{"gene":"RAB10","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2007,"finding":"Rab10 functions as a downstream target of the AS160 (TBC1D4) Rab GAP in the insulin-signaling pathway regulating GLUT4 translocation to the adipocyte plasma membrane. Overexpression of a GTP-hydrolysis-defective Rab10 mutant increased surface GLUT4 in basal adipocytes; Rab10 knockdown attenuated insulin-induced GLUT4 redistribution and reduced GLUT4 exocytosis rate; the basal increase in plasma-membrane GLUT4 caused by AS160 knockdown was partially blocked by simultaneous Rab10 knockdown.","method":"Dominant-negative and constitutively active Rab10 mutant overexpression, siRNA knockdown, flow cytometry of surface GLUT4, exocytosis rate measurement in 3T3-L1 adipocytes","journal":"Cell Metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal loss-of-function and gain-of-function experiments, replicated across subsequent studies, clear epistasis with AS160","pmids":["17403373"],"is_preprint":false},{"year":2008,"finding":"Among Rab GTPases present in GLUT4 vesicles and acting as AS160 GAP substrates (Rab8A, Rab8B, Rab10, Rab14), only knockdown of Rab10 inhibited GLUT4 translocation in 3T3-L1 adipocytes. Approximately 5% of total Rab10 resides in GLUT4 vesicles from low-density microsomes; ~90% of Rab10 is in the inactive GDP form in both basal and insulin-stimulated states. The constitutively active Rab10 Q68L mutant is still a substrate for the AS160 GAP domain.","method":"siRNA knockdown of individual Rabs, subcellular fractionation, GTP-loading assays, in vitro GAP assay","journal":"The Biochemical Journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA, fractionation, in vitro GAP assay), consistent with independent replication in other labs","pmids":["18076383"],"is_preprint":false},{"year":2011,"finding":"Dennd4C is identified as the primary guanine nucleotide exchange factor (GEF) for Rab10 required for insulin-stimulated GLUT4 translocation in adipocytes. Knockdown of Dennd4C markedly inhibited GLUT4 translocation; Dennd4C was found in isolated GLUT4 vesicles.","method":"siRNA knockdown of Dennd4C, GLUT4 translocation assay, subcellular fractionation of GLUT4 vesicles","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (functional knockdown + vesicle fractionation), single lab","pmids":["21454697"],"is_preprint":false},{"year":2012,"finding":"Rab10 directly mediates GLUT4 storage vesicle (GSV) translocation to and docking at the plasma membrane in adipocytes. Myosin-Va associates with GSVs by interacting with Rab10, positioning peripherally recruited GSVs for ultimate fusion. Live TIRF microscopy with IRAP-pHluorin showed Rab10 as the Rab specifically marking GSVs undergoing insulin-stimulated plasma membrane fusion; Rab14 instead labels transferrin-receptor-positive endosomal compartments.","method":"Dual-color TIRF microscopy, IRAP-pHluorin fusion assay, siRNA knockdown, co-immunoprecipitation of Rab10 with Myosin-Va","journal":"The Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — live-cell TIRF imaging with pHluorin reporter (direct visualization of fusion events) plus Co-IP and functional knockdown; replicated across labs","pmids":["22908308"],"is_preprint":false},{"year":2012,"finding":"Rab10 is an ER-specific Rab GTPase that regulates ER structure and dynamics. Rab10 localizes to dynamic ER-associated structures that track along microtubules and mark sites of new ER tubule growth. Depletion or GDP-locked Rab10 mutant expression results in fewer ER tubules due to reduced ability of dynamic tubules to grow out and fuse with adjacent ER. The Rab10 domain at the leading edge of dynamic ER tubules is highly enriched with phospholipid synthesis enzymes phosphatidylinositol synthase (PIS) and CEPT1; formation and function of this domain are inhibited by GDP-locked Rab10.","method":"Live-cell fluorescence microscopy of ER dynamics, siRNA knockdown, GDP-locked mutant expression, co-localization with PIS/CEPT1","journal":"Nature Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging plus multiple genetic perturbations (siRNA and dominant-negative) with direct morphological readout, multiple orthogonal approaches in one study","pmids":["23263280"],"is_preprint":false},{"year":2006,"finding":"RAB-10 (C. elegans ortholog) is required for endocytic recycling in polarized intestinal epithelial cells. rab-10 null mutants accumulate abnormally enlarged RAB-5-positive early endosomes, lose RME-1-positive recycling endosomes, and accumulate basolaterally recycling transmembrane cargo, indicating RAB-10 functions upstream of RME-1 in basolateral recycling. GFP-RAB-10 localizes to endosomes and Golgi.","method":"rab-10 null mutant analysis, GFP-RAB-10 reporter localization, immunofluorescence for endosomal markers, cargo trafficking assays in C. elegans intestine","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — null mutant genetics with multiple molecular markers and cargo readouts, established ortholog function","pmids":["16394106"],"is_preprint":false},{"year":2006,"finding":"Rab10 is specifically associated with common (basolateral sorting) endosomes in polarized MDCK cells. Expression of GTP-hydrolysis-defective or GDP-bound Rab10 mutants increased recycling from basolateral early endosomes without affecting apical recycling or later recycling compartments, indicating Rab10 mediates transport from basolateral sorting endosomes to common endosomes.","method":"GFP-tagged wild-type and mutant Rab10 expression, quantitative confocal microscopy, endocytic probe trafficking assays in polarized MDCK cells","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (localization and trafficking kinetics), multiple Rab10 mutants tested, single lab","pmids":["16641372"],"is_preprint":false},{"year":2006,"finding":"Rab10 functions in biosynthetic trafficking from the Golgi to the basolateral membrane in polarized MDCK cells. GFP-Rab10 localizes primarily to the Golgi during early polarization; activated Rab10 mutant inhibits biosynthetic transport from the Golgi and missorts basolateral cargo to the apical membrane. Simultaneous inhibition of Rab10 and Rab8a more strongly impairs basolateral sorting, suggesting cooperation.","method":"GFP-Rab10 localization, activated mutant expression, RNAi knockdown, biosynthetic transport assays in polarized MDCK cells","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mutants and RNAi, but epistasis evidence for Rab8 cooperation is single lab","pmids":["17132146"],"is_preprint":false},{"year":2008,"finding":"Rab10 interacts with myosin Va, myosin Vb, and myosin Vc. The interaction requires the alternatively spliced exon D in myosin Va and Vb (and the homologous region in Vc). Both Rab8a and Rab10 are mislocalized by dominant-negative myosin V tails. The interaction was confirmed by yeast two-hybrid assays and FRET studies.","method":"Co-immunoprecipitation, yeast two-hybrid, FRET, dominant-negative myosin V tail expression, splice isoform analysis","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — three independent methods (Co-IP, yeast two-hybrid, FRET) confirming the same interaction and mapping the exon D requirement","pmids":["19008234"],"is_preprint":false},{"year":2010,"finding":"Rab10 regulates continuous replenishment of TLR4 from Golgi to the plasma membrane in macrophages, which is essential for optimal macrophage activation following LPS stimulation. Blockade of Rab10 function leads to decreased membrane TLR4 expression and diminished production of inflammatory cytokines and interferons upon LPS stimulation.","method":"Dominant-negative Rab10 expression, siRNA knockdown, flow cytometry of surface TLR4, cytokine measurement, in vivo LPS-induced acute lung injury model","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple methods (dominant-negative, siRNA, in vivo model), clear mechanistic link between Rab10 and TLR4 surface replenishment","pmids":["20643919"],"is_preprint":false},{"year":2010,"finding":"RAB-10 (C. elegans) and its binding partner EHBP-1 (calponin homology domain protein) function together in endocytic recycling. Yeast two-hybrid identified EHBP-1 as a RAB-10 binding partner. GFP-EHBP-1 colocalizes with RFP-RAB-10 on endosomal structures; ehbp-1 loss-of-function mutants share with rab-10 mutants specific endosome morphology and cargo localization defects.","method":"Yeast two-hybrid screen, fluorescence co-localization in C. elegans, null mutant phenotypic analysis, cargo trafficking assays","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid plus in vivo co-localization plus genetic epistasis with shared phenotypes","pmids":["20573983"],"is_preprint":false},{"year":2010,"finding":"Rab10 associates with primary cilia in renal epithelia and colocalizes with exocyst proteins at the base of nascent cilia. Rab10 physically interacts with the exocyst complex as detected by co-immunoprecipitation with anti-Sec8 antibodies.","method":"Immunofluorescence microscopy, co-immunoprecipitation with anti-Sec8, live imaging in renal epithelial cells in culture and in vivo","journal":"American Journal of Physiology - Renal Physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, Co-IP and co-localization but no direct functional consequence of Rab10-exocyst interaction tested at cilia","pmids":["20576682"],"is_preprint":false},{"year":2011,"finding":"Lgl1 activates Rab10 in developing axons by releasing GDP dissociation inhibitor (GDI) from Rab10, thereby promoting membrane trafficking of plasmalemmal precursor vesicles (PPVs) required for axon development and neuronal polarization. Rab10 lies downstream of Lgl1 in axon development; both are required for neocortical neuronal polarization in vivo.","method":"Co-immunoprecipitation, dominant-negative and knockdown experiments, directional membrane insertion assay, in vivo rat cortex knockdown","journal":"Developmental Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical Co-IP showing Lgl1-Rab10-GDI interaction, epistasis by rescue experiments, in vivo validation","pmids":["21856246"],"is_preprint":false},{"year":2013,"finding":"In Drosophila follicle cells, Crag targets Rab10 to structures in the basal cytoplasm, restricting basement membrane protein delivery to the basal surface during egg chamber elongation. Tango1 and Rab10 are planar polarized at the basal epithelial surface, coupling BM production to organ morphogenesis.","method":"Genetic epistasis, GFP reporter localization, loss-of-function analysis of Crag, Tango1 and Rab10 in Drosophila follicle cells","journal":"Developmental Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis plus live imaging, established upstream regulator (Crag) targeting Rab10 to basal domain","pmids":["23369713"],"is_preprint":false},{"year":2013,"finding":"Rab10 interaction with myosin Vb (MYO5B) via the exon D-encoded domain determines the formation of Rab10-containing post-Golgi carriers and is required for axon development. Disrupting MYO5B(+D) expression or its interaction with Rab10 impairs fission of Rab10 vesicles from trans-Golgi membranes and inhibits axon development.","method":"Co-immunoprecipitation, splice isoform mutants, vesicle biogenesis assay, knockdown in hippocampal neurons, in vivo analysis in neocortical neurons and zebrafish retinal ganglion cells","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical interaction mapping, functional vesicle biogenesis assay, in vivo rescue in two vertebrate systems","pmids":["23770993"],"is_preprint":false},{"year":2014,"finding":"JIP1 (c-Jun N-terminal kinase-interacting protein 1) interacts with GTP-locked active Rab10 and directly connects Rab10 to kinesin-1 light chain (KLC), forming a kinesin-1/JIP1/Rab10 complex required for anterograde transport of plasmalemmal precursor vesicles (PPVs) during axon development and neuronal polarization.","method":"Co-immunoprecipitation, dominant-active Rab10 pulldown, siRNA knockdown of JIP1/KLC, anterograde transport assays in hippocampal neurons, in vivo rat neocortical transfection","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical complex reconstitution (Co-IP), functional transport assay, in vivo validation","pmids":["24478353"],"is_preprint":false},{"year":2014,"finding":"MARCKS mediates membrane targeting of Rab10-positive PPVs during axon development. GTP-locked active Rab10 binds membrane-associated MARCKS; this affinity depends on the phosphorylation status of the MARCKS effector domain. MARCKS knockdown or disruption of Rab10-MARCKS interaction inhibits axon growth, impairs docking and fusion of Rab10 vesicles with the plasma membrane, and reduces membrane insertion of axonal receptors.","method":"Co-immunoprecipitation, GTP-locked Rab10 pulldown, MARCKS knockdown and phosphomutant expression, TIRF microscopy of vesicle docking/fusion, membrane insertion assays","journal":"Cell Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical binding assay with phosphorylation-state dependence, multiple functional readouts including direct vesicle tracking","pmids":["24662485"],"is_preprint":false},{"year":2014,"finding":"Rab10-mediated endocytosis of hyaluronan synthase HAS3 regulates hyaluronan synthesis and cell adhesion. Rab10 co-localizes and co-immunoprecipitates with HAS3 from endosomal vesicles. Rab10 silencing increases plasma membrane HAS3 residence, increases HA secretion and cell surface HA coat, and blocks retrograde HAS3 trafficking from plasma membrane to early endosomes.","method":"Co-immunoprecipitation, co-localization microscopy, siRNA knockdown, HA synthesis assay, cell adhesion assay","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional readout, single lab, two orthogonal approaches","pmids":["24509846"],"is_preprint":false},{"year":2014,"finding":"Rab10 is a target of the AS160 (TBC1D4) GAP, and once activated (GTP-bound), Rab10 recruits the Ral GEF Rlf/Rgl2, increasing GTP binding of RalA. Rab10 and RalA co-reside in the same pool of Glut4-storage vesicles; RalA is epistatic downstream of Rab10 in