Affinage

RAB11FIP4

Rab11 family-interacting protein 4 · UniProt Q86YS3

Length
637 aa
Mass
71.9 kDa
Annotated
2026-06-10
25 papers in source corpus 10 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAB11FIP4 is a member of the Rab11-FIP family of Rab11 effectors that couples GTP-loaded Rab11 to the regulation of endocytic recycling, autophagy, and lysosomal trafficking (PMID:12470645, PMID:39434668). Through its C-terminal Rab/ERM-binding region it binds GTP-Rab11 in a nucleotide-dependent manner and self-associates as well as heterodimerizes with other Rab11-FIP family members (Rip11, Rab11-FIP2, Rab11-FIP3), forming oligomeric platforms on the perinuclear Rab11-positive recycling compartment where it colocalizes with transferrin (PMID:12470645, PMID:11944901). Reconstitution in cystinotic fibroblasts shows that RAB11FIP4 acts as a Rab11A effector to normalize autophagosome levels, drive LAMP2A localization to the lysosomal membrane, relieve ER stress, and restore megalin recycling to the plasma membrane, with the ER-stress component being partially Rab11-dependent (PMID:39434668). Distinct from its endosomal effector role, the N-terminal EF-hand-containing region mediates a Rab11-independent function in cell-cycle exit during retinal development, acting within a Shh/PKA-regulated pathway that controls p57Kip2 induction and cyclin D1 levels and the production of bipolar cells and Müller glia (PMID:16457799, PMID:17089410). In hepatocellular carcinoma, RAB11FIP4 is transcriptionally induced by HIF-1α under hypoxia and promotes migration, invasion, and lung metastasis through mTOR-dependent PRAS40 phosphorylation (PMID:25745995), and it interacts with ARF5 to promote cancer stem cell-like features via CDK1/cyclin B cell-cycle proteins (PMID:37458957). The ARF5 interaction is conserved in mouse oocytes, where RAB11FIP4 supports a recycling-endosome pathway that protects internalized cargo from lysosomal degradation (PMID:40720586).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 Medium

    Established RAB11FIP4 as a bona fide Rab11 effector by showing GTP-dependent Rab11 binding and defining the C-terminal region as the module for Rab binding and for homo/hetero-oligomerization with other Rab11-FIPs.

    Evidence Co-immunoprecipitation, two-hybrid, and pulldowns with GTP/GDP-loaded Rab11 plus truncation mapping in cultured cells

    PMID:11944901 PMID:12470645

    Open questions at the time
    • No structure of the Rab-binding interface
    • Functional consequence of FIP heterodimerization not resolved
    • Selectivity against RCP unexplained mechanistically
  2. 2002 Medium

    Placed RAB11FIP4 on the perinuclear Rab11 recycling compartment but distinguished its role from bulk transferrin recycling, indicating a regulatory rather than core-transport effector function.

    Evidence Fluorescence microscopy, subcellular fractionation, and transferrin recycling assays with truncation mutants in HeLa cells

    PMID:12470645

    Open questions at the time
    • The specific recycling cargo it does control was not identified
    • Mechanism by which it condenses the Rab11 compartment unknown
  3. 2007 Medium

    Revealed a Rab11-independent developmental function: the N-terminal EF-hand region, not the Rab11-binding domain, drives retinal progenitor cell-cycle exit within Shh/PKA signaling controlling p57Kip2 and cyclin D1.

    Evidence Morpholino knockdown in zebrafish with p57Kip2/dominant-negative PKA rescue, and bidirectional retinal electroporation with truncation analysis in mouse

    PMID:16457799 PMID:17089410

    Open questions at the time
    • Molecular partners of the EF-hand region not identified
    • Direct mechanistic link to Shh/PKA components missing
    • Relevance to mammalian development beyond retina untested
  4. 2010 Low

    Linked RAB11FIP4 to the proteasome by identifying it as an Ecm29-binding partner tethering 26S proteasomes to endosomes, hinting at a broader endosomal scaffolding role.

    Evidence Genome-wide two-hybrid, mass spectrometry, and confocal microscopy

    PMID:20682791

    Open questions at the time
    • Identified only as a screen hit with no functional follow-up for RAB11FIP4
    • Interaction not validated reciprocally for this protein
    • Physiological role of proteasome-endosome link via RAB11FIP4 unknown
  5. 2015 Medium

    Defined an oncogenic axis: HIF-1α transcriptionally induces RAB11FIP4 under hypoxia to drive HCC metastasis through mTOR-dependent PRAS40 phosphorylation.

