RAB11FIP5

RAB11FIP5 (Rip11/Gaf-1) is a Rab11 effector that organizes cargo trafficking through recycling endosomes, directing internalized receptors and other cargo toward the apical/plasma membrane in polarized epithelia (PMID:11163216, PMID:18957512). It is recruited to subapical recycling endosomes through direct binding to Rab11 and a Mg2+-dependent interaction of its C2 domain with neutral phospholipids, an association governed by a phosphorylation/dephosphorylation cycle (PMID:11163216). Through its membrane-binding domain it routes internalized receptors into a slow recycling pathway in complex with kinesin II, linking recycling endosomes to microtubule-based transport (PMID:18957512). RAB11FIP5 controls specific cargoes rather than bulk recycling: it mediates insulin-stimulated GLUT4 and FAT/CD36 surface delivery in adipocytes via a Rab11a-dependent route while forming a Rab11-independent complex with the Rab-GAP AS160 that dissociates upon insulin stimulation (PMID:18003705, PMID:17854769), and it selectively recycles integrin α6β1 to support cell migration on laminin (PMID:29759989). Its activity is regulated by signal-driven phosphorylation and ubiquitination: ERK phosphorylates RAB11FIP5 downstream of a Yes-EGFR cascade to drive pIgA-pIgR transcytosis (PMID:21037565), PKA phosphorylates it during cAMP-potentiated insulin secretion (PMID:19335615), TRIM21 attaches activating K6-linked polyubiquitin chains that promote transcytosis (PMID:34638806), and the deubiquitinase USP52 stabilizes the protein by removing K48-linked chains at K583/K586 (PMID:42207639). By competitively sequestering RAB11A away from RAB11FIP1, RAB11FIP5 restrains transferrin receptor recycling and iron uptake, thereby suppressing ferroptosis and supporting tumor growth in HNSCC (PMID:42207639). RAB11FIP5 also interacts with γ-SNAP at the outer mitochondrial membrane (PMID:11278501) and with ephrinB1 to enable its recycling during telencephalon development (PMID:33462110), and in mice it is selectively required for hippocampal long-term depression but not LTP (PMID:25972173).

1. 2000 High

   Established RAB11FIP5 as a Rab11 effector that physically links recycling endosomes to the apical membrane trafficking route, answering what molecular machinery drives apical cargo delivery.

   Evidence Co-IP, transport assays, lipid-binding and localization in polarized epithelial cells

   PMID:11163216

   Open questions at the time

   • The kinase/phosphatase pair controlling the membrane-association cycle was not identified
   • Specific apical cargoes not defined at this stage
2. 2001 Medium

   Identified γ-SNAP and the outer mitochondrial membrane as a binding partner and localization distinct from recycling endosomes, raising the question of a non-canonical role.

   Evidence Yeast two-hybrid, reciprocal co-precipitation, fractionation and imaging

   PMID:11278501

   Open questions at the time

   • Functional consequence of γ-SNAP binding undefined
   • Relationship between mitochondrial and endosomal pools unresolved
3. 2007 High

   Placed RAB11FIP5 in insulin-regulated cargo trafficking, distinguishing it from FIP2 in routing GLUT4 versus FAT/CD36 and revealing a Rab11-independent AS160 complex.

   Evidence siRNA knockdown with glucose-uptake and surface-abundance assays, Co-IP, microscopy in adipocyte/cardiomyocyte lines

   PMID:17854769 PMID:18003705

   Open questions at the time

   • Mechanism by which insulin triggers AS160 dissociation not defined
   • How cargo selectivity between FIP isoforms is encoded unclear
4. 2008 High

   Defined the RAB11FIP5-kinesin II complex as the route channeling internalized receptors into a slow perinuclear recycling pathway, connecting endosome sorting to microtubule motors.

   Evidence siRNA knockdown, EM, fluorescence microscopy, Co-IP identifying kinesin II

   PMID:18957512

   Open questions at the time

   • Direct vs. indirect nature of kinesin II binding not resolved
   • Cargo selectivity of the slow pathway not mapped
5. 2009 Medium

   Positioned RAB11FIP5 downstream of PKA in cAMP-potentiated insulin secretion, identifying it as a phosphorylation target in regulated secretion.

   Evidence Localization, secretion assays, PKA phosphorylation assay, epistasis with Epac2 in beta-cells

   PMID:19335615

   Open questions at the time

   • PKA phosphosites on RAB11FIP5 not mapped
   • Effect of phosphorylation on Rab11 binding not tested
6. 2010 High

   Identified RAB11FIP5 as an ERK substrate within a Yes-EGFR-ERK cascade that controls Rab11a endosome distribution and pIgA-pIgR transcytosis, linking receptor signaling to recycling.