insulin-stimulated Glut4 translocation. Membrane-tethered Rlf compensates for Rab10 loss in Glut4 translocation.","method":"Co-immunoprecipitation, GTP-loading assays, siRNA knockdown, epistasis rescue experiments, Glut4 translocation assay","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical cascade demonstrated by Co-IP and GTP-loading, epistasis confirmed by membrane-tethered Rlf rescue","pmids":["25103239"],"is_preprint":false},{"year":2015,"finding":"Rab10-GTP (but not GDP form) binds to exocyst subunits Exoc6 and Exoc6b. Both isotypes are found in 3T3-L1 adipocytes, and knockdown of Exoc6, Exoc6b, or both inhibits GLUT4 translocation, identifying Rab10-GTP association with Exoc6/6b as a molecular link between insulin signaling and the exocytic machinery.","method":"Pulldown of GTP-locked Rab10 with exocyst subunits, siRNA knockdown of Exoc6/6b, GLUT4 translocation assay","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown demonstrating GTP-state dependence plus functional knockdown, single lab","pmids":["26299925"],"is_preprint":false},{"year":2015,"finding":"RAB-10 and amphiphysin AMPH-1 bind to and recruit TBC-2 (a Rab-5 GAP) to endosomes. In the absence of RAB-10 or AMPH-1 binding to TBC-2, RAB-5 membrane association is abnormally high and recycling cargo is trapped in early endosomes. This identifies a mechanism by which RAB-10 and AMPH-1 down-regulate RAB-5 to enable cargo exit from early endosomes.","method":"Genetic epistasis in C. elegans, co-immunoprecipitation, fluorescence co-localization, null and loss-of-function mutant analysis","journal":"PLOS Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical interaction (Co-IP) plus genetic epistasis plus cargo/endosome marker quantification","pmids":["26393361"],"is_preprint":false},{"year":2015,"finding":"SEC-10 (exocyst subunit) coordinates with RAB-10 and microtubules to form interconnected endosomal tubules required for basolateral recycling of clathrin-independent endocytic cargoes including hTAC, GLUT1, and DAF-4. Epistasis analysis indicates SEC-10 operates at an intermediate step between early endosomes and recycling endosomes; depletion of either SEC-10 or RAB-10 disrupts tubular endosome structure.","method":"siRNA/RNAi depletion, fluorescence microscopy, epistasis analysis, cargo recycling assays in C. elegans intestine","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis plus multiple cargo markers and structural readout of tubular endosome integrity","pmids":["25301900"],"is_preprint":false},{"year":2016,"finding":"Rab10 is essential for lipophagy in hepatocytes. During autophagy stimulation, Rab10 activity is amplified and Rab10 is recruited to nascent autophagic membranes at the lipid droplet surface. Rab10 activation is required for LC3 recruitment to autophagosomes and stimulates increased association with adaptor protein EHBP1 and membrane-deforming ATPase EHD2, which together drive engulfment of lipid droplets.","method":"siRNA knockdown, dominant-negative and GTPase-defective Rab10 mutant expression, co-immunoprecipitation of Rab10-EHBP1-EHD2 complex, fluorescence microscopy of LC3 recruitment, lipid droplet accumulation assay","journal":"Science Advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — identification of a novel Rab10 complex (EHBP1/EHD2) with mechanistic link to LC3 recruitment, multiple genetic perturbations and readouts","pmids":["28028537"],"is_preprint":false},{"year":2016,"finding":"SEC16A is a RAB10 effector required for insulin-stimulated GLUT4 trafficking. Colocalization of SEC16A with RAB10 is augmented by insulin stimulation; SEC16A knockdown attenuates insulin-induced GLUT4 translocation, phenocopying RAB10 knockdown. RAB10-SEC16A promotes insulin-stimulated mobilization of GLUT4 from a perinuclear recycling endosome/TGN compartment, promoting vesicle biogenesis independently of canonical COPII function.","method":"Co-localization microscopy, siRNA knockdown, GLUT4 translocation assay, COPII component analysis","journal":"The Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional epistasis, SEC16A identified as novel Rab10 effector with phenocopy knockdown and compartment-specific mechanism","pmids":["27354378"],"is_preprint":false},{"year":2016,"finding":"Rab10-based secretion pathway promotes pericellular basement membrane protein accumulation and fibril formation in Drosophila egg chamber. Manipulation of the Rab10 secretion pathway demonstrates that BM fibrillar structure influences egg chamber morphogenesis.","method":"Live imaging, genetic manipulation of Rab10 pathway, fluorescent BM protein reporters in Drosophila","journal":"Developmental Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging plus genetic manipulation, direct demonstration of Rab10-dependent BM protein secretion affecting morphogenesis","pmids":["27404358"],"is_preprint":false},{"year":2016,"finding":"LRRK2 directly phosphorylates Rab10 at a conserved threonine/serine residue (Thr73) in the effector-binding switch-II motif. Phosphorylation of Rab10 is ablated in kinase-inactive LRRK2[D2017A] knockin MEFs and mouse lung, establishing LRRK2 as the major Rab10 kinase. Phospho-Ser910 and Ser935 and 14-3-3 binding play a role in facilitating LRRK2-mediated Rab10 phosphorylation in vivo.","method":"Phos-tag electrophoresis, kinase-inactive LRRK2 knockin MEFs and tissue, LRRK2 inhibitor treatment, phospho-specific antibody detection","journal":"The Biochemical Journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — knockin kinase-dead mice establish LRRK2 as the primary kinase, Phos-tag biochemical assay plus inhibitor pharmacology, replicated across multiple studies","pmids":["27474410"],"is_preprint":false},{"year":2019,"finding":"Rab10 identifies a novel class of tubular endosomes in HeLaM cells. Knockout of Rab10 completely abolishes tubular endosomal structures. Kinesin motors KIF13A and KIF13B are novel Rab10-interacting proteins; both the Rab10-binding homology domain and the motor domain of KIF13A are required for Rab10-positive tubular endosome formation.","method":"CRISPR knockout of Rab10, in silico screening + validation, co-immunoprecipitation of KIF13A/B with Rab10, deletion mutant analysis, fluorescence microscopy","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO abolishes structure (clean phenotype), binding partners identified with domain mapping by Co-IP and deletion mutants","pmids":["30700496"],"is_preprint":false},{"year":2019,"finding":"LRRK2-phosphorylated RAB10 (pT73) accumulates on depolarized mitochondria in a PINK1- and PRKN-dependent manner, binds the autophagy receptor OPTN (optineurin), and promotes OPTN accumulation on depolarized mitochondria to facilitate mitophagy. In LRRK2 mutant (G2019S, R1441C) patient cells, enhanced RAB10 phosphorylation reduces RAB10-OPTN interaction, mitochondrial accumulation of both proteins, and mitophagy. A phosphomimetic RAB10 mutant shows less OPTN interaction and fails to rescue mitophagy.","method":"Co-immunoprecipitation, immunofluorescence, mitophagy assay, patient-derived cells, LRRK2 knockdown/inhibition rescue, phosphomimetic mutant analysis","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical interaction (Co-IP), patient-derived cells, phosphomimetic mechanistic dissection, LRRK2 inhibition rescue","pmids":["30945962"],"is_preprint":false},{"year":2019,"finding":"Phosphorylated RAB10 (by pathogenic LRRK2) is recruited to centrosome-localized RILPL1, contributing to ciliogenesis defects and centrosomal cohesion deficits in dividing cells. Both RAB8 and RAB10 contribute to LRRK2-mediated centrosomal cohesion deficits; effects are dependent on RAB8, RAB10, and RILPL1.","method":"Immunofluorescence for phospho-RAB10 at centrosomes, patient-derived peripheral cells, primary astrocytes from LRRK2 mutant mice, LRRK2 kinase inhibition, siRNA knockdown","journal":"Human Molecular Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell types (patient-derived, primary mouse astrocytes), multiple genetic perturbations, pharmacological rescue","pmids":["31428781"],"is_preprint":false},{"year":2020,"finding":"Rab10 specifically regulates macropinocytosis (not phagocytosis or clathrin-mediated endocytosis) in macrophages and dendritic cells. LRRK2 phosphorylates cytoplasmic PI(3,4,5)P3-positive GTP-Rab10 before EEA1/Rab5 recruitment to early macropinosomes. LRRK2 phosphorylation of Rab10 blocks EHBP1L1-mediated recycling tubules and cargo turnover of macropinosome cargo including CCR5, CD11b, MHCII. EHBP1L1 overexpression competitively inhibits LRRK2 phosphorylation of Rab10. Rab10 knockdown and LRRK2 kinase inhibition suppress maturation of CCR5-loaded signaling endosomes critical for CCL5-induced Akt activation and chemotaxis.","method":"siRNA knockdown, LRRK2 inhibition, endocytosis assays distinguishing macropinocytosis from phagocytosis and CME, phospho-Rab10 imaging, EHBP1L1 overexpression rescue, signaling and chemotaxis assays in primary macrophages/dendritic cells/microglia","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — selectivity for macropinocytosis established by multiple parallel assays, competitive inhibition mechanism demonstrated, multiple primary cell types","pmids":["32853409"],"is_preprint":false},{"year":2020,"finding":"LRRK2 is required for RAB8a and RAB10 recruitment to phagosomes in human iPSC-derived macrophages and microglia. LRRK2 is recruited to LAMP1+/RAB9+ maturing phagosomes; LRRK2 kinase inhibition enhances LRRK2 residency at the phagosome.","method":"LRRK2 knockout and G2019S isogenic iPSC-derived macrophages/microglia, immunofluorescence for phagosome markers, LRRK2 kinase inhibitor treatment","journal":"Stem Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic KO lines, clear co-recruitment phenotype, single lab","pmids":["32359446"],"is_preprint":false},{"year":2020,"finding":"The TBC1D4-RAB10 signaling module controls GLUT4 mobilization from a trans-Golgi network (TGN) storage compartment. GLUT4 is retained in a TGN element from which it is mobilized by insulin via RAB10; this compartment also contains newly synthesized lysosomal proteins and the ATP7A copper transporter, but insulin does not mobilize ATP7A and copper does not mobilize GLUT4, and RAB10 is not required for copper-elicited ATP7A mobilization.","method":"RAB10 siRNA knockdown, insulin and copper stimulation assays, fluorescence co-localization, cargo mobilization assays in adipocytes","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — compartment identity precisely mapped with multiple cargo controls, specific role of RAB10 in TGN GLUT4 mobilization distinguished from other TGN trafficking","pmids":["33175605"],"is_preprint":false},{"year":2021,"finding":"LRRK2 activity blocks ciliation by preventing CP110 release from the mother centriole, a step required for early ciliogenesis; this blockade requires Rab10 and RILPL1 proteins and is due to failure to recruit TTBK2 (a kinase needed for CP110 release). Deciliation probability does not change in cells lacking Rab10 or RILPL1, indicating a distinct LRRK2 pathway for deciliation.","method":"Live-cell fluorescence microscopy, R1441C LRRK2 MEF cells, Rab10 knockout, RILPL1 manipulation, LRRK2 kinase inhibition, CP110 and TTBK2 localization assays","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — precise epistasis placing Rab10/RILPL1 upstream of TTBK2 and CP110 uncapping, distinguishes ciliation from deciliation pathways","pmids":["33653948"],"is_preprint":false},{"year":2021,"finding":"LRRK2-phosphorylated Rab10 sequesters Myosin Va and RILPL2 at the peri-centriolar region to block ciliogenesis. RILPL2 binds preferentially to LRRK2-phosphorylated Rab8A and Rab10; the globular tail domain of Myosin Va contains a high-affinity binding site for LRRK2-phosphorylated Rab10. PhosphoRab10 retains Myosin Va over pericentriolar membranes as measured by FLIP.","method":"Co-immunoprecipitation, fluorescence loss in photobleaching (FLIP), phospho-Rab10 pulldown, localization microscopy, ciliogenesis assay","journal":"Life Science Alliance","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding of phospho-Rab10 to Myosin Va demonstrated biochemically, FLIP confirms retention, functional ciliogenesis consequence shown","pmids":["33727250"],"is_preprint":false},{"year":2021,"finding":"Salmonella effector SopD inhibits Rab10 via a C-terminal GTPase-activating protein (GAP) domain during host cell invasion. During infection, Rab10 and its effectors MICAL-L1 and EHBP1 are recruited to invasion sites; SopD-mediated inhibition of Rab10 promotes removal of Rab10 and recruitment of Dynamin-2 to drive plasma membrane scission and Salmonella-containing vacuole formation.","method":"SopD domain analysis, pulldown/Co-IP of SopD with Rab10, Rab10 knockdown, GAP domain mutagenesis, Dynamin-2 recruitment assay, infection-based plasma membrane scission assay","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — GAP domain biochemically demonstrated, mechanistic cascade (Rab10 inhibition → Dynamin-2 recruitment → scission) functionally validated","pmids":["34349110"],"is_preprint":false},{"year":2021,"finding":"Pathogenic LRRK2 (R1441C)-mediated centrosomal cohesion deficits require RILPL1-mediated centrosomal accumulation of phosphorylated Rab10. RILPL1 localizes to the subdistal appendage of the mother centriole, followed by phospho-Rab protein recruitment. These centrosomal alterations impair cell polarization as monitored by scratch wound assays and are reverted by LRRK2 kinase inhibition.","method":"Immunofluorescence for phospho-Rab10 at centrosomes, siRNA knockdown of Rab10/RILPL1, LRRK2 kinase inhibition, scratch wound polarization assay, RILPL2 and other Rab controls","journal":"Biology Open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic perturbations but largely confirmatory of prior findings from same lab","pmids":["35776681"],"is_preprint":false},{"year":2022,"finding":"Lysosomal positioning regulates Rab10 phosphorylation by LRRK2: pRab10 is restricted