    Evidence Promoter reporter, ChIP, knockdown/overexpression with migration/invasion assays and in vivo xenograft lung metastasis

    PMID:25745995

    Open questions at the time
    • How an endosomal effector engages mTOR/PRAS40 is unresolved
    • Whether the metastatic effect requires Rab11 binding untested
    • Direct versus indirect regulation of PRAS40 not distinguished
  6. 2023 Medium

    Identified ARF5 as a RAB11FIP4 partner and connected RAB11FIP4 to cancer stemness and chemoresistance via CDK1/cyclin B cell-cycle proteins.

    Evidence Co-immunoprecipitation, bidirectional knockdown/overexpression, sphere formation, and stemness/CDK1-cyclin B Western blots in HCC

    PMID:37458957

    Open questions at the time
    • Direct versus indirect ARF5 binding not mapped
    • Mechanism connecting ARF5 to CDK1/cyclin B regulation unclear
    • Relationship to the HIF-1α/mTOR axis not integrated
  7. 2024 Medium

    Demonstrated that RAB11FIP4 acts as a Rab11A effector regulating autophagy flux, LAMP2A lysosomal membrane localization, and megalin recycling, with rescue activity in a cystinosis model.

    Evidence Reconstitution in Ctns-/- fibroblasts with autophagy flux, LAMP2A/megalin localization, and dominant-negative Rab11 epistasis

    PMID:39434668

    Open questions at the time
    • Which steps are Rab11-dependent versus independent only partly delineated
    • Direct substrate/cargo handling not biochemically reconstituted
    • Connection to the EF-hand developmental role unaddressed
  8. 2025 Medium

    Extended the ARF5-linked recycling role to mouse oocytes, where RAB11FIP4 supports maturation and protects internalized cargo from lysosomal degradation via recycling endosomes.

    Evidence Co-immunoprecipitation, siRNA knockdown, transcriptome and endocytic inhibitor experiments, TEM in mouse oocytes

    PMID:40720586

    Open questions at the time
    • Mechanism of cargo diversion from lysosome to recycling route unresolved
    • Role of Rab11 binding in this context untested
  9. 2025 Low

    Genetic screening in Drosophila motor neurons positioned the Nuf/Rab11FIP4 ortholog as a motor adaptor restricting presynaptic EV cargo, opposing MyoV/Rbo and partitioning Rab11 effectors into cargo-promoting versus cargo-restricting roles.

    Evidence Directed genetic screen and rab11 mutant analysis with EV cargo imaging in Drosophila (preprint)

    PMID:42124713

    Open questions at the time
    • Preprint without biochemical reconstitution
    • Ortholog finding not confirmed in mammals
    • Direct motor adaptor activity not demonstrated biochemically

