Affinage

GID8

Glucose-induced degradation protein 8 homolog · UniProt Q9NWU2

Length
228 aa
Mass
26.7 kDa
Annotated
2026-06-10
8 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GID8/Twa1 is a conserved LisH-CTLH-CRA domain protein that functions as a nuclear retention factor for β-catenin in Wnt/Wg signaling (PMID:28829046). It constitutively forms stable, predominantly α-helical homodimers through its LisH-CTLH-CRA domains, independently of disulfide bonding (PMID:27920276, PMID:29067546), and assembles into a nuclear complex with RanBPM and hMuskelin (PMID:12559565). In the absence of Wnt, Twa1 associates with β-catenin in the Axin destruction complex and is ubiquitinated and degraded; upon Wnt activation it translocates into the nucleus where it binds and retains β-catenin, and its depletion attenuates Wnt-stimulated gene expression, dorsal development in zebrafish, and CRC xenograft growth (PMID:28829046). Nuclear translocation of both Twa1 and β-catenin is governed by the CRA domain and requires physical association with the IFT-A component IFT140, which Twa1 binds independently of pathway activation; CRA-domain mutants fail to enter the nucleus and act as dominant inhibitors of Wg/Wnt signaling (PMID:41931626). Beyond Wnt signaling, GID8 sustains glutamine uptake and metabolism by regulating SLC1A3 and glutaminase (GLS) expression to drive colorectal cancer progression, and its own translation is enhanced by YTHDF1 in an m6A-dependent manner (PMID:39151722).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2003 Medium

    Established GID8/Twa1 as a nuclear protein embedded in a defined protein complex, giving the first clue to its molecular context.

    Evidence Yeast two-hybrid, reciprocal Co-IP, and gel filtration identifying a RanBPM/hMuskelin complex

    PMID:12559565

    Open questions at the time
    • Functional role of the complex undefined
    • No link to a signaling pathway yet
    • LisH-CTLH motif function not tested
  2. 2017 High

    Resolved the oligomeric state of the protein, showing it is an obligate homodimer assembled through its LisH-CTLH-CRA domains rather than transient or disulfide-linked association.

    Evidence SEC-MALS, native PAGE, CD spectroscopy on recombinant tag-free mouse TWA1 with Cys139 control; NMR chemical-shift assignment of the human LisH domain homodimer

    PMID:27920276 PMID:29067546

    Open questions at the time
    • No full solution or crystal structure
    • Functional consequence of dimerization for partner binding untested
  3. 2017 High

    Defined the central mechanistic role: Twa1 is a Wnt-regulated nuclear retention factor for β-catenin, linking its degradation in the Axin complex to nuclear accumulation upon pathway activation.

    Evidence Co-IP, siRNA/shRNA knockdown, reporter assays, nuclear/cytoplasmic fractionation, zebrafish epistasis, and CRC xenografts

    PMID:28829046

    Open questions at the time
    • Mechanism of Wnt-triggered nuclear translocation not resolved at this stage
    • Identity of the responsible ubiquitin ligase unspecified
    • Domain requirements not mapped
  4. 2024 Medium

    Extended GID8 function beyond Wnt to metabolic control, showing it drives glutamine uptake and CRC progression via SLC1A3/GLS, and that its expression is set by m6A-dependent translation.

    Evidence Knockdown/overexpression, metabolic assays, in vivo xenograft, and m6A-dependent translation reporter (YTHDF1)

    PMID:39151722

    Open questions at the time
    • Direct vs indirect regulation of SLC1A3/GLS unclear
    • Relationship between metabolic and Wnt roles undefined
    • Single lab without orthogonal confirmation
  5. 2026 High

    Mapped the translocation mechanism to the CRA domain and identified IFT140 as the physical partner enabling β-catenin nuclear import, explaining how Twa1 ferries β-catenin into the nucleus.

    Evidence Drosophila loss-of-function genetics, reciprocal Co-IP (Psv-IFT140), CRA domain mutagenesis, epistasis, and β-catenin/Arm localization imaging

    PMID:41931626

    Open questions at the time
    • Structural basis of CRA-mediated nuclear entry unknown
    • How IFT-A component mediates import mechanistically unresolved
    • Conservation of IFT140 dependence in mammalian CRC not directly tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the homodimeric LisH-CTLH-CRA architecture, Axin-complex degradation, IFT140-dependent import, and glutamine metabolic control are mechanistically integrated remains unresolved.
  • No structure of the Twa1-β-catenin or Twa1-IFT140 complex
  • Ubiquitin ligase acting on Twa1 unidentified
  • Causal connection between Wnt and metabolic functions unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1430728 Metabolism 1
Partners
CTNNB1IFT140MKLN1RANBPM
Complex memberships
Axin destruction complex