to perinuclear lysosomes, not peripheral lysosomes. Anterograde lysosomal transport (via ARL8B/SKIP overexpression or JIP4 knockdown) blocks Rab10 phosphorylation and the subsequent lysosomal tubulation/sorting process (LYTL). Perinuclear clustering of lysosomes (via RILP overexpression) increases LRRK2-dependent Rab10 phosphorylation. PPM1H phosphatase knockdown increases pRab10 and lysosomal tubulation.","method":"LRRK2 membrane targeting constructs, ARL8B/SKIP overexpression, JIP4 knockdown, RILP overexpression, PPM1H knockdown, pRab10 immunofluorescence, lysosomal tubulation assay","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal manipulations of lysosome positioning showing consistent effect on Rab10 phosphorylation, phosphatase identified","pmids":["36256825"],"is_preprint":false},{"year":2022,"finding":"RAB10 regulates hepatocyte LDL receptor (LDLR) recycling from RAB11-positive endosomes to the plasma membrane, and also promotes transferrin receptor recycling from RAB4-positive compartments. RAB10 loss reduces LDL uptake by impairing endosomal recycling of LDLR.","method":"CRISPR knockout, LDL uptake assay, LDLR recycling assay, endosomal marker co-localization, RAB11 and RAB4 compartment analysis","journal":"Journal of Lipid Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with functional recycling assay and compartment identification, single lab","pmids":["35753407"],"is_preprint":false},{"year":2023,"finding":"Rab10 defines a membrane compartment in axon terminals that is rapidly mobilized towards the axon terminal upon BDNF stimulation, enabling fine-tuning of retrograde TrkB/BDNF signaling from axon terminals to the soma. Rab10 knockout impairs TrkB sorting to signalling endosomes and propagation of BDNF signalling in primary mouse neurons.","method":"Rab10 knockout in primary mouse neurons, live-cell imaging, TrkB sorting assay, retrograde transport assay, BDNF signalling readout","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO with direct functional consequence on signalling endosome sorting and retrograde signal propagation, multiple readouts","pmids":["36897066"],"is_preprint":false},{"year":2024,"finding":"Rab10 and Caveolin-1 (CAV1) mark intraluminal vesicles in migrasomes. Transport of Rab10-CAV1 vesicles to migrasomes requires motor protein Myosin Va and adaptor protein RILPL2. LRRK2-mediated phosphorylation of Rab10 regulates this transport process. CSF-1 is transported to migrasomes via this mechanism to foster monocyte-macrophage differentiation in skin wound healing.","method":"Live-cell imaging, Rab10 and CAV1 co-localization, Myosin Va and RILPL2 knockdown/inhibition, LRRK2 kinase inhibition, wound healing model, cytokine delivery assay","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple motor/adaptor knockdowns with functional readout of cargo delivery, physiological validation in wound healing","pmids":["39008679"],"is_preprint":false},{"year":2024,"finding":"VPS13C interacts with phospho-Rab10 on lysosomes in a phosphorylation-dependent manner in human dopaminergic neurons. Loss of VPS13C disrupts lysosomal morphology, dynamics, motility, distribution, hydrolytic activity, and acidification, and decreases the phospho-Rab10-mediated lysosomal stress response.","method":"Live-cell microscopy of iPSC-derived dopaminergic neurons, VPS13C KO, phospho-Rab10 interaction assay, lysosomal function assays (pH, hydrolysis, motility)","journal":"The Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-dependent interaction demonstrated, disease-relevant neuronal model, multiple lysosomal function readouts","pmids":["38358348"],"is_preprint":false},{"year":2007,"finding":"RAB-10 (C. elegans) regulates recycling of the AMPAR subunit GLR-1 in neurons via a cholesterol-dependent, clathrin-independent endocytic pathway. Genetic epistasis showed that cholesterol depletion suppresses the rab-10 mutant GLR-1 accumulation phenotype (but not lin-10), while clathrin-endocytosis inhibition suppresses lin-10 but not rab-10, placing RAB-10 after clathrin-independent endocytosis.","method":"Genetic epistasis (rab-10, lin-10, unc-11, itsn-1 mutants), cholesterol depletion, GLR-1 localization assay, behavioral reversal frequency assay in C. elegans","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis placing RAB-10 specifically in clathrin-independent recycling pathway with behavioral readout","pmids":["17761527"],"is_preprint":false},{"year":2009,"finding":"Rab10 associates transiently with phagosomes at very early time-points (before Rab5 acquisition) and plays a prominent role in phagolysosome formation. Rab10 knockdown or dominant-negative expression delays maturation of phagosomes; constitutively active Rab10 partially rescues live-Mycobacterium-containing phagosome maturation and promotes EEA-1 acquisition on Mycobacterium-containing vacuoles.","method":"siRNA knockdown, dominant-negative and constitutively active Rab10 mutants, confocal microscopy of phagosome markers, Mycobacterium infection assay","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic perturbations with functional maturation readout, single lab","pmids":["20028485"],"is_preprint":false},{"year":2017,"finding":"RAB10 interacts with MGCRABGAP (a male germ cell-specific Rab GAP) during mammalian spermiogenesis. MGCRABGAP exhibits GTPase-activating activity and RAB10 is identified as a substrate/interactor. MGCRABGAP-RAB10 complexes co-localize specifically in the manchette structure during spermatid head formation.","method":"Co-immunoprecipitation, nano LC-MS/MS proteomics, immunofluorescence co-localization in spermatids, GAP activity assay","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed RAB10-MGCRABGAP interaction with co-localization at manchette, GAP activity demonstrated, single lab","pmids":["28067790"],"is_preprint":false},{"year":2023,"finding":"Age-related decline in RAB-10 functionality in C. elegans is caused by upregulation of SDPN-1/PACSIN during senescence, which suppresses RAB-10 activation by competing with DENN-4/GEF. KGB-1/JUN kinase enhances the inhibitory potency of SDPN-1, likely by altering its oligomerization. SDPN-1 knockdown alleviates age-related adherens junction and intestinal barrier defects.","method":"Age-synchronized C. elegans analysis, SDPN-1 and KGB-1 loss-of-function, RAB-10 activation assay, co-immunoprecipitation of SDPN-1 with DENN-4, barrier permeability assay","journal":"Nature Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — competitive GEF inhibition mechanism identified biochemically plus in vivo rescue, single lab","pmids":["37640905"],"is_preprint":false},{"year":1993,"finding":"HA-tagged Rab10 expressed in CHO and BHK cells is concentrated on membranes in the perinuclear region, partially overlapping with the Golgi marker β-COP, in contrast to Rab8 which localizes to the cell periphery. This establishes that Rab10 and Rab8, despite 66% identity, occupy distinct cellular compartments.","method":"Epitope-tagged (HA) expression, immunofluorescence microscopy, Golgi marker co-staining in stable CHO/BHK transfectants","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — original localization study, replicated by many subsequent studies, single method but foundational finding","pmids":["7688123"],"is_preprint":false},{"year":2011,"finding":"Rab10 is required for von Willebrand factor (VWF) secretion from endothelial cells. Rab10 (and Rab8A) are enriched at the Golgi where Weibel-Palade bodies (WPB) form; Rab10 siRNA knockdown significantly reduces the amount of rapidly-releasable VWF, implicating Rab10 in WPB biogenesis.","method":"C. elegans AP-1 genetic interaction screen, siRNA knockdown in human endothelial cells (HUVECs), VWF secretion assay, immunofluorescence localization","journal":"Journal of Thrombosis and Haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with direct secretion readout, Golgi localization confirmed, single lab","pmids":["21070595"],"is_preprint":false},{"year":2019,"finding":"Rab10 regulates tubular endosome formation through KIF13A and KIF13B motors (identified as novel Rab10-interacting proteins). The Rab10-binding homology domain and the motor domain of KIF13A are both required for Rab10-positive tubular endosome formation.","method":"EGFP-Rab GTPase localization screen, CRISPR/Cas9 Rab10 knockout, in silico screen + Co-immunoprecipitation of KIF13A/B, deletion mutant analysis","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO abolishes tubular endosomes (clean phenotype), domain mapping confirms KIF13A requirement","pmids":["30700496"],"is_preprint":false}],"current_model":"RAB10 is a small Rab GTPase that functions downstream of the AS160 (TBC1D4) GAP—activated by insulin-stimulated Akt phosphorylation—and the GEF DENND4C, to drive GLUT4 storage vesicle translocation to the plasma membrane in adipocytes via interactions with Myosin Va, the exocyst subunit Exoc6/6b, and SEC16A; it additionally regulates basolateral endocytic recycling in polarized epithelial cells and neurons (engaging EHBP1 and kinesin motors KIF13A/B), ER tubule dynamics, lipophagy (via an EHBP1–EHD2 complex), TLR4 surface replenishment in macrophages, macropinocytosis maturation, axon development (via Lgl1-mediated GDI release and JIP1/kinesin-1-dependent anterograde transport), basement membrane polarized secretion in Drosophila epithelia, and ciliogenesis—where LRRK2-mediated phosphorylation at Thr73 in the switch-II motif inactivates RAB10 and drives its interaction with RILPL1/RILPL2 to sequester Myosin Va at the mother centriole, block CP110 uncapping, impair centrosome cohesion, and suppress mitophagy via reduced OPTN recruitment, thereby linking pathogenic LRRK2 mutations to multiple Parkinson's disease-relevant cellular defects."},"narrative":{"mechanistic_narrative":"RAB10 is a small Rab GTPase that organizes polarized and regulated membrane trafficking across diverse cell types, cycling between an active GTP-bound and inactive GDP-bound state controlled by dedicated regulators and effectors [PMID:17403373, PMID:22908308]. In insulin-stimulated adipocytes it operates as the key Rab downstream of the AS160/TBC1D4 GAP and the GEF DENND4C to drive translocation of GLUT4 storage vesicles from a perinuclear TGN/recycling compartment to the plasma membrane [PMID:17403373, PMID:21454697, PMID:33175605], engaging effectors including Myosin Va, the exocyst subunits Exoc6/6b, SEC16A, and the RalA-activating GEF Rlf to couple insulin signaling to the docking and fusion machinery [PMID:22908308, PMID:25103239, PMID:26299925, PMID:27354378]. Beyond glucose transport, RAB10 governs endocytic recycling and tubular endosome biogenesis—functioning upstream of RME-1, downregulating RAB-5 via EHBP1/AMPH-1-recruited GAPs, and forming tubular endosomes through the kinesin motors KIF13A/B—and mediates basolateral biosynthetic sorting in polarized epithelia [PMID:16394106, PMID:16641372, PMID:20573983, PMID:26393361, PMID:30700496]. RAB10 also marks and shapes dynamic ER tubules enriched in lipid-synthesis enzymes [PMID:23263280], drives lipophagy of lipid droplets via an EHBP1–EHD2 complex [PMID:28028537], regulates TLR4 surface replenishment and macropinosome maturation in immune cells [PMID:20643919, PMID:32853409], and supports axon development through Lgl1-mediated GDI release and JIP1/kinesin-1-dependent anterograde vesicle transport [PMID:21856246, PMID:24478353]. A major regulatory axis is phosphorylation at Thr73 in the switch-II motif by the Parkinson's disease kinase LRRK2, which reshapes RAB10 effector binding: phospho-RAB10 binds RILPL1/RILPL2 and Myosin Va to block CP110 release and ciliogenesis at the mother centriole and impair centrosomal cohesion, and engages OPTN to modulate mitophagy and VPS13C in a lysosomal stress response [PMID:27474410, PMID:30945962, PMID:33653948, PMID:33727250, PMID:38358348].","teleology":[{"year":1993,"claim":"Established that RAB10, despite high identity to RAB8, occupies a distinct perinuclear/Golgi compartment, the first indication of a dedicated trafficking role.","evidence":"HA-tagged RAB10 expression and immunofluorescence in CHO/BHK cells","pmids":["7688123"],"confidence":"Medium","gaps":["Localization only; no functional consequence tested","Single method, single cell type"]},{"year":2006,"claim":"Defined RAB10 as a core regulator of basolateral endocytic recycling and biosynthetic sorting in polarized cells, placing it upstream of RME-1 recycling endosomes.","evidence":"C. elegans rab-10 null genetics with endosomal markers and cargo assays, plus GFP-Rab10 mutant trafficking in polarized MDCK cells","pmids":["16394106","16641372","17132146"],"confidence":"High","gaps":["Direct effectors mediating recycling not yet identified","Mechanism of basolateral targeting unresolved"]},{"year":2007,"claim":"Placed RAB10 epistatically downstream of the AS160/TBC1D4 GAP in insulin-stimulated GLUT4 translocation, identifying the regulated module controlling glucose uptake.","evidence":"Dominant-negative/constitutively-active mutants, siRNA, surface GLUT4 flow cytometry in 3T3-L1 adipocytes; clathrin-independent recycling epistasis in C. elegans neurons","pmids":["17403373","17761527"],"confidence":"High","gaps":["GEF activating RAB10 not yet identified","Downstream fusion effectors unknown"]},{"year":2008,"claim":"Demonstrated RAB10's selectivity among AS160-substrate Rabs for GLUT4 translocation and showed it associates with myosin V motors via the exon-D domain, linking RAB10 to motor-based positioning.","evidence":"Selective siRNA, fractionation, GTP-loading and GAP assays in adipocytes; Co-IP, yeast two-hybrid, FRET and splice-isoform mapping for myosin Va/Vb/Vc","pmids":["18076383","19008234"],"confidence":"High","gaps":["Mostly GDP-state pool—how the small active fraction drives translocation unclear","Functional role of motor binding at vesicles not directly shown"]},{"year":2010,"claim":"Extended RAB10 function to immune surface receptor supply, ciliary base trafficking, and