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RAB11FIP4 toggles between its Rab11-dependent endosomal/lysosomal effector functions and its Rab11-independent EF-hand developmental and oncogenic signaling roles remains unresolved.
  • No structural model integrating the EF-hand and Rab-binding domains
  • Mechanism coupling endosomal scaffolding to mTOR/PRAS40 and CDK1/cyclin B signaling unknown
  • Direct cargo and substrate identities largely undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005768 endosome 3
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9612973 Autophagy 1
Partners
ARF5ECM29RAB11ARAB11FIP2RAB11FIP3RAB11FIP5
Complex memberships
Rab11-FIP oligomeric complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 RAB11FIP4 was identified as the sixth member of the Rab11-FIP family and interacts with Rab11 in a GTP-dependent manner; its C-terminal region mediates self-interaction and interactions with Rip11, Rab11-FIP2, and Rab11-FIP3, but not with RCP (Rab coupling protein). Co-immunoprecipitation, pulldown assays with GTP/GDP-loaded Rab11 Biochemical and biophysical research communications Medium 12470645
2002 RAB11FIP4 colocalizes with transferrin and Rab11 in HeLa cells; overexpression condenses the Rab11-positive compartment in the perinuclear region, while expression of the C-terminal region alone disperses it to the cell periphery without inhibiting transferrin recycling, suggesting a Rab11 effector role distinct from transferrin recycling. Fluorescence microscopy, subcellular fractionation, transferrin recycling assay, overexpression of truncation mutants Biochemical and biophysical research communications Medium 12470645
2002 RAB11FIP4 family members can homo- and hetero-interact primarily through their C-terminal region (containing the Rab-binding domain within a predicted coiled-coil or ERM motif), forming potential protein 'platforms' regulated by Rab11 activity. Co-immunoprecipitation and two-hybrid interaction assays Biochemical and biophysical research communications Medium 11944901 12470645
2006 Zebrafish Rab11-FIP4A (neural-specific isoform) is required for proliferation and cell-cycle exit of retinal progenitors; morpholino knockdown produces small-eye phenotype with impaired proliferation, delayed cell-cycle exit, lack of p57kip2 induction, and enhanced cyclin D1; phenotype rescued by p57Kip2 overexpression or dominant-negative PKA, placing Rab11-FIP4A in a Shh/PKA-regulated pathway. Antisense morpholino knockdown in zebrafish, in situ hybridization, immunostaining, rescue by p57Kip2 and dominant-negative PKA overexpression Developmental biology Medium 16457799
2007 Mouse Rab11-FIP4A gain-of-function in retina promotes cell cycle exit and increases bipolar cells and Müller glia; loss-of-function reverses this; truncation analysis shows the N-terminal EF-hand-containing region is essential, while the Rab11-binding domain is dispensable, indicating a Rab11-independent mechanism in retinal development. In vivo retinal electroporation (gain- and loss-of-function), truncation mutant analysis, cell-type immunostaining Developmental dynamics Medium 17089410
2010 The N-terminal region of Ecm29 binds RAB11FIP4 (and other endocytic proteins), linking the 26S proteasome to endosomal compartments; Ecm29-26S proteasome complexes are present on flotillin-positive endosomes. Genome-wide two-hybrid screen, mass spectrometry, confocal microscopy, glycerol gradient fractionation The Journal of biological chemistry Low 20682791
2015 HIF-1α transcriptionally activates RAB11FIP4 under hypoxia by binding its promoter; elevated RAB11FIP4 promotes HCC cell migration and invasion in vitro and lung metastasis in vivo through phosphorylation of PRAS40, regulated by mTOR. Promoter reporter assay, ChIP, siRNA knockdown and overexpression, migration/invasion assays, in vivo xenograft lung metastasis, Western blot for PRAS40 phosphorylation Oncogene Medium 25745995
2023 RAB11FIP4 interacts with ARF5; elevated RAB11FIP4 in HCC promotes cancer stem cell-like features (sphere formation, stemness markers ALDH1A1, CD133, NANOG, OCT4) through modulation of CDK1/cyclin B cell cycle proteins; knockdown reduces stemness and increases sorafenib sensitivity. Co-immunoprecipitation, siRNA knockdown, overexpression, sphere formation assay, Western blot for stemness markers and CDK1/cyclin B Journal of physiology and biochemistry Medium 37458957
2024 Reconstitution of RAB11FIP4 expression in cystinotic (Ctns−/−) fibroblasts restores normal autophagosome levels, decreases LC3B-II, increases LAMP2A localization at the lysosomal membrane, decreases ER stress, and increases megalin at the plasma membrane of proximal tubule cells; a dominant-negative Rab11 partially blocks the ER stress rescue, indicating RAB11FIP4 acts as a Rab11A effector to regulate autophagy, lysosomal trafficking, and endocytic receptor recycling. mRNA array, Western blot, immunofluorescence/localization of LAMP2A and megalin, LC3B-II quantification, dominant-negative Rab11 epistasis, pharmacological CMA activation Molecular and cellular biology Medium 39434668
2025 In Drosophila motor neurons, the Rab11FIP4 ortholog (Nuf/Rab11FIP4) acts as a motor adaptor that restricts presynaptic EV cargo levels, opposing the action of MyoV and PI4KIIIα component Rbo; genetic screen demonstrates Rab11FIP4 and PI4KIIIβ homolog Fwd reduce EV cargo at synapses while other Rab11 effectors sustain them. Directed genetic screen in Drosophila motor neurons, rab11 mutant analysis, fluorescence imaging of EV cargo distribution bioRxivpreprint Low 42124713
2025 Rab11fip4 interacts with Arf5 in mouse oocytes (confirmed by Co-IP); knockdown of Rab11fip4 impairs oocyte maturation and nanoparticle internalization; Rab11fip4-mediated recycling endosome pathway protects internalized nanoparticles from lysosomal degradation. Co-immunoprecipitation, siRNA knockdown, transcriptome analysis, endocytic inhibitor experiments, TEM ACS applied materials & interfaces Medium 40720586

