology journal 176 30019807
2008 Two cap-binding proteins CBP20 and CBP80 are involved in processing primary MicroRNAs. Plant & cell physiology 138 18829588
1996 The yeast splicing factor Mud13p is a commitment complex component and corresponds to CBP20, the small subunit of the nuclear cap-binding complex. Genes & development 130 8682299
2019 Hypoxic cancer-associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling. Science signaling 99 30723174
2020 NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models. PLoS genetics 38 32053595
2016 Phosphorylation of CBP20 Links MicroRNA to Root Growth in the Ethylene Response. PLoS genetics 32 27870849
2012 Genetic interactions of hypomorphic mutations in the m7G cap-binding pocket of yeast nuclear cap binding complex: an essential role for Cbc2 in meiosis via splicing of MER3 pre-mRNA. RNA (New York, N.Y.) 26 23002122
2023 m7G-related genes-NCBP2 and EIF4E3 determine immune contexture in head and neck squamous cell carcinoma by regulating CCL4/CCL5 expression. Molecular carcinogenesis 21 37067401
2010 Binding properties and dynamic localization of an alternative isoform of the cap-binding complex subunit CBP20. Nucleus (Austin, Tex.) 18 21326824
2023 The m7G Reader NCBP2 Promotes Pancreatic Cancer Progression by Upregulating MAPK/ERK Signaling. Cancers 16 38001714
2020 Cuticular waxes-A shield of barley mutant in CBP20 (Cap-Binding Protein 20) gene when struggling with drought stress. Plant science : an international journal of experimental plant biology 12 33180718
2023 Anisomycin inhibits the activity of human ovarian cancer stem cells via regulating antisense RNA NCBP2-AS2/MEK/ERK/STAT3 signaling. The journal of gene medicine 4 37483091
2025 NCBP2-AS2 is a mitochondrial microprotein, regulates energy metabolism and neurogenesis, and is downregulated in Alzheimer's disease. bioRxiv : the preprint server for biology 3 39975220
2024 Comprehensive investigation in oncogenic functions and immunological roles of NCBP2 and its validation in prostate cancer. Translational oncology 3 38964031
2025 Comprehensive profiling of RNA modification-related genes identifies RNA m7G binding protein CBP20 as a therapeutic target for tumor growth inhibition. Experimental & molecular medicine 2 40887503
1994 The production and preclinical characterization of a chimeric anti-breast-cancer antibody, cBC2. Therapeutic immunology 2 7584487
2026 NCBP2 drives colorectal cancer growth and metastasis through LIPG-mediated lipid droplet accumulation. Communications biology 0 41872454
2026 NCBP2 Regulates PGAM5-Mediated Mitophagy Via KIF23 Alternative Splicing To Promote Cervical Cancer ProgressionRun Title: NCBP2 Promotes Cervical Cancer Via Mitophagy. Applied biochemistry and biotechnology 0 41874817
2025 A2M-AS1, DBH-AS1, and NCBP2-AS2 in breast cancer: expression patterns, CA125-3 association, and a DBH-AS1-NCBP2-AS2 axis. Molecular biology reports 0 41065851

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