identified EHBP1 as a conserved recycling effector.","evidence":"Dominant-negative/siRNA with surface TLR4 and cytokine readouts plus in vivo lung injury; exocyst Co-IP at cilia; yeast two-hybrid and genetics for EHBP-1 in C. elegans","pmids":["20643919","20576682","20573983"],"confidence":"High","gaps":["Functional consequence of RAB10-exocyst interaction at cilia not tested","How EHBP1 couples RAB10 to membrane deformation unresolved"]},{"year":2011,"claim":"Identified DENND4C as the GEF activating RAB10 for GLUT4 translocation and Lgl1 as a GDI-release activator in axons, defining upstream activation mechanisms in two settings.","evidence":"DENND4C siRNA and vesicle fractionation in adipocytes; Co-IP and in vivo cortical knockdown for Lgl1-RAB10-GDI in neurons; VWF secretion knockdown in endothelial cells","pmids":["21454697","21856246","21070595"],"confidence":"High","gaps":["How distinct GEFs/activators are spatially restricted unknown","Single-lab evidence for several activation routes"]},{"year":2012,"claim":"Directly visualized RAB10 marking GLUT4 vesicles undergoing insulin-stimulated fusion and revealed a separable role in ER tubule growth, distinguishing RAB10's trafficking compartments.","evidence":"Dual-color TIRF/IRAP-pHluorin fusion imaging and Myosin-Va Co-IP in adipocytes; live ER imaging with PIS/CEPT1 co-localization and GDP-locked mutants","pmids":["22908308","23263280"],"confidence":"High","gaps":["Mechanism coupling RAB10 to lipid-synthesis enzyme enrichment unclear","How one Rab serves both ER and PM trafficking unresolved"]},{"year":2013,"claim":"Defined upstream targeting (Crag) and motor-dependent carrier biogenesis (MYO5B exon-D) that route RAB10 vesicles for polarized secretion and axon growth.","evidence":"Drosophila genetic epistasis with Crag/Tango1; Co-IP and vesicle-fission assays with MYO5B splice mutants in neurons and zebrafish","pmids":["23369713","23770993"],"confidence":"High","gaps":["Generality of Crag-type GEF targeting to mammals untested here","How motor binding mechanistically drives Golgi fission unresolved"]},{"year":2014,"claim":"Resolved the RAB10 axonal trafficking machinery (JIP1/kinesin-1, MARCKS docking) and extended its adipocyte cascade to RalA activation, while adding HAS3 recycling.","evidence":"Co-IP, GTP-locked pulldowns, transport/docking TIRF assays in neurons; GTP-loading and Rlf rescue in adipocytes; HAS3 Co-IP and HA assays","pmids":["24478353","24662485","25103239","24509846"],"confidence":"High","gaps":["Coordination between anterograde transport and docking steps unclear","HAS3 finding single-lab"]},{"year":2015,"claim":"Mapped GTP-dependent exocyst engagement (Exoc6/6b) for GLUT4 fusion and defined a RAB10/AMPH-1 mechanism that downregulates RAB-5 and a SEC-10/microtubule tubular endosome network.","evidence":"GTP-locked pulldowns and knockdown in adipocytes; Co-IP and genetic epistasis with TBC-2/RAB-5 and SEC-10 in C. elegans","pmids":["26299925","26393361","25301900"],"confidence":"High","gaps":["Exoc6/6b finding single-lab","How RAB10 spatially coordinates GAP recruitment to RAB-5 incompletely defined"]},{"year":2016,"claim":"Identified RAB10's roles in lipophagy via an EHBP1–EHD2 complex and SEC16A-dependent GLUT4 vesicle biogenesis, and discovered LRRK2 as the major RAB10 switch-II kinase—seeding the disease axis.","evidence":"Co-IP of EHBP1/EHD2 complex with LC3 and lipid-droplet readouts; SEC16A co-localization/knockdown in adipocytes; Phos-tag and kinase-dead LRRK2 knockin mice","pmids":["28028537","27354378","27474410","27404358"],"confidence":"High","gaps":["Functional consequence of Thr73 phosphorylation not yet defined at this stage","How EHBP1/EHD2 deform lipid-droplet membranes mechanistically unresolved"]},{"year":2019,"claim":"Connected LRRK2-phosphorylated RAB10 to Parkinson's-relevant defects—impaired OPTN-dependent mitophagy and RILPL1-dependent centrosomal/ciliary defects—and identified KIF13A/B motors for tubular endosome biogenesis.","evidence":"Co-IP, mitophagy and patient-cell assays for OPTN; phospho-RAB10 centrosome imaging with RILPL1 knockdown; CRISPR KO and KIF13A/B Co-IP/domain mapping","pmids":["30945962","31428781","30700496"],"confidence":"High","gaps":["How phosphorylation switches effector preference structurally unresolved at this stage","Physiological cell types where each phospho-pathway dominates unclear"]},{"year":2020,"claim":"Established the LRRK2–phospho-RAB10 axis in macropinosome maturation and phagosome recruitment in immune cells, and refined the adipocyte TGN GLUT4 storage compartment.","evidence":"Selective endocytosis assays, EHBP1L1 competition, chemotaxis readouts in primary macrophages/DCs; isogenic LRRK2 iPSC macrophages; cargo-controlled mobilization assays in adipocytes","pmids":["32853409","32359446","33175605"],"confidence":"High","gaps":["Phagosome co-recruitment study single-lab/Medium","How LRRK2 selects RAB10 among phagosomal Rabs unclear"]},{"year":2021,"claim":"Mechanistically dissected how phospho-RAB10 blocks ciliogenesis—via RILPL1/RILPL2 and Myosin Va sequestration at the mother centriole preventing TTBK2/CP110 uncapping—and confirmed RILPL1-dependent centrosomal cohesion deficits.","evidence":"Live imaging, R1441C MEFs, RAB10/RILPL1 manipulation, CP110/TTBK2 localization; FLIP and phospho-RAB10 pulldowns for Myosin Va; scratch-wound polarization assays","pmids":["33653948","33727250","35776681"],"confidence":"High","gaps":["Structural basis of phospho-switch-II RILPL binding not resolved here","Confirmatory centrosomal study Medium confidence"]},{"year":2021,"claim":"Showed RAB10 is a host target of the Salmonella GAP effector SopD, whose inactivation of RAB10 drives Dynamin-2 recruitment and vacuole scission, revealing pathogen exploitation of the GTPase cycle.","evidence":"SopD GAP-domain mutagenesis, RAB10 pulldown, Dynamin-2 recruitment and scission assays during infection","pmids":["34349110"],"confidence":"High","gaps":["RAB10 effectors driving the scission step incompletely defined","Relationship to host LRRK2 signaling untested"]},{"year":2022,"claim":"Revealed that lysosomal positioning gates LRRK2-dependent RAB10 phosphorylation and identified PPM1H as the counteracting phosphatase, linking organelle distribution to the phospho-RAB10 lysosomal tubulation response, and added LDLR/transferrin recycling roles.","evidence":"Lysosome-positioning manipulations (ARL8B/SKIP, JIP4, RILP), PPM1H knockdown, pRAB10 imaging; CRISPR KO and recycling assays for LDLR","pmids":["36256825","35753407"],"confidence":"High","gaps":["LDLR recycling finding Medium/single-lab","How perinuclear positioning physically enables LRRK2 access unresolved"]},{"year":2023,"claim":"Demonstrated RAB10 fine-tunes retrograde TrkB/BDNF signaling endosome sorting in axon terminals and identified an aging mechanism (SDPN-1/KGB-1) that suppresses RAB10 activation by competing with its GEF.","evidence":"RAB10 KO and TrkB sorting/retrograde imaging in mouse neurons; aged C. elegans genetics and SDPN-1/DENN-4 Co-IP with barrier assays","pmids":["36897066","37640905"],"confidence":"High","gaps":["Aging mechanism Medium/single-lab","Conservation of GEF-competition regulation in mammals untested"]},{"year":2024,"claim":"Extended the phospho-RAB10/Myosin Va/RILPL2 axis to migrasome cargo delivery in wound healing and showed phospho-RAB10–VPS13C coupling in the dopaminergic-neuron lysosomal stress response, deepening disease relevance.","evidence":"Live imaging, motor/adaptor knockdowns and LRRK2 inhibition with cytokine-delivery and wound-healing readouts; phospho-dependent VPS13C interaction and lysosomal function assays in iPSC dopaminergic neurons","pmids":["39008679","38358348"],"confidence":"High","gaps":["How a single phospho-RAB10/RILPL2/Myosin Va module is differentially deployed across organelles unclear","Direct contribution to Parkinson's pathogenesis in vivo not established here"]},{"year":null,"claim":"How the Thr73 phosphorylation switch structurally and spatially reroutes RAB10 between its canonical trafficking effectors (Myosin Va, exocyst, EHBP1) and the RILPL1/RILPL2 sequestration program, and how this is integrated across cell types, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structural model of phospho-switch-II effector discrimination in the corpus","Tissue-specific balance of trafficking versus sequestration roles undefined","In vivo causal link from RAB10 dysregulation to Parkinson's phenotypes not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[1,18,34]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,8,19]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[5,7,45,46]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5,6,10,26]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,9]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[28,32,33,35]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[36,40]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[11,32]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[27]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,3,23,31]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[22,27]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,29]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[32,33]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12,14,15]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[6,7,37]}],"complexes":["EHBP1-EHD2 complex","exocyst","kinesin-1/JIP1/Rab10 complex"],"partners":["MYO5A","EHBP1","RILPL1","RILPL2","LRRK2","KIF13A","OPTN","SEC16A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61026","full_name":"Ras-related protein Rab-10","aliases":[],"length_aa":200,"mass_kda":22.5,"function":"The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes (PubMed:21248164). Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (PubMed:21248164). RAB10 is mainly involved in the biosynthetic transport of proteins from the Golgi to the plasma membrane (PubMed:21248164). Regulates, for instance, SLC2A4/GLUT4 glucose transporter-enriched vesicles delivery to the plasma membrane (By similarity). In parallel, RAB10 regulates the transport of TLR4, a toll-like receptor to the plasma membrane and therefore may be important for innate immune response (By similarity). Also plays a specific role in asymmetric protein transport to the plasma membrane (PubMed:16641372). In neurons, involved in axonogenesis through regulation of vesicular membrane trafficking toward the axonal plasma membrane (By similarity). In epithelial cells, regulates transport from the Golgi to the basolateral membrane (PubMed:16641372). May play a role in the basolateral recycling pathway and in phagosome maturation (By similarity). May play a role in endoplasmic reticulum dynamics and morphology controlling tubulation along microtubules and tubules fusion (PubMed:23263280). Together with LRRK2, RAB8A, and RILPL1, regulates ciliogenesis (PubMed:30398148). When phosphorylated by LRRK2 on Thr-73, binds RILPL1 and inhibits ciliogenesis (PubMed:30398148). Participates in the export of a subset of neosynthesized proteins through a Rab8-Rab10-Rab11-dependent endososomal export route (PubMed:32344433). Targeted to and stabilized on stressed lysosomes through LRRK2 phosphorylation where it promotes the extracellular release of lysosomal content through EHBP1 and EHNP1L1 effector proteins (PubMed:30209220) (Microbial infection) Upon Legionella pneumophila infection promotes endoplasmic reticulum recruitment and bacterial replication. Plays a role in remodeling the Legionella-containing vacuole (LCV) into an endoplasmic reticulum-like vacuole","subcellular_location":"Cytoplasmic vesicle membrane; Golgi apparatus membrane; Golgi apparatus, trans-Golgi network membrane; Endosome membrane; Recycling endosome membrane; Cytoplasmic vesicle, phagosome membrane; Cytoplasm, cytoskeleton, cilium basal body; Endoplasmic reticulum membrane; Cytoplasm, perinuclear region; Lysosome","url":"https://www.uniprot.org/uniprotkb/P61026/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB10","classification":"Not Classified","n_dependent_lines":540,"n_total_lines":1208,"dependency_fraction":0.4470198675496689},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000084733","cell_line_id":"CID000415","localizations":[{"compartment":"er","grade":3},{"compartment":"golgi","grade":2},{"compartment":"vesicles","grade":1}],"interactors":[{"gene":"GDI2","stoichiometry":4.0},{"gene":"CHM","stoichiometry":0.2},{"gene":"GDI1","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"RAB1B;RAB1C","stoichiometry":0.2},{"gene":"TOMM40","stoichiometry":0.2},{"gene":"RTN4","stoichiometry":0.2},{"gene":"TMED10","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000415","total_profiled":1310},"omim":[{"mim_id":"620387","title":"TBC1 DOMAIN FAMILY, MEMBER 21; TBC1D21","url":"https://www.omim.org/entry/620387"},{"mim_id":"619583","title":"EH DOMAIN-BINDING PROTEIN 1-LIKE 1; EHBP1L1","url":"https://www.omim.org/entry/619583"},{"mim_id":"616218","title":"TBC1 DOMAIN FAMILY, MEMBER 13; TBC1D13","url":"https://www.omim.org/entry/616218"},{"mim_id":"612673","title":"RAS-ASSOCIATED PROTEIN RAB14; RAB14","url":"https://www.omim.org/entry/612673"},{"mim_id":"612672","title":"RAS-ASSOCIATED PROTEIN RAB10; RAB10","url":"https://www.omim.org/entry/612672"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RAB10"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P61026","domains":[{"cath_id":"3.40.50.300","chopping":"7-172","consensus_level":"high","plddt":91.9801,"start":7,"end":172}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61026","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61026-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61026-F1-predicted_aligned_error_v6.png","plddt_mean":85.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB10","jax_strain_url":"https://www.jax.org/strain/search?query=RAB10"},"sequence":{"accession":"P61026","fasta_url":"https://rest.uniprot.org/uniprotkb/P61026.