   Evidence In vitro kinase assay, mass spectrometry, siRNA KD, pharmacological inhibition, in vivo rat pIgA injection

   PMID:21037565

   Open questions at the time

   • How phosphorylation alters FIP5 membrane/Rab11 interactions mechanistically not resolved
7. 2011 Medium

   Extended RAB11FIP5 function to acidosis-induced V-ATPase delivery to the plasma membrane downstream of Rab11b, broadening its cargo repertoire.

   Evidence siRNA knockdown, immunofluorescence, fractionation in salivary duct cells

   PMID:20717956

   Open questions at the time

   • Direct interaction with V-ATPase not shown
   • Single cell-type context
8. 2015 High

   Genetic knockout revealed a selective requirement for RAB11FIP5 in hippocampal LTD but not LTP, implicating endosomal recycling specifically in synaptic depression.

   Evidence Conditional KO mice, hippocampal slice and chemical LTD electrophysiology, shRNA rescue, behavior

   PMID:25972173

   Open questions at the time

   • Synaptic cargo recycled by RAB11FIP5 during LTD not identified
   • Molecular partners in neurons not defined
9. 2015 Medium

   Defined the kinetic basis of insulin-driven plasma-membrane accumulation as inhibition of RAB11FIP5 endocytosis requiring dynamin and PI3-kinase but not Akt.

   Evidence Live-cell imaging with kinetic analysis and pharmacological dissection

   PMID:26515129

   Open questions at the time

   • The signaling effector downstream of PI3-kinase not identified
   • Link to AS160 dissociation not established
10. 2018 Medium

    Demonstrated cargo-specific recycling of integrin α6β1 by RAB11FIP5, requiring its membrane-binding domain and driving cancer cell migration on laminin.

    Evidence siRNA KD, recycling and migration assays, PDX tumor model in prostate cancer cells

    PMID:29759989

    Open questions at the time

    • Determinant of α6β1 selectivity over other integrins not defined
    • Single tumor context
11. 2020 Medium

    Identified an antiviral role in which RAB11FIP5 binds KSHV ORF45 and routes it to lysosomal degradation, restricting virion release.

    Evidence Reciprocal Co-IP, gain/loss-of-function with virion release and lysosomal inhibition assays

    PMID:33315947

    Open questions at the time

    • Mechanism directing ORF45 to lysosomes vs. recycling unclear
    • Physiological relevance during natural infection not addressed
12. 2021 Medium

    Showed that TRIM21-mediated K6-linked polyubiquitination activates RAB11FIP5 to facilitate pIgA transcytosis, and that FIP5 and FIP1 act additively, revealing ubiquitin control of effector activity.

    Evidence siRNA KD, Co-IP, ubiquitination mapping, transcytosis assays in polarized/incompletely polarized cells

    PMID:34638806

    Open questions at the time

    • Structural effect of K6 ubiquitination on FIP5 activity unknown
    • Ubiquitinated lysines not fully mapped here
13. 2021 Medium

    Linked RAB11FIP5 to development by mapping a Rab-binding-domain interaction with ephrinB1 whose recycling is required for telencephalon growth and proliferation.

    Evidence Co-IP domain mapping, morpholino KD with overexpression rescue in Xenopus

    PMID:33462110

    Open questions at the time

    • Conservation of the ephrinB1 interaction in mammals not shown
    • Downstream signaling of recycled ephrinB1 not dissected
14. 2025 Low

    Associated RAB11FIP5 with primary cilia via KLC3 interaction at basal bodies and with axonemal glutamylation changes in polycystic kidney disease.

    Evidence Co-localization, Co-IP, siRNA KD of KLC3, PKD patient-derived cells

    PMID:41225582

    Open questions at the time

    • Functional role of RAB11FIP5 in ciliary trafficking not directly tested
    • Direct vs. indirect KLC3 binding unresolved
    • Causal contribution to PKD not established
15. 2026 High

    Defined a competitive sequestration mechanism in which RAB11FIP5 traps RAB11A from RAB11FIP1 to limit transferrin receptor recycling, iron uptake and ferroptosis, with USP52 stabilizing it by removing K48 chains at K583/K586.

    Evidence Co-IP, recycling/iron-uptake/ferroptosis assays, site-specific mutagenesis, USP52 perturbation, xenografts in HNSCC

    PMID:42207639

    Open questions at the time

    • Stoichiometry of RAB11A competition between FIP5 and FIP1 not quantified
    • Ferroptosis-independent tumor mechanism not defined

• How RAB11FIP5 integrates its multiple post-translational modifications (PKA/ERK phosphorylation, K6 vs. K48 ubiquitination) to select among its many cargoes in a given cell type remains unresolved.
• No unified model linking modification state to cargo selectivity
• Tissue-specific partner usage not systematically mapped