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 The C2 domains of the class I Rab11 family of interacting proteins target recycling vesicles to the plasma membrane. Journal of cell science 85 15304524
2002 The novel Rab11-FIP/Rip/RCP family of proteins displays extensive homo- and hetero-interacting abilities. Biochemical and biophysical research communications 71 11944901
2010 A protein interaction network for Ecm29 links the 26 S proteasome to molecular motors and endosomal components. The Journal of biological chemistry 66 20682791
2015 Systematic transcriptome analysis reveals tumor-specific isoforms for ovarian cancer diagnosis and therapy. Proceedings of the National Academy of Sciences of the United States of America 59 26015570
2002 Rab11-FIP4 interacts with Rab11 in a GTP-dependent manner and its overexpression condenses the Rab11 positive compartment in HeLa cells. Biochemical and biophysical research communications 57 12470645
2015 Hypoxia upregulates Rab11-family interacting protein 4 through HIF-1α to promote the metastasis of hepatocellular carcinoma. Oncogene 36 25745995
2003 Complete physical map and gene content of the human NF1 tumor suppressor region in human and mouse. Genes, chromosomes & cancer 35 12696059
2006 Rab11-FIP4 is predominantly expressed in neural tissues and involved in proliferation as well as in differentiation during zebrafish retinal development. Developmental biology 28 16457799
2016 Mycobacterium bovis BCG Interferes with miR-3619-5p Control of Cathepsin S in the Process of Autophagy. Frontiers in cellular and infection microbiology 27 27014637
2019 NF1 microdeletion syndrome: case report of two new patients. Italian journal of pediatrics 23 31703719
2008 Expression analysis of genes lying in the NF1 microdeletion interval points to four candidate modifiers for neurofibroma formation. Neurogenetics 17 18850118
2007 Mouse Rab11-FIP4 regulates proliferation and differentiation of retinal progenitors in a Rab11-independent manner. Developmental dynamics : an official publication of the American Association of Anatomists 17 17089410
2007 Mapping of a novel type III variant of Knobloch syndrome (KNO3) to chromosome 17q11.2. American journal of medical genetics. Part A 15 17975799
2020 Complex genetic dependencies among growth and neurological phenotypes in healthy children: Towards deciphering developmental mechanisms. PloS one 11 33270668
2017 Analytical Strategy to Prioritize Alzheimer's Disease Candidate Genes in Gene Regulatory Networks Using Public Expression Data. Journal of Alzheimer's disease : JAD 11 28800327
2022 Transcriptome-based insights into the regulatory role of immune-responsive circular RNAs in Litopanaeus vannamei upon WSSV infection. Fish & shellfish immunology 8 36549581
2023 Rab11-FIP4 interacts with ARF5 to promote cancer stemness in hepatocellular carcinoma. Journal of physiology and biochemistry 6 37458957
2024 Burden re-analysis of neurodevelopmental disorder cohorts for prioritization of candidate genes. European journal of human genetics : EJHG 3 38965372
2025 Resveratrol-Loaded PLGA Enhanced Vitrified Oocyte Viability through Rab11fip4/Arf5-Mediated Internalization Route. ACS applied materials & interfaces 2 40720586
2024 Reconstitution of Rab11-FIP4 Expression Rescues Cellular Homeostasis in Cystinosis. Molecular and cellular biology 2 39434668
2025 Untangling Traffic Jams: RAB11FIP4 Orchestrates Cellular Recovery in Cystinosis. Autophagy reports 1 40395987
2025 Genetic fine-mapping of body weight and size traits at 120 days of age in Lion-head geese. BMC genomics 1 40707914
2024 Responsiveness of anti-VEGF treatment for polypoidal choroidal vasculopathy based on aqueous humour proteomics: A preliminary study. Acta ophthalmologica 1 39420792
2026 Distinct Rab11-associated membrane trafficking pathways bidirectionally control neuronal extracellular vesicle cargo traffic. bioRxiv : the preprint server for biology 0 42124713
2025 Can We Develop Glioma Subtype-Specific Precision Medicines? An Integrative Machine Learning Pipeline for Biomarker Discovery and Drug Repurposing for Glioblastoma and Low-Grade Glioma. Omics : a journal of integrative biology 0 41468121

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