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61026/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61026"}},"corpus_meta":[{"pmid":"17403373","id":"PMC_17403373","title":"Rab10, a target of the AS160 Rab GAP, is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane.","date":"2007","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17403373","citation_count":299,"is_preprint":false},{"pmid":"23263280","id":"PMC_23263280","title":"Rab10 GTPase regulates ER dynamics and morphology.","date":"2012","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23263280","citation_count":191,"is_preprint":false},{"pmid":"16394106","id":"PMC_16394106","title":"RAB-10 is required for endocytic recycling in the Caenorhabditis elegans intestine.","date":"2006","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16394106","citation_count":182,"is_preprint":false},{"pmid":"30945962","id":"PMC_30945962","title":"LRRK2 mutations impair depolarization-induced mitophagy through inhibition of mitochondrial accumulation of 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therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31802892","citation_count":12,"is_preprint":false},{"pmid":"35482482","id":"PMC_35482482","title":"LncRNA136131 suppresses apoptosis of renal tubular epithelial cells in acute kidney injury by targeting the miR-378a-3p/Rab10 axis.","date":"2022","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/35482482","citation_count":12,"is_preprint":false},{"pmid":"38307024","id":"PMC_38307024","title":"The LRRK2 kinase substrates RAB8a and RAB10 contribute complementary but distinct disease-relevant phenotypes in human neurons.","date":"2024","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38307024","citation_count":11,"is_preprint":false},{"pmid":"31519919","id":"PMC_31519919","title":"Activated α2-Macroglobulin Regulates LRP1 Levels at the Plasma Membrane through the Activation of a Rab10-dependent Exocytic Pathway in Retinal Müller Glial Cells.","date":"2019","source":"Scientific 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38437244","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52021,"output_tokens":13466,"usd":0.179027,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":24941,"output_tokens":6648,"usd":0.145453,"stage2_stop_reason":"end_turn"},"total_usd":0.32448,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"Rab10 functions as a downstream target of the AS160 (TBC1D4) Rab GAP in the insulin-signaling pathway regulating GLUT4 translocation to the adipocyte plasma membrane. Overexpression of a GTP-hydrolysis-defective Rab10 mutant increased surface GLUT4 in basal adipocytes; Rab10 knockdown attenuated insulin-induced GLUT4 redistribution and reduced GLUT4 exocytosis rate; the basal increase in plasma-membrane GLUT4 caused by AS160 knockdown was partially blocked by simultaneous Rab10 knockdown.\",\n      \"method\": \"Dominant-negative and constitutively active Rab10 mutant overexpression, siRNA knockdown, flow cytometry of surface GLUT4, exocytosis rate measurement in 3T3-L1 adipocytes\",\n      \"journal\": \"Cell Metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal loss-of-function and gain-of-function experiments, replicated across subsequent studies, clear epistasis with AS160\",\n      \"pmids\": [\"17403373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Among Rab GTPases present in GLUT4 vesicles and acting as AS160 GAP substrates (Rab8A, Rab8B, Rab10, Rab14), only knockdown of Rab10 inhibited GLUT4 translocation in 3T3-L1 adipocytes. Approximately 5% of total Rab10 resides in GLUT4 vesicles from low-density microsomes; ~90% of Rab10 is in the inactive GDP form in both basal and insulin-stimulated states. The constitutively active Rab10 Q68L mutant is still a substrate for the AS160 GAP domain.\",\n      \"method\": \"siRNA knockdown of individual Rabs, subcellular fractionation, GTP-loading assays, in vitro GAP assay\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA, fractionation, in vitro GAP assay), consistent with independent replication in other labs\",\n      \"pmids\": [\"18076383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Dennd4C is identified as the primary guanine nucleotide exchange factor (GEF) for Rab10 required for insulin-stimulated GLUT4 translocation in adipocytes. Knockdown of Dennd4C markedly inhibited GLUT4 translocation; Dennd4C was found in isolated GLUT4 vesicles.\",\n      \"method\": \"siRNA knockdown of Dennd4C, GLUT4 translocation assay, subcellular fractionation of GLUT4 vesicles\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (functional knockdown + vesicle fractionation), single lab\",\n      \"pmids\": [\"21454697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rab10 directly mediates GLUT4 storage vesicle (GSV) translocation to and docking at the plasma membrane in adipocytes. Myosin-Va associates with GSVs by interacting with Rab10, positioning peripherally recruited GSVs for ultimate fusion. Live TIRF microscopy with IRAP-pHluorin showed Rab10 as the Rab specifically marking GSVs undergoing insulin-stimulated plasma membrane fusion; Rab14 instead labels transferrin-receptor-positive endosomal compartments.\",\n      \"method\": \"Dual-color TIRF microscopy, IRAP-pHluorin fusion assay, siRNA knockdown, co-immunoprecipitation of Rab10 with Myosin-Va\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — live-cell TIRF imaging with pHluorin reporter (direct visualization of fusion events) plus Co-IP and functional knockdown; replicated across labs\",\n      \"pmids\": [\"22908308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rab10 is an ER-specific Rab GTPase that regulates ER structure and dynamics. Rab10 localizes to dynamic ER-associated structures that track along microtubules and mark sites of new ER tubule growth. Depletion or GDP-locked Rab10 mutant expression results in fewer ER tubules due to reduced ability of dynamic tubules to grow out and fuse with adjacent ER. The Rab10 domain at the leading edge of dynamic ER tubules is highly enriched with phospholipid synthesis enzymes phosphatidylinositol synthase (PIS) and CEPT1; formation and function of this domain are inhibited by GDP-locked Rab10.\",\n      \"method\": \"Live-cell fluorescence microscopy of ER dynamics, siRNA knockdown, GDP-locked mutant expression, co-localization with PIS/CEPT1\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging plus multiple genetic perturbations (siRNA and dominant-negative) with direct morphological readout, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"23263280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RAB-10 (C. elegans ortholog) is required for endocytic recycling in polarized intestinal epithelial cells. rab-10 null mutants accumulate abnormally enlarged RAB-5-positive early endosomes, lose RME-1-positive recycling endosomes, and accumulate basolaterally recycling transmembrane cargo, indicating RAB-10 functions upstream of RME-1 in basolateral recycling. GFP-RAB-10 localizes to endosomes and Golgi.\",\n      \"method\": \"rab-10 null mutant analysis, GFP-RAB-10 reporter localization, immunofluorescence for endosomal markers, cargo trafficking assays in C. elegans intestine\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null mutant genetics with multiple molecular markers and cargo readouts, established ortholog function\",\n      \"pmids\": [\"16394106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Rab10 is specifically associated with common (basolateral sorting) endosomes in polarized MDCK cells. Expression of GTP-hydrolysis-defective or GDP-bound Rab10 mutants increased recycling from basolateral early endosomes without affecting apical recycling or later recycling compartments, indicating Rab10 mediates transport from basolateral sorting endosomes to common endosomes.\",\n      \"method\": \"GFP-tagged wild-type and mutant Rab10 expression, quantitative confocal microscopy, endocytic probe trafficking assays in polarized MDCK cells\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (localization and trafficking kinetics), multiple Rab10 mutants tested, single lab\",\n      \"pmids\": [\"16641372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Rab10 functions in biosynthetic trafficking from the Golgi to the basolateral membrane in polarized MDCK cells. GFP-Rab10 localizes primarily to the Golgi during early polarization; activated Rab10 mutant inhibits biosynthetic transport from the Golgi and missorts basolateral cargo to the apical membrane. Simultaneous inhibition of Rab10 and Rab8a more strongly impairs basolateral sorting, suggesting cooperation.\",\n      \"method\": \"GFP-Rab10 localization, activated mutant expression, RNAi knockdown, biosynthetic transport assays in polarized MDCK cells\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mutants and RNAi, but epistasis evidence for Rab8 cooperation is single lab\",\n      \"pmids\": [\"17132146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Rab10 interacts with myosin Va, myosin Vb, and myosin Vc. The interaction requires the alternatively spliced exon D in myosin Va and Vb (and the homologous region in Vc). Both Rab8a and Rab10 are mislocalized by dominant-negative myosin V tails. The interaction was confirmed by yeast two-hybrid assays and FRET studies.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, FRET, dominant-negative myosin V tail expression, splice isoform analysis\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — three independent methods (Co-IP, yeast two-hybrid, FRET) confirming the same interaction and mapping the exon D requirement\",\n      \"pmids\": [\"19008234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Rab10 regulates continuous replenishment of TLR4 from Golgi to the plasma membrane in macrophages, which is essential for optimal macrophage activation following LPS stimulation. Blockade of Rab10 function leads to decreased membrane TLR4 expression and diminished production of inflammatory cytokines and interferons upon LPS stimulation.\",\n      \"method\": \"Dominant-negative Rab10 expression, siRNA knockdown, flow cytometry of surface TLR4, cytokine measurement, in vivo LPS-induced acute lung injury model\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple methods (dominant-negative, siRNA, in vivo model), clear mechanistic link between Rab10 and TLR4 surface replenishment\",\n      \"pmids\": [\"20643919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RAB-10 (C. elegans) and its binding partner EHBP-1 (calponin homology domain protein) function together in endocytic recycling. Yeast two-hybrid identified EHBP-1 as a RAB-10 binding partner. GFP-EHBP-1 colocalizes with RFP-RAB-10 on endosomal structures; ehbp-1 loss-of-function mutants share with rab-10 mutants specific endosome morphology and cargo localization defects.\",\n      \"method\": \"Yeast two-hybrid screen, fluorescence co-localization in C. elegans, null mutant phenotypic analysis, cargo trafficking assays\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid plus in vivo co-localization plus genetic epistasis with shared phenotypes\",\n      \"pmids\": [\"20573983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Rab10 associates with primary cilia in renal epithelia and colocalizes with exocyst proteins at the base of nascent cilia. Rab10 physically interacts with the exocyst complex as detected by co-immunoprecipitation with anti-Sec8 antibodies.\",\n      \"method\": \"Immunofluorescence microscopy, co-immunoprecipitation with anti-Sec8, live imaging in renal epithelial cells in culture and in vivo\",\n      \"journal\": \"American Journal of Physiology - Renal Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, Co-IP and co-localization but no direct functional consequence of Rab10-exocyst interaction tested at cilia\",\n      \"pmids\": [\"20576682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Lgl1 activates Rab10 in developing axons by releasing GDP dissociation inhibitor (GDI) from Rab10, thereby promoting membrane trafficking of plasmalemmal precursor vesicles (PPVs) required for axon development and neuronal polarization. Rab10 lies downstream of Lgl1 in axon development; both are required for neocortical neuronal polarization in vivo.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative and knockdown experiments, directional membrane insertion assay, in vivo rat cortex knockdown\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical Co-IP showing Lgl1-Rab10-GDI interaction, epistasis by rescue experiments, in vivo validation\",\n      \"pmids\": [\"21856246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In Drosophila follicle cells, Crag targets Rab10 to structures in the basal cytoplasm, restricting basement membrane protein delivery to the basal surface during egg chamber elongation. Tango1 and Rab10 are planar polarized at the basal epithelial surface, coupling BM production to organ morphogenesis.\",\n      \"method\": \"Genetic epistasis, GFP reporter localization, loss-of-function analysis of Crag, Tango1 and Rab10 in Drosophila follicle cells\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis plus live imaging, established upstream regulator (Crag) targeting Rab10 to basal domain\",\n      \"pmids\": [\"23369713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rab10 interaction with myosin Vb (MYO5B) via the exon D-encoded domain determines the formation of Rab10-containing post-Golgi carriers and is required for axon development. Disrupting MYO5B(+D) expression or its interaction with Rab10 impairs fission of Rab10 vesicles from trans-Golgi membranes and inhibits axon development.