{"gene":"RAB3IP","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1995,"finding":"Rabin3 (RAB3IP) was identified as a novel protein that specifically interacts with Rab3A and Rab3D (but not Rab3C, Rab2, Ran, or Ras) via the effector domain of Rab3A, as shown by yeast two-hybrid and GST pulldown. The interaction requires the Rab3A effector domain (mutations F51L, V55E, G56D abolish binding). The protein contains a coiled-coil domain and a region with similarity to yeast Sec2p.","method":"Yeast two-hybrid, GST pulldown, point mutagenesis of Rab3A effector domain","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding assay with mutagenesis, original discovery paper","pmids":["7532276"],"is_preprint":false},{"year":2002,"finding":"RAB3IP (human homolog of Rabin3) interacts directly with the cancer-related protein SSX2 via SSX2's N-terminal moiety, as shown by yeast two-hybrid and GST pulldown. Coexpression of RAB3IP and SSX2 causes relocalization of normally cytoplasmic RAB3IP to the nucleus.","method":"Yeast two-hybrid, GST pulldown, immunofluorescence of transfected cells","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal yeast two-hybrid plus in vitro GST pulldown confirming direct interaction; single lab","pmids":["12007189"],"is_preprint":false},{"year":2005,"finding":"Rabin8 (human) and Rabin3 (rat equivalent, RAB3IP orthologs) function as guanine nucleotide exchange factors (GEFs) for Rab8 but not for Rab3A or Rab5. Endogenous and ectopic Rabin8 colocalizes with cortical actin, and this association is increased by cytochalasin D and phorbol esters, which also induce translocation of both Rabin8 and Rab8 to lamellipodia-like structures. Coexpression with dominant-negative Rab8 causes Rabin8 to accumulate on vesicular structures in cell protrusions.","method":"Nucleotide exchange assay, live-cell imaging, yeast two-hybrid, dominant-negative expression","journal":"Methods in enzymology","confidence":"High","confidence_rationale":"Tier 1 — in vitro GEF activity assay with substrate specificity determination, functional localization studies","pmids":["16473595"],"is_preprint":false},{"year":2011,"finding":"Upon serum withdrawal, Rabin8 relocalizes to Rab11-positive vesicles that are transported to the centrosome to initiate ciliogenesis. Rab11-GTP associates with the Rabin8 C-terminal region and is required for Rabin8 preciliary membrane trafficking to the centrosome. The TRAPPII complex associates with the Rabin8 N-terminal domain, colocalizes with centrosomal Rabin8, and is required for Rabin8 preciliary targeting and ciliogenesis.","method":"Live-cell microscopy, tandem affinity purification/mass spectrometry, Co-IP, siRNA knockdown, zebrafish epistasis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (live imaging, TAP-MS, Co-IP, genetic epistasis in zebrafish), highly cited foundational paper","pmids":["21273506"],"is_preprint":false},{"year":2011,"finding":"Rabin8 (RAB3IP) interacts with the GTPase Rheb by co-immunoprecipitation, and overexpression of Rabin8 suppresses phosphorylation of Ser235/Ser236 in ribosomal protein S6 (a downstream readout of mTORC1), while Rabin8 siRNA knockdown increases this phosphorylation, suggesting Rabin8 negatively regulates mTORC1 signaling.","method":"Co-immunoprecipitation, siRNA knockdown, Western blotting","journal":"Acta naturae","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP without reciprocal validation; single lab, single methods","pmids":["22649696"],"is_preprint":false},{"year":2012,"finding":"NDR1/2 kinases phosphorylate Rabin8 (RAB3IP) in the brain, as identified by chemical genetics (analog-sensitive kinase allele plus mass spectrometry). NDR1/2 activity promotes dendritic spine development, and Rabin8 was shown to regulate spine development downstream of NDR1/2.","method":"Chemical genetics (analog-sensitive kinase), mass spectrometry substrate identification, dominant-negative/constitutively active expression, siRNA","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 — chemical genetic substrate identification with MS, validