Affinage

DENND4C

DENN domain-containing protein 4C · UniProt Q5VZ89

Round 2 corrected
Length
1909 aa
Mass
212.7 kDa
Annotated
2026-04-28
39 papers in source corpus 4 papers cited in narrative 4 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DENND4C is a DENN domain-containing guanine nucleotide exchange factor (GEF) specific for Rab10, localized to a tubular Golgi-adjacent membrane compartment and to GLUT4 storage vesicles (PMID:20937701, PMID:21454697). Its constitutive GEF activity generates GTP-bound Rab10 required for insulin-stimulated GLUT4 translocation to the plasma membrane in adipocytes, functioning downstream of the insulin-regulated GAP AS160/TBC1D4, which tonically inactivates the same Rab10 pool (PMID:21454697, PMID:23804653). Retromer directly recruits DENND4C to the endosomal retrieval sub-domain, coupling Rab10 GTPase switching with cargo recycling (PMID:40738907).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2010 High

    Systematic biochemical analysis of the DENN protein family resolved the long-standing question of substrate specificity for DENND4C, establishing it as a Rab10-specific GEF that localizes to a tubular Golgi-adjacent compartment.

    Evidence Family-wide in vitro GEF activity assays and subcellular localization of all 17 human DENN domain proteins

    PMID:20937701

    Open questions at the time
    • Physiological consequence of DENND4C-mediated Rab10 activation was not determined
    • Regulation of DENND4C GEF activity not addressed
    • No structural basis for Rab10 selectivity
  2. 2011 High

    Loss-of-function and gain-of-function experiments placed DENND4C as the Rab10 GEF required for insulin-stimulated GLUT4 translocation, linking it to a specific physiological trafficking pathway in adipocytes.

    Evidence siRNA knockdown and ectopic overexpression with quantitative GLUT4 translocation assays; subcellular fractionation showing DENND4C on GLUT4 vesicles in 3T3-L1 adipocytes

    PMID:21454697

    Open questions at the time
    • Whether DENND4C GEF activity is itself regulated by insulin signaling was unknown
    • Mechanism of DENND4C recruitment to GLUT4 vesicles not identified
    • Contribution of other DENND4 family members (DENND4A/B) not excluded
  3. 2013 Medium

    Epistasis analysis revealed that DENND4C GEF activity is constitutive rather than insulin-stimulated, clarifying that insulin regulation of the Rab10 cycle operates through suppression of AS160/TBC1D4 GAP activity rather than activation of DENND4C.

    Evidence Pathway dissection using insulin stimulation, AS160 manipulation, and GLUT4 translocation assays in adipocytes

    PMID:23804653

    Open questions at the time
    • Single-lab finding; independent confirmation in additional cell systems or in vivo models lacking
    • Post-translational regulation of DENND4C (e.g. phosphorylation) not investigated
    • No direct measurement of DENND4C catalytic rate in basal vs. stimulated conditions
  4. 2025 High

    Discovery that Retromer directly recruits DENND4C to the endosomal retrieval sub-domain expanded its functional context beyond GLUT4 vesicles, revealing that Rab10 GTPase switching is spatially coordinated with cargo recycling at endosomes.

    Evidence BioID proximity proteomics of Retromer/Retriever components; X-ray crystallography; biochemical co-purification; cellular imaging

    PMID:40738907

    Open questions at the time
    • Structural details of the DENND4C–Retromer interaction interface not fully resolved
    • Functional consequences of disrupting DENND4C recruitment to endosomes on specific cargo recycling not tested
    • Whether Retromer-recruited DENND4C activates an endosomal pool of Rab10 distinct from the GLUT4-vesicle pool is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how DENND4C is partitioned between the Golgi-adjacent compartment, GLUT4 vesicles, and endosomal retrieval sub-domains, and whether tissue-specific regulatory mechanisms control its GEF activity in vivo.
  • No in vivo animal model phenotype reported for DENND4C loss
  • No high-resolution structure of the DENND4C DENN domain–Rab10 complex
  • Potential non-Rab10 substrates or scaffolding functions not systematically explored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4
Localization
GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-162582 Signal Transduction 2
Partners
DENND4ARAB10TBC1D1TBC1D4VPS35

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 DENND4C (as part of the DENND4 subfamily) is a specific guanine nucleotide exchange factor (GEF) for Rab10, localizing to a tubular membrane compartment adjacent to the Golgi, suggesting a function in basolateral polarized sorting in epithelial cells. Systematic family-wide GEF activity assays and subcellular localization studies of all 17 human DENN domain proteins The Journal of cell biology High 20937701
2011 DENND4C is the primary GEF required for insulin-stimulated GLUT4 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, placing it as the Rab10 GEF in the insulin-signaling pathway downstream of TBC1D4/AS160 suppression. siRNA knockdown with GLUT4 translocation assay; ectopic overexpression; subcellular fractionation of GLUT4 vesicles The Journal of biological chemistry High 21454697
2013 Activation of Rab10 by DENND4C does not require insulin stimulation, distinguishing DENND4C's constitutive GEF activity from the insulin-regulated GAP activity of AS160/TBC1D4 on the same Rab10 pool required for GLUT4 translocation. Epistasis analysis in adipocytes using insulin stimulation, AS160 manipulation, and GLUT4 translocation assays Molecular biology of the cell Medium 23804653
2025 Retromer directly associates with and recruits DENND4C (together with DENND4A, TBC1D1, and TBC1D4) to the endosomal retrieval sub-domain to regulate RAB10 GTPase switching, identifying Retromer as a hub that integrates cargo recycling with regulated RAB GTPase activation. Proximity proteomics (BioID) of Retromer/Retriever components; X-ray crystallography; in silico structural predictions; biochemical co-purification; cellular imaging analysis Nature communications High 40738907

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2013 Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions. Science signaling 383 24255178
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors. The Journal of cell biology 279 20937701
2004 Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. Nature biotechnology 266 15146197
2014 Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of proteomics 215 25281560
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2015 A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 198 26673895
2014 E-cadherin interactome complexity and robustness resolved by quantitative proteomics. Science signaling 162 25468996
2019 Knockdown of circDENND4C inhibits glycolysis, migration and invasion by up-regulating miR-200b/c in breast cancer under hypoxia. Journal of experimental & clinical cancer research : CR 145 31488193
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2019 The p300/YY1/miR-500a-5p/HDAC2 signalling axis regulates cell proliferation in human colorectal cancer. Nature communications 115 30737378
2004 DNA sequence and analysis of human chromosome 9. Nature 86 15164053
2017 A Single Adaptable Cochaperone-Scaffold Complex Delivers Nascent Iron-Sulfur Clusters to Mammalian Respiratory Chain Complexes I-III. Cell metabolism 78 28380382
2011 Insulin-stimulated GLUT4 protein translocation in adipocytes requires the Rab10 guanine nucleotide exchange factor Dennd4C. The Journal of biological chemistry 65 21454697
2020 Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D. Nature communications 60 31980649
2018 Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy. Proceedings of the National Academy of Sciences of the United States of America 59 29987050
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
2014 Substrate trapping proteomics reveals targets of the βTrCP2/FBXW11 ubiquitin ligase. Molecular and cellular biology 56 25332235
2023 A central chaperone-like role for 14-3-3 proteins in human cells. Molecular cell 54 36931259
2019 KHDRBS3 regulates the permeability of blood-tumor barrier via cDENND4C/miR-577 axis. Cell death & disease 35 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 23 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
2018 Identification of nine novel loci related to hematological traits in a Japanese population. Physiological genomics 5 29958078
2025 Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation. Nature communications 3 40738907
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