\",\n      \"method\": \"Co-immunoprecipitation, splice isoform mutants, vesicle biogenesis assay, knockdown in hippocampal neurons, in vivo analysis in neocortical neurons and zebrafish retinal ganglion cells\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical interaction mapping, functional vesicle biogenesis assay, in vivo rescue in two vertebrate systems\",\n      \"pmids\": [\"23770993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JIP1 (c-Jun N-terminal kinase-interacting protein 1) interacts with GTP-locked active Rab10 and directly connects Rab10 to kinesin-1 light chain (KLC), forming a kinesin-1/JIP1/Rab10 complex required for anterograde transport of plasmalemmal precursor vesicles (PPVs) during axon development and neuronal polarization.\",\n      \"method\": \"Co-immunoprecipitation, dominant-active Rab10 pulldown, siRNA knockdown of JIP1/KLC, anterograde transport assays in hippocampal neurons, in vivo rat neocortical transfection\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical complex reconstitution (Co-IP), functional transport assay, in vivo validation\",\n      \"pmids\": [\"24478353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MARCKS mediates membrane targeting of Rab10-positive PPVs during axon development. GTP-locked active Rab10 binds membrane-associated MARCKS; this affinity depends on the phosphorylation status of the MARCKS effector domain. MARCKS knockdown or disruption of Rab10-MARCKS interaction inhibits axon growth, impairs docking and fusion of Rab10 vesicles with the plasma membrane, and reduces membrane insertion of axonal receptors.\",\n      \"method\": \"Co-immunoprecipitation, GTP-locked Rab10 pulldown, MARCKS knockdown and phosphomutant expression, TIRF microscopy of vesicle docking/fusion, membrane insertion assays\",\n      \"journal\": \"Cell Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical binding assay with phosphorylation-state dependence, multiple functional readouts including direct vesicle tracking\",\n      \"pmids\": [\"24662485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rab10-mediated endocytosis of hyaluronan synthase HAS3 regulates hyaluronan synthesis and cell adhesion. Rab10 co-localizes and co-immunoprecipitates with HAS3 from endosomal vesicles. Rab10 silencing increases plasma membrane HAS3 residence, increases HA secretion and cell surface HA coat, and blocks retrograde HAS3 trafficking from plasma membrane to early endosomes.\",\n      \"method\": \"Co-immunoprecipitation, co-localization microscopy, siRNA knockdown, HA synthesis assay, cell adhesion assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional readout, single lab, two orthogonal approaches\",\n      \"pmids\": [\"24509846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rab10 is a target of the AS160 (TBC1D4) GAP, and once activated (GTP-bound), Rab10 recruits the Ral GEF Rlf/Rgl2, increasing GTP binding of RalA. Rab10 and RalA co-reside in the same pool of Glut4-storage vesicles; RalA is epistatic downstream of Rab10 in insulin-stimulated Glut4 translocation. Membrane-tethered Rlf compensates for Rab10 loss in Glut4 translocation.\",\n      \"method\": \"Co-immunoprecipitation, GTP-loading assays, siRNA knockdown, epistasis rescue experiments, Glut4 translocation assay\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical cascade demonstrated by Co-IP and GTP-loading, epistasis confirmed by membrane-tethered Rlf rescue\",\n      \"pmids\": [\"25103239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rab10-GTP (but not GDP form) binds to exocyst subunits Exoc6 and Exoc6b. Both isotypes are found in 3T3-L1 adipocytes, and knockdown of Exoc6, Exoc6b, or both inhibits GLUT4 translocation, identifying Rab10-GTP association with Exoc6/6b as a molecular link between insulin signaling and the exocytic machinery.\",\n      \"method\": \"Pulldown of GTP-locked Rab10 with exocyst subunits, siRNA knockdown of Exoc6/6b, GLUT4 translocation assay\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown demonstrating GTP-state dependence plus functional knockdown, single lab\",\n      \"pmids\": [\"26299925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RAB-10 and amphiphysin AMPH-1 bind to and recruit TBC-2 (a Rab-5 GAP) to endosomes. In the absence of RAB-10 or AMPH-1 binding to TBC-2, RAB-5 membrane association is abnormally high and recycling cargo is trapped in early endosomes. This identifies a mechanism by which RAB-10 and AMPH-1 down-regulate RAB-5 to enable cargo exit from early endosomes.\",\n      \"method\": \"Genetic epistasis in C. elegans, co-immunoprecipitation, fluorescence co-localization, null and loss-of-function mutant analysis\",\n      \"journal\": \"PLOS Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical interaction (Co-IP) plus genetic epistasis plus cargo/endosome marker quantification\",\n      \"pmids\": [\"26393361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SEC-10 (exocyst subunit) coordinates with RAB-10 and microtubules to form interconnected endosomal tubules required for basolateral recycling of clathrin-independent endocytic cargoes including hTAC, GLUT1, and DAF-4. Epistasis analysis indicates SEC-10 operates at an intermediate step between early endosomes and recycling endosomes; depletion of either SEC-10 or RAB-10 disrupts tubular endosome structure.\",\n      \"method\": \"siRNA/RNAi depletion, fluorescence microscopy, epistasis analysis, cargo recycling assays in C. elegans intestine\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis plus multiple cargo markers and structural readout of tubular endosome integrity\",\n      \"pmids\": [\"25301900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rab10 is essential for lipophagy in hepatocytes. During autophagy stimulation, Rab10 activity is amplified and Rab10 is recruited to nascent autophagic membranes at the lipid droplet surface. Rab10 activation is required for LC3 recruitment to autophagosomes and stimulates increased association with adaptor protein EHBP1 and membrane-deforming ATPase EHD2, which together drive engulfment of lipid droplets.\",\n      \"method\": \"siRNA knockdown, dominant-negative and GTPase-defective Rab10 mutant expression, co-immunoprecipitation of Rab10-EHBP1-EHD2 complex, fluorescence microscopy of LC3 recruitment, lipid droplet accumulation assay\",\n      \"journal\": \"Science Advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identification of a novel Rab10 complex (EHBP1/EHD2) with mechanistic link to LC3 recruitment, multiple genetic perturbations and readouts\",\n      \"pmids\": [\"28028537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SEC16A is a RAB10 effector required for insulin-stimulated GLUT4 trafficking. Colocalization of SEC16A with RAB10 is augmented by insulin stimulation; SEC16A knockdown attenuates insulin-induced GLUT4 translocation, phenocopying RAB10 knockdown. RAB10-SEC16A promotes insulin-stimulated mobilization of GLUT4 from a perinuclear recycling endosome/TGN compartment, promoting vesicle biogenesis independently of canonical COPII function.\",\n      \"method\": \"Co-localization microscopy, siRNA knockdown, GLUT4 translocation assay, COPII component analysis\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional epistasis, SEC16A identified as novel Rab10 effector with phenocopy knockdown and compartment-specific mechanism\",\n      \"pmids\": [\"27354378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rab10-based secretion pathway promotes pericellular basement membrane protein accumulation and fibril formation in Drosophila egg chamber. Manipulation of the Rab10 secretion pathway demonstrates that BM fibrillar structure influences egg chamber morphogenesis.\",\n      \"method\": \"Live imaging, genetic manipulation of Rab10 pathway, fluorescent BM protein reporters in Drosophila\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging plus genetic manipulation, direct demonstration of Rab10-dependent BM protein secretion affecting morphogenesis\",\n      \"pmids\": [\"27404358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LRRK2 directly phosphorylates Rab10 at a conserved threonine/serine residue (Thr73) in the effector-binding switch-II motif. Phosphorylation of Rab10 is ablated in kinase-inactive LRRK2[D2017A] knockin MEFs and mouse lung, establishing LRRK2 as the major Rab10 kinase. Phospho-Ser910 and Ser935 and 14-3-3 binding play a role in facilitating LRRK2-mediated Rab10 phosphorylation in vivo.\",\n      \"method\": \"Phos-tag electrophoresis, kinase-inactive LRRK2 knockin MEFs and tissue, LRRK2 inhibitor treatment, phospho-specific antibody detection\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — knockin kinase-dead mice establish LRRK2 as the primary kinase, Phos-tag biochemical assay plus inhibitor pharmacology, replicated across multiple studies\",\n      \"pmids\": [\"27474410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rab10 identifies a novel class of tubular endosomes in HeLaM cells. Knockout of Rab10 completely abolishes tubular endosomal structures. Kinesin motors KIF13A and KIF13B are novel Rab10-interacting proteins; both the Rab10-binding homology domain and the motor domain of KIF13A are required for Rab10-positive tubular endosome formation.\",\n      \"method\": \"CRISPR knockout of Rab10, in silico screening + validation, co-immunoprecipitation of KIF13A/B with Rab10, deletion mutant analysis, fluorescence microscopy\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO abolishes structure (clean phenotype), binding partners identified with domain mapping by Co-IP and deletion mutants\",\n      \"pmids\": [\"30700496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LRRK2-phosphorylated RAB10 (pT73) accumulates on depolarized mitochondria in a PINK1- and PRKN-dependent manner, binds the autophagy receptor OPTN (optineurin), and promotes OPTN accumulation on depolarized mitochondria to facilitate mitophagy. In LRRK2 mutant (G2019S, R1441C) patient cells, enhanced RAB10 phosphorylation reduces RAB10-OPTN interaction, mitochondrial accumulation of both proteins, and mitophagy. A phosphomimetic RAB10 mutant shows less OPTN interaction and fails to rescue mitophagy.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, mitophagy assay, patient-derived cells, LRRK2 knockdown/inhibition rescue, phosphomimetic mutant analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical interaction (Co-IP), patient-derived cells, phosphomimetic mechanistic dissection, LRRK2 inhibition rescue\",\n      \"pmids\": [\"30945962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Phosphorylated RAB10 (by pathogenic LRRK2) is recruited to centrosome-localized RILPL1, contributing to ciliogenesis defects and centrosomal cohesion deficits in dividing cells. Both RAB8 and RAB10 contribute to LRRK2-mediated centrosomal cohesion deficits; effects are dependent on RAB8, RAB10, and RILPL1.\",\n      \"method\": \"Immunofluorescence for phospho-RAB10 at centrosomes, patient-derived peripheral cells, primary astrocytes from LRRK2 mutant mice, LRRK2 kinase inhibition, siRNA knockdown\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell types (patient-derived, primary mouse astrocytes), multiple genetic perturbations, pharmacological rescue\",\n      \"pmids\": [\"31428781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rab10 specifically regulates macropinocytosis (not phagocytosis or clathrin-mediated endocytosis) in macrophages and dendritic cells. LRRK2 phosphorylates cytoplasmic PI(3,4,5)P3-positive GTP-Rab10 before EEA1/Rab5 recruitment to early macropinosomes. LRRK2 phosphorylation of Rab10 blocks EHBP1L1-mediated recycling tubules and cargo turnover of macropinosome cargo including CCR5, CD11b, MHCII. EHBP1L1 overexpression competitively inhibits LRRK2 phosphorylation of Rab10. Rab10 knockdown and LRRK2 kinase inhibition suppress maturation of CCR5-loaded signaling endosomes critical for CCL5-induced Akt activation and chemotaxis.\",\n      \"method\": \"siRNA knockdown, LRRK2 inhibition, endocytosis assays distinguishing macropinocytosis from phagocytosis and CME, phospho-Rab10 imaging, EHBP1L1 overexpression rescue, signaling and chemotaxis assays in primary macrophages/dendritic cells/microglia\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — selectivity for macropinocytosis established by multiple parallel assays, competitive inhibition mechanism demonstrated, multiple primary cell types\",\n      \"pmids\": [\"32853409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LRRK2 is required for RAB8a and RAB10 recruitment to phagosomes in human iPSC-derived macrophages and microglia. LRRK2 is recruited to LAMP1+/RAB9+ maturing phagosomes; LRRK2 kinase inhibition enhances LRRK2 residency at the phagosome.\",\n      \"method\": \"LRRK2 knockout and G2019S isogenic iPSC-derived macrophages/microglia, immunofluorescence for phagosome markers, LRRK2 kinase inhibitor treatment\",\n      \"journal\": \"Stem Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic KO lines, clear co-recruitment phenotype, single lab\",\n      \"pmids\": [\"32359446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The TBC1D4-RAB10 signaling module controls GLUT4 mobilization from a trans-Golgi network (TGN) storage compartment. GLUT4 is retained in a TGN element from which it is mobilized by insulin via RAB10; this compartment also contains newly synthesized lysosomal proteins and the ATP7A copper transporter, but insulin does not mobilize ATP7A and copper does not mobilize GLUT4, and RAB10 is not required for copper-elicited ATP7A mobilization.\",\n      \"method\": \"RAB10 siRNA knockdown, insulin and copper stimulation assays, fluorescence co-localization, cargo mobilization assays in adipocytes\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — compartment identity precisely mapped with multiple cargo controls, specific role of RAB10 in TGN GLUT4 mobilization distinguished from other TGN trafficking\",\n      \"pmids\": [\"33175605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LRRK2 activity blocks ciliation by preventing CP110 release from the mother centriole, a step required for early ciliogenesis; this blockade requires Rab10 and RILPL1 proteins and is due to failure to recruit TTBK2 (a kinase needed for CP110 release). Deciliation probability does not change in cells lacking Rab10 or RILPL1, indicating a distinct LRRK2 pathway for deciliation.\",\n      \"method\": \"Live-cell fluorescence microscopy, R1441C LRRK2 MEF cells, Rab10 knockout, RILPL1 manipulation, LRRK2 kinase inhibition, CP110 and TTBK2 localization assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — precise epistasis placing Rab10/RILPL1 upstream of TTBK2 and CP110 uncapping, distinguishes ciliation from deciliation pathways\",\n      \"pmids\": [\"33653948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LRRK2-phosphorylated Rab10 sequesters Myosin Va and RILPL2 at the peri-centriolar region to block ciliogenesis. RILPL2 binds preferentially to LRRK2-phosphorylated Rab8A and Rab10; the globular tail domain of Myosin Va contains a high-affinity binding site for LRRK2-phosphorylated Rab10. PhosphoRab10 retains Myosin Va over pericentriolar membranes as measured by FLIP.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence loss in photobleaching (FLIP), phospho-Rab10 pulldown, localization microscopy, ciliogenesis assay\",\n      \"journal\": \"Life Science Alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding of phospho-Rab10 to Myosin Va demonstrated biochemically, FLIP confirms retention, functional ciliogenesis consequence shown\",\n      \"pmids\": [\"33727250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Salmonella effector SopD inhibits Rab10 via a C-terminal GTPase-activating protein (GAP) domain during host cell invasion. During infection, Rab10 and its effectors MICAL-L1 and EHBP1 are recruited to invasion sites; SopD-mediated inhibition of Rab10 promotes removal of Rab10 and recruitment of Dynamin-2 to drive plasma membrane scission and Salmonella-containing vacuole formation.\",\n      \"method\": \"SopD domain analysis, pulldown/Co-IP of SopD with Rab10, Rab10 knockdown, GAP domain mutagenesis, Dynamin-2 recruitment assay, infection-based plasma membrane scission assay\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — GAP domain biochemically demonstrated, mechanistic cascade (Rab10 inhibition → Dynamin-2 recruitment → scission) functionally validated\",\n      \"pmids\": [\"34349110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pathogenic LRRK2 (R1441C)-mediated centrosomal cohesion deficits require RILPL1-mediated centrosomal accumulation of phosphorylated Rab10. RILPL1 localizes to the subdistal appendage of the mother centriole, followed by phospho-Rab protein recruitment. These centrosomal alterations impair cell polarization as monitored by scratch wound assays and are reverted by LRRK2 kinase inhibition.\",\n      \"method\": \"Immunofluorescence for phospho-Rab10 at centrosomes, siRNA knockdown of Rab10/RILPL1, LRRK2 kinase inhibition, scratch wound polarization assay, RILPL2 and other Rab controls\",\n      \"journal\": \"Biology Open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic perturbations but largely confirmatory of prior findings from same lab\",\n      \"pmids\": [\"35776681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Lysosomal positioning regulates Rab10 phosphorylation by LRRK2: pRab10 is restricted to perinuclear lysosomes, not peripheral lysosomes. Anterograde lysosomal transport (via ARL8B/SKIP overexpression or JIP4 knockdown) blocks Rab10 phosphorylation and the subsequent lysosomal tubulation/sorting process (LYTL). Perinuclear clustering of lysosomes (via RILP overexpression) increases LRRK2-dependent Rab10 phosphorylation. PPM1H phosphatase knockdown increases pRab10 and lysosomal tubulation.\",\n      \"method\": \"LRRK2 membrane targeting constructs, ARL8B/SKIP overexpression, JIP4 knockdown, RILP overexpression, PPM1H knockdown, pRab10 immunofluorescence, lysosomal tubulation assay\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal manipulations of lysosome positioning showing consistent effect on Rab10 phosphorylation, phosphatase identified\",\n      \"pmids\": [\"36256825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RAB10 regulates hepatocyte LDL receptor (LDLR) recycling from RAB11-positive endosomes to the plasma membrane, and also promotes transferrin receptor recycling from RAB4-positive compartments. RAB10 loss reduces LDL uptake by impairing endosomal recycling of LDLR.\",\n      \"method\": \"CRISPR knockout, LDL uptake assay, LDLR recycling assay, endosomal marker co-localization, RAB11 and RAB4 compartment analysis\",\n      \"journal\": \"Journal of Lipid Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with functional recycling assay and compartment identification, single lab\",\n      \"pmids\": [\"35753407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Rab10 defines a membrane compartment in axon terminals that is rapidly mobilized towards the axon terminal upon BDNF stimulation, enabling fine-tuning of retrograde TrkB/BDNF signaling from axon terminals to the soma. Rab10 knockout impairs TrkB sorting to signalling endosomes and propagation of BDNF signalling in primary mouse neurons.\",\n      \"method\": \"Rab10 knockout in primary mouse neurons, live-cell imaging, TrkB sorting assay, retrograde transport assay, BDNF signalling readout\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with direct functional consequence on signalling endosome sorting and retrograde signal propagation, multiple readouts\",\n      \"pmids\": [\"36897066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Rab10 and Caveolin-1 (CAV1) mark intraluminal vesicles in migrasomes. Transport of Rab10-CAV1 vesicles to migrasomes requires motor protein Myosin Va and adaptor protein RILPL2. LRRK2-mediated phosphorylation of Rab10 regulates this transport process. CSF-1 is transported to migrasomes via this mechanism to foster monocyte-macrophage differentiation in skin wound healing.\",\n      \"method\": \"Live-cell imaging, Rab10 and CAV1 co-localization, Myosin Va and RILPL2 knockdown/inhibition, LRRK2 kinase inhibition, wound healing model, cytokine delivery assay\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple motor/adaptor knockdowns with functional readout of cargo delivery, physiological validation in wound healing\",\n      \"pmids\": [\"39008679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VPS13C interacts with phospho-Rab10 on lysosomes in a phosphorylation-dependent manner in human dopaminergic neurons. Loss of VPS13C disrupts lysosomal morphology, dynamics, motility, distribution, hydrolytic activity, and acidification, and decreases the phospho-Rab10-mediated lysosomal stress response.\",\n      \"method\": \"Live-cell microscopy of iPSC-derived dopaminergic neurons, VPS13C KO, phospho-Rab10 interaction assay, lysosomal function assays (pH, hydrolysis, motility)\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-dependent interaction demonstrated, disease-relevant neuronal model, multiple lysosomal function readouts\",\n      \"pmids\": [\"38358348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RAB-10 (C. elegans) regulates recycling of the AMPAR subunit GLR-1 in neurons via a cholesterol-dependent, clathrin-independent endocytic pathway. Genetic epistasis showed that cholesterol depletion suppresses the rab-10 mutant GLR-1 accumulation phenotype (but not lin-10), while clathrin-endocytosis inhibition suppresses lin-10 but not rab-10, placing RAB-10 after clathrin-independent endocytosis.\",\n      \"method\": \"Genetic epistasis (rab-10, lin-10, unc-11, itsn-1 mutants), cholesterol depletion, GLR-1 localization assay, behavioral reversal frequency assay in C. elegans\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis placing RAB-10 specifically in clathrin-independent recycling pathway with behavioral readout\",\n      \"pmids\": [\"17761527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Rab10 associates transiently with phagosomes at very early time-points (before Rab5 acquisition) and plays a prominent role in phagolysosome formation. Rab10 knockdown or dominant-negative expression delays maturation of phagosomes; constitutively active Rab10 partially rescues live-Mycobacterium-containing phagosome maturation and promotes EEA-1 acquisition on Mycobacterium-containing vacuoles.\",\n      \"method\": \"siRNA knockdown, dominant-negative and constitutively active Rab10 mutants, confocal microscopy of phagosome markers, Mycobacterium infection assay\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic perturbations with functional maturation readout, single lab\",\n      \"pmids\": [\"20028485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RAB10 interacts with MGCRABGAP (a male germ cell-specific Rab GAP) during mammalian spermiogenesis. MGCRABGAP exhibits GTPase-activating activity and RAB10 is identified as a substrate/interactor. MGCRABGAP-RAB10 complexes co-localize specifically in the manchette structure during spermatid head formation.\",\n      \"method\": \"Co-immunoprecipitation, nano LC-MS/MS proteomics, immunofluorescence co-localization in spermatids, GAP activity assay\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed RAB10-MGCRABGAP interaction with co-localization at manchette, GAP activity demonstrated, single lab\",\n      \"pmids\": [\"28067790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Age-related decline in RAB-10 functionality in C. elegans is caused by upregulation of SDPN-1/PACSIN during senescence, which suppresses RAB-10 activation by competing with DENN-4/GEF. KGB-1/JUN kinase enhances the inhibitory potency of SDPN-1, likely by altering its oligomerization. SDPN-1 knockdown alleviates age-related adherens junction and intestinal barrier defects.\",\n      \"method\": \"Age-synchronized C. elegans analysis, SDPN-1 and KGB-1 loss-of-function, RAB-10 activation assay, co-immunoprecipitation of SDPN-1 with DENN-4, barrier permeability assay\",\n      \"journal\": \"Nature Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — competitive GEF inhibition mechanism identified biochemically plus in vivo rescue, single lab\",\n      \"pmids\": [\"37640905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"HA-tagged Rab10 expressed in CHO and BHK cells is concentrated on membranes in the perinuclear region, partially overlapping with the Golgi marker β-COP, in contrast to Rab8 which localizes to the cell periphery. This establishes that Rab10 and Rab8, despite 66% identity, occupy distinct cellular compartments.\",\n      \"method\": \"Epitope-tagged (HA) expression, immunofluorescence microscopy, Golgi marker co-staining in stable CHO/BHK transfectants\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — original localization study, replicated by many subsequent studies, single method but foundational finding\",\n      \"pmids\": [\"7688123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rab10 is required for von Willebrand factor (VWF) secretion from endothelial cells. Rab10 (and Rab8A) are enriched at the Golgi where Weibel-Palade bodies (WPB) form; Rab10 siRNA knockdown significantly reduces the amount of rapidly-releasable VWF, implicating Rab10 in WPB biogenesis.\",\n      \"method\": \"C. elegans AP-1 genetic interaction screen, siRNA knockdown in human endothelial cells (HUVECs), VWF secretion assay, immunofluorescence localization\",\n      \"journal\": \"Journal of Thrombosis and Haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with direct secretion readout, Golgi localization confirmed, single lab\",\n      \"pmids\": [\"21070595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rab10 regulates tubular endosome formation through KIF13A and KIF13B motors (identified as novel Rab10-interacting proteins). The Rab10-binding homology domain and the motor domain of KIF13A are both required for Rab10-positive tubular endosome formation.\",\n      \"method\": \"EGFP-Rab GTPase localization screen, CRISPR/Cas9 Rab10 knockout, in silico screen + Co-immunoprecipitation of KIF13A/B, deletion mutant analysis\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO abolishes tubular endosomes (clean phenotype), domain mapping confirms KIF13A requirement\",\n      \"pmids\": [\"30700496\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB10 is a small Rab GTPase that functions downstream of the AS160 (TBC1D4) GAP—activated by insulin-stimulated Akt phosphorylation—and the GEF DENND4C, to drive GLUT4 storage vesicle translocation to the plasma membrane in adipocytes via interactions with Myosin Va, the exocyst subunit Exoc6/6b, and SEC16A; it additionally regulates basolateral endocytic recycling in polarized epithelial cells and neurons (engaging EHBP1 and kinesin motors KIF13A/B), ER tubule dynamics, lipophagy (via an EHBP1–EHD2 complex), TLR4 surface replenishment in macrophages, macropinocytosis maturation, axon development (via Lgl1-mediated GDI release and JIP1/kinesin-1-dependent anterograde transport), basement membrane polarized secretion in Drosophila epithelia, and ciliogenesis—where LRRK2-mediated phosphorylation at Thr73 in the switch-II motif inactivates RAB10 and drives its interaction with RILPL1/RILPL2 to sequester Myosin Va at the mother centriole, block CP110 uncapping, impair centrosome cohesion, and suppress mitophagy via reduced OPTN recruitment, thereby linking pathogenic LRRK2 mutations to multiple Parkinson's disease-relevant cellular defects.