Affinage

DENND4C

DENN domain-containing protein 4C · UniProt Q5VZ89

Length
1909 aa
Mass
212.7 kDa
Annotated
2026-06-09
9 papers in source corpus 4 papers cited in narrative 4 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DENND4C is a guanine nucleotide exchange factor (GEF) for the small GTPase RAB10 that functions in regulated membrane trafficking, most notably insulin-stimulated GLUT4 vesicle delivery to the plasma membrane in adipocytes (PMID:21454697). It localizes to GLUT4-containing vesicles, and loss of DENND4C markedly impairs GLUT4 translocation, identifying it as the primary RAB10 GEF in this pathway (PMID:21454697). Its GEF activity toward RAB10 is constitutive and insulin-independent, so insulin regulation of the pathway is imposed not by activating DENND4C but through suppression of the RAB10 GAP AS160 (PMID:23804653). DENND4C is also directly bound and recruited by Retromer to the endosomal retrieval sub-domain, placing its RAB10 GTPase-switching activity within an endosomal cargo-recycling hub (PMID:40738907).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2011 High

    Established which GEF drives RAB10 activation during regulated GLUT4 trafficking, identifying DENND4C as the molecular link between RAB10 and insulin-responsive glucose uptake.

    Evidence siRNA knockdown, overexpression, GLUT4 translocation assays, and GLUT4-vesicle fractionation in adipocytes

    PMID:21454697

    Open questions at the time
    • Direct nucleotide-exchange kinetics on RAB10 not measured in this study
    • Domain of DENND4C responsible for GEF activity not mapped
    • Mechanism of vesicle targeting not defined
  2. 2013 Medium

    Resolved where insulin acts in the pathway by showing DENND4C GEF activity is constitutive, so insulin operates downstream through GAP (AS160) suppression rather than GEF activation.

    Evidence Pathway/epistasis analysis combining insulin stimulation with RAB10 activation assays in adipocytes

    PMID:23804653

    Open questions at the time
    • Single-lab pathway placement without reconstituted biochemistry
    • How DENND4C itself is spatially regulated remains undefined
    • Interplay with RAB14 hierarchy not fully resolved
  3. 2025 High

    Defined how DENND4C is positioned at endosomes by showing Retromer directly binds and recruits it to the retrieval sub-domain, coupling cargo recycling to RAB10 GTPase switching.

    Evidence Proximity proteomics, X-ray crystallography, biochemical pulldown/co-IP, and cellular analysis

    PMID:40738907

    Open questions at the time
    • Functional consequence of Retromer recruitment for GLUT4 trafficking not directly tested
    • Structural basis of the DENND4C-Retromer interface within the full complex not detailed here
    • Whether recruitment alters RAB10 GEF kinetics not measured

Open questions

Synthesis pass · forward-looking unresolved questions
  • How constitutive DENND4C GEF activity, vesicle targeting, and Retromer-mediated endosomal recruitment are integrated to spatially restrict RAB10 activation remains unresolved.
  • No structural model of DENND4C catalytic engagement with RAB10
  • Tissue and cargo specificity of DENND4C function beyond adipocyte GLUT4 not mapped
  • Regulation of DENND4C localization between GLUT4 vesicles and endosomal sub-domains undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3
Localization
GO:0005768 endosome 1 GO:0031410 cytoplasmic vesicle 1
Pathway
GO:0005215 transporter activity 1
Partners
RAB10VPS35

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 DENND4C is the primary guanine nucleotide exchange factor (GEF) for Rab10 required for insulin-stimulated GLUT4 vesicle translocation to the plasma membrane in adipocytes. Knockdown of DENND4C markedly inhibited GLUT4 translocation, ectopic expression slightly stimulated it, and DENND4C was found in isolated GLUT4 vesicles. siRNA knockdown, ectopic overexpression, GLUT4 translocation assay, subcellular fractionation of GLUT4 vesicles The Journal of biological chemistry High 21454697
2013 Activation of Rab10 by DENND4C (its GEF) does not require insulin stimulation, establishing that DENND4C's GEF activity toward Rab10 is constitutive and that insulin regulation of Rab10 in the GLUT4 translocation pathway operates through suppression of the GAP AS160, not through activation of DENND4C. Epistasis/pathway analysis in adipocytes; insulin-stimulation experiments combined with Rab10 activation assays Molecular biology of the cell Medium 23804653
2025 Retromer directly associates with and recruits DENND4C (along with DENND4A, TBC1D1, and TBC1D4) to the endosomal retrieval sub-domain to regulate RAB10 GTPase switching, establishing Retromer as a hub linking cargo recycling with RAB GTPase regulation. Proximity proteomics, X-ray crystallography, in silico structural predictions, biochemical pulldown/co-IP, cellular analysis Nature communications High 40738907
2024 Retromer directly associates with DENND4C and recruits it to the endosomal retrieval sub-domain for RAB10 regulation (preprint version of the above finding, same data). Proximity proteomics, X-ray crystallography, biochemical and cellular analysis bioRxivpreprint High bio_10.1101_2024.11.22.622898

Source papers

Stage 0 corpus · 9 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Insulin-stimulated GLUT4 protein translocation in adipocytes requires the Rab10 guanine nucleotide exchange factor Dennd4C. The Journal of biological chemistry 67 21454697
2013 Specialized sorting of GLUT4 and its recruitment to the cell surface are independently regulated by distinct Rabs. Molecular biology of the cell 58 23804653
2019 KHDRBS3 regulates the permeability of blood-tumor barrier via cDENND4C/miR-577 axis. Cell death & disease 36 31296839
2024 Circ DENND4C inhibits pyroptosis and alleviates ischemia-reperfusion acute kidney injury by exosomes secreted from human urine-derived stem cells. Chemico-biological interactions 24 38412628
2020 Circ-DENND4C up-regulates TCF4 expression to modulate hepatocellular carcinoma cell proliferation and apoptosis via activating Wnt/β-catenin signal pathway. Cancer cell international 15 32669971
2025 Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation. Nature communications 5 40738907
2018 Identification of nine novel loci related to hematological traits in a Japanese population. Physiological genomics 5 29958078
2020 Circular RNA-DENND4C in H9c2 cells relieves OGD/R-induced injury by down regulation of microRNA-320. Cell cycle (Georgetown, Tex.) 3 33090893
2025 Circular RNA DENND4C Regulates Cell Malignant Behaviors in Breast Cancer Through the miR-26a-5p/HSPA8 Axis. Breast cancer (Dove Medical Press) 0 41358261

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