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Twa1 (GID8) was identified as a novel nuclear protein that forms a protein complex with RanBPM and hMuskelin, demonstrated by two-hybrid screening, immunoprecipitation, and gel-filtration analyses. Twa1 contains LisH-CTLH motifs and localizes within the nucleus. Yeast two-hybrid screening, co-immunoprecipitation, gel-filtration chromatography Gene Medium 12559565
2017 TWA1/GID8 constitutively forms stable homodimers via its LisH-CTLH-CRA domains, as shown by gel filtration, SEC-MALS, and native PAGE with recombinant tag-free mouse TWA1; dimerization is independent of its single cysteine residue (Cys139) and is not disulfide-mediated. CD spectroscopy showed it is predominantly α-helical. Gel filtration chromatography, SEC-MALS, native PAGE, CD spectroscopy, recombinant protein purification Bioscience reports High 27920276
2017 NMR chemical shift assignments of the LisH domain homodimer of human Twa1/GID8 were determined, confirming homodimerization of the LisH domain in solution and providing the first step toward its solution structure. NMR spectroscopy (1H, 13C, 15N chemical shift assignment) Biomolecular NMR assignments Medium 29067546
2017 Twa1/GID8 acts as a nuclear retention factor for β-catenin in Wnt signaling. In the absence of Wnt, Twa1 associates with β-catenin in the Axin destruction complex and undergoes ubiquitination and degradation. Upon Wnt activation, Twa1 translocates into the nucleus where it binds and retains β-catenin. Depletion of Twa1 attenuates Wnt-stimulated gene expression, dorsal development in zebrafish embryos, and xenograft tumor growth of CRC cells. Co-immunoprecipitation, siRNA/shRNA knockdown, reporter gene assays, zebrafish embryo epistasis, xenograft tumor assay, nuclear/cytoplasmic fractionation Cell research High 28829046
2024 GID8/Twa1 maintains active glutamine uptake and metabolism by regulating expression of excitatory amino acid transporter SLC1A3 and glutaminase (GLS), facilitating CRC progression. YTHDF1 promotes GID8 translation efficiency in an m6A-dependent manner. In vitro knockdown/overexpression assays, in vivo xenograft, m6A-dependent translation reporter, metabolic assays Cancer letters Medium 39151722
2026 Drosophila Pasovec (Psv; mammalian Gid8 ortholog) is required for nuclear translocation of β-catenin/Armadillo in Wg/Wnt signaling. Psv physically binds IFT140, a core component of the IFT-A complex, independently of Wg/Wnt activation. The CRA domain of Psv/Gid8 mediates its own nuclear localization and that of β-catenin/Arm; CRA domain mutations abolish nuclear localization of both Psv and β-catenin, and a CRA-mutant Psv acts as a dominant inhibitor of Wg/Wnt signaling. Drosophila loss-of-function genetics, co-immunoprecipitation (Psv-IFT140 interaction), domain mutagenesis (CRA domain mutants), epistasis analysis, fluorescence imaging of β-catenin/Arm localization Science advances High 41931626

Source papers

Stage 0 corpus · 8 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 A novel nuclear protein, Twa1, and Muskelin comprise a complex with RanBPM. Gene 62 12559565
2017 Twa1/Gid8 is a β-catenin nuclear retention factor in Wnt signaling and colorectal tumorigenesis. Cell research 52 28829046
2021 circ_C20orf11 enhances DDP resistance by inhibiting miR-527/YWHAZ through the promotion of extracellular vesicle-mediated macrophage M2 polarization in ovarian cancer. Cancer biology & therapy 27 34382916
2024 YTHDF1 regulates GID8-mediated glutamine metabolism to promote colorectal cancer progression in m6A-dependent manner. Cancer letters 20 39151722
2017 Studies of recombinant TWA1 reveal constitutive dimerization. Bioscience reports 7 27920276
2017 1H, 13C and 15N chemical shift assignment of lissencephaly-1 homology (LisH) domain homodimer of human two-hybrid-associated protein 1 with RanBPM (Twa1). Biomolecular NMR assignments 2 29067546
2026 Nuclear translocation of β-catenin in Wg/Wnt signaling via the IFT-A microtubule-associated complex requires Pasovec/Gid8 proteins. Science advances 0 41931626
2025 circ-C20orf11 promotes karyopherin alpha 2 expression through miR-495-3p and affects non-small cell lung cancer development. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 0 40350652

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