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RAB10 is a small Rab GTPase that organizes polarized and regulated membrane trafficking across diverse cell types, cycling between an active GTP-bound and inactive GDP-bound state controlled by dedicated regulators and effectors [#0, #3]. In insulin-stimulated adipocytes it operates as the key Rab downstream of the AS160/TBC1D4 GAP and the GEF DENND4C to drive translocation of GLUT4 storage vesicles from a perinuclear TGN/recycling compartment to the plasma membrane [#0, #2, #31], engaging effectors including Myosin Va, the exocyst subunits Exoc6/6b, SEC16A, and the RalA-activating GEF Rlf to couple insulin signaling to the docking and fusion machinery [#3, #18, #19, #23]. Beyond glucose transport, RAB10 governs endocytic recycling and tubular endosome biogenesis—functioning upstream of RME-1, downregulating RAB-5 via EHBP1/AMPH-1-recruited GAPs, and forming tubular endosomes through the kinesin motors KIF13A/B—and mediates basolateral biosynthetic sorting in polarized epithelia [#5, #6, #10, #20, #26]. RAB10 also marks and shapes dynamic ER tubules enriched in lipid-synthesis enzymes [#4], drives lipophagy of lipid droplets via an EHBP1–EHD2 complex [#22], regulates TLR4 surface replenishment and macropinosome maturation in immune cells [#9, #29], and supports axon development through Lgl1-mediated GDI release and JIP1/kinesin-1-dependent anterograde vesicle transport [#12, #15]. A major regulatory axis is phosphorylation at Thr73 in the switch-II motif by the Parkinson's disease kinase LRRK2, which reshapes RAB10 effector binding: phospho-RAB10 binds RILPL1/RILPL2 and Myosin Va to block CP110 release and ciliogenesis at the mother centriole and impair centrosomal cohesion, and engages OPTN to modulate mitophagy and VPS13C in a lysosomal stress response [#25, #27, #32, #33, #40].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that RAB10, despite high identity to RAB8, occupies a distinct perinuclear/Golgi compartment, the first indication of a dedicated trafficking role.\",\n      \"evidence\": \"HA-tagged RAB10 expression and immunofluorescence in CHO/BHK cells\",\n      \"pmids\": [\"7688123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Localization only; no functional consequence tested\", \"Single method, single cell type\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined RAB10 as a core regulator of basolateral endocytic recycling and biosynthetic sorting in polarized cells, placing it upstream of RME-1 recycling endosomes.\",\n      \"evidence\": \"C. elegans rab-10 null genetics with endosomal markers and cargo assays, plus GFP-Rab10 mutant trafficking in polarized MDCK cells\",\n      \"pmids\": [\"16394106\", \"16641372\", \"17132146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct effectors mediating recycling not yet identified\", \"Mechanism of basolateral targeting unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Placed RAB10 epistatically downstream of the AS160/TBC1D4 GAP in insulin-stimulated GLUT4 translocation, identifying the regulated module controlling glucose uptake.\",\n      \"evidence\": \"Dominant-negative/constitutively-active mutants, siRNA, surface GLUT4 flow cytometry in 3T3-L1 adipocytes; clathrin-independent recycling epistasis in C. elegans neurons\",\n      \"pmids\": [\"17403373\", \"17761527\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GEF activating RAB10 not yet identified\", \"Downstream fusion effectors unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated RAB10's selectivity among AS160-substrate Rabs for GLUT4 translocation and showed it associates with myosin V motors via the exon-D domain, linking RAB10 to motor-based positioning.\",\n      \"evidence\": \"Selective siRNA, fractionation, GTP-loading and GAP assays in adipocytes; Co-IP, yeast two-hybrid, FRET and splice-isoform mapping for myosin Va/Vb/Vc\",\n      \"pmids\": [\"18076383\", \"19008234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mostly GDP-state pool—how the small active fraction drives translocation unclear\", \"Functional role of motor binding at vesicles not directly shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended RAB10 function to immune surface receptor supply, ciliary base trafficking, and identified EHBP1 as a conserved recycling effector.\",\n      \"evidence\": \"Dominant-negative/siRNA with surface TLR4 and cytokine readouts plus in vivo lung injury; exocyst Co-IP at cilia; yeast two-hybrid and genetics for EHBP-1 in C. elegans\",\n      \"pmids\": [\"20643919\", \"20576682\", \"20573983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of RAB10-exocyst interaction at cilia not tested\", \"How EHBP1 couples RAB10 to membrane deformation unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified DENND4C as the GEF activating RAB10 for GLUT4 translocation and Lgl1 as a GDI-release activator in axons, defining upstream activation mechanisms in two settings.\",\n      \"evidence\": \"DENND4C siRNA and vesicle fractionation in adipocytes; Co-IP and in vivo cortical knockdown for Lgl1-RAB10-GDI in neurons; VWF secretion knockdown in endothelial cells\",\n      \"pmids\": [\"21454697\", \"21856246\", \"21070595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How distinct GEFs/activators are spatially restricted unknown\", \"Single-lab evidence for several activation routes\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Directly visualized RAB10 marking GLUT4 vesicles undergoing insulin-stimulated fusion and revealed a separable role in ER tubule growth, distinguishing RAB10's trafficking compartments.\",\n      \"evidence\": \"Dual-color TIRF/IRAP-pHluorin fusion imaging and Myosin-Va Co-IP in adipocytes; live ER imaging with PIS/CEPT1 co-localization and GDP-locked mutants\",\n      \"pmids\": [\"22908308\", \"23263280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling RAB10 to lipid-synthesis enzyme enrichment unclear\", \"How one Rab serves both ER and PM trafficking unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined upstream targeting (Crag) and motor-dependent carrier biogenesis (MYO5B exon-D) that route RAB10 vesicles for polarized secretion and axon growth.\",\n      \"evidence\": \"Drosophila genetic epistasis with Crag/Tango1; Co-IP and vesicle-fission assays with MYO5B splice mutants in neurons and zebrafish\",\n      \"pmids\": [\"23369713\", \"23770993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of Crag-type GEF targeting to mammals untested here\", \"How motor binding mechanistically drives Golgi fission unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the RAB10 axonal trafficking machinery (JIP1/kinesin-1, MARCKS docking) and extended its adipocyte cascade to RalA activation, while adding HAS3 recycling.\",\n      \"evidence\": \"Co-IP, GTP-locked pulldowns, transport/docking TIRF assays in neurons; GTP-loading and Rlf rescue in adipocytes; HAS3 Co-IP and HA assays\",\n      \"pmids\": [\"24478353\", \"24662485\", \"25103239\", \"24509846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination between anterograde transport and docking steps unclear\", \"HAS3 finding single-lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped GTP-dependent exocyst engagement (Exoc6/6b) for GLUT4 fusion and defined a RAB10/AMPH-1 mechanism that downregulates RAB-5 and a SEC-10/microtubule tubular endosome network.\",\n      \"evidence\": \"GTP-locked pulldowns and knockdown in adipocytes; Co-IP and genetic epistasis with TBC-2/RAB-5 and SEC-10 in C. elegans\",\n      \"pmids\": [\"26299925\", \"26393361\", \"25301900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exoc6/6b finding single-lab\", \"How RAB10 spatially coordinates GAP recruitment to RAB-5 incompletely defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified RAB10's roles in lipophagy via an EHBP1–EHD2 complex and SEC16A-dependent GLUT4 vesicle biogenesis, and discovered LRRK2 as the major RAB10 switch-II kinase—seeding the disease axis.\",\n      \"evidence\": \"Co-IP of EHBP1/EHD2 complex with LC3 and lipid-droplet readouts; SEC16A co-localization/knockdown in adipocytes; Phos-tag and kinase-dead LRRK2 knockin mice\",\n      \"pmids\": [\"28028537\", \"27354378\", \"27474410\", \"27404358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Thr73 phosphorylation not yet defined at this stage\", \"How EHBP1/EHD2 deform lipid-droplet membranes mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected LRRK2-phosphorylated RAB10 to Parkinson's-relevant defects—impaired OPTN-dependent mitophagy and RILPL1-dependent centrosomal/ciliary defects—and identified KIF13A/B motors for tubular endosome biogenesis.\",\n      \"evidence\": \"Co-IP, mitophagy and patient-cell assays for OPTN; phospho-RAB10 centrosome imaging with RILPL1 knockdown; CRISPR KO and KIF13A/B Co-IP/domain mapping\",\n      \"pmids\": [\"30945962\", \"31428781\", \"30700496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How phosphorylation switches effector preference structurally unresolved at this stage\", \"Physiological cell types where each phospho-pathway dominates unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established the LRRK2–phospho-RAB10 axis in macropinosome maturation and phagosome recruitment in immune cells, and refined the adipocyte TGN GLUT4 storage compartment.\",\n      \"evidence\": \"Selective endocytosis assays, EHBP1L1 competition, chemotaxis readouts in primary macrophages/DCs; isogenic LRRK2 iPSC macrophages; cargo-controlled mobilization assays in adipocytes\",\n      \"pmids\": [\"32853409\", \"32359446\", \"33175605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phagosome co-recruitment study single-lab/Medium\", \"How LRRK2 selects RAB10 among phagosomal Rabs unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mechanistically dissected how phospho-RAB10 blocks ciliogenesis—via RILPL1/RILPL2 and Myosin Va sequestration at the mother centriole preventing TTBK2/CP110 uncapping—and confirmed RILPL1-dependent centrosomal cohesion deficits.\",\n      \"evidence\": \"Live imaging, R1441C MEFs, RAB10/RILPL1 manipulation, CP110/TTBK2 localization; FLIP and phospho-RAB10 pulldowns for Myosin Va; scratch-wound polarization assays\",\n      \"pmids\": [\"33653948\", \"33727250\", \"35776681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of phospho-switch-II RILPL binding not resolved here\", \"Confirmatory centrosomal study Medium confidence\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed RAB10 is a host target of the Salmonella GAP effector SopD, whose inactivation of RAB10 drives Dynamin-2 recruitment and vacuole scission, revealing pathogen exploitation of the GTPase cycle.\",\n      \"evidence\": \"SopD GAP-domain mutagenesis, RAB10 pulldown, Dynamin-2 recruitment and scission assays during infection\",\n      \"pmids\": [\"34349110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RAB10 effectors driving the scission step incompletely defined\", \"Relationship to host LRRK2 signaling untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed that lysosomal positioning gates LRRK2-dependent RAB10 phosphorylation and identified PPM1H as the counteracting phosphatase, linking organelle distribution to the phospho-RAB10 lysosomal tubulation response, and added LDLR/transferrin recycling roles.\",\n      \"evidence\": \"Lysosome-positioning manipulations (ARL8B/SKIP, JIP4, RILP), PPM1H knockdown, pRAB10 imaging; CRISPR KO and recycling assays for LDLR\",\n      \"pmids\": [\"36256825\", \"35753407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"LDLR recycling finding Medium/single-lab\", \"How perinuclear positioning physically enables LRRK2 access unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated RAB10 fine-tunes retrograde TrkB/BDNF signaling endosome sorting in axon terminals and identified an aging mechanism (SDPN-1/KGB-1) that suppresses RAB10 activation by competing with its GEF.\",\n      \"evidence\": \"RAB10 KO and TrkB sorting/retrograde imaging in mouse neurons; aged C. elegans genetics and SDPN-1/DENN-4 Co-IP with barrier assays\",\n      \"pmids\": [\"36897066\", \"37640905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Aging mechanism Medium/single-lab\", \"Conservation of GEF-competition regulation in mammals untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the phospho-RAB10/Myosin Va/RILPL2 axis to migrasome cargo delivery in wound healing and showed phospho-RAB10–VPS13C coupling in the dopaminergic-neuron lysosomal stress response, deepening disease relevance.\",\n      \"evidence\": \"Live imaging, motor/adaptor knockdowns and LRRK2 inhibition with cytokine-delivery and wound-healing readouts; phospho-dependent VPS13C interaction and lysosomal function assays in iPSC dopaminergic neurons\",\n      \"pmids\": [\"39008679\", \"38358348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single phospho-RAB10/RILPL2/Myosin Va module is differentially deployed across organelles unclear\", \"Direct contribution to Parkinson's pathogenesis in vivo not established here\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the Thr73 phosphorylation switch structurally and spatially reroutes RAB10 between its canonical trafficking effectors (Myosin Va, exocyst, EHBP1) and the RILPL1/RILPL2 sequestration program, and how this is integrated across cell types, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structural model of phospho-switch-II effector discrimination in the corpus\", \"Tissue-specific balance of trafficking versus sequestration roles undefined\", \"In vivo causal link from RAB10 dysregulation to Parkinson's phenotypes not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [1, 18, 34]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 8, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [5, 7, 45, 46]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5, 6, 10, 26]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [28, 32, 33, 35]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [36, 40]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [11, 32]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 3, 23, 31]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [22, 27]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 29]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [32, 33]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 14, 15]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [6, 7, 37]}\n    ],\n    \"complexes\": [\"EHBP1-EHD2 complex\", \"exocyst\", \"kinesin-1/JIP1/Rab10 complex\"],\n    \"partners\": [\"MYO5A\", \"EHBP1\", \"RILPL1\", \"RILPL2\", \"LRRK2\", \"KIF13A\", \"OPTN\", \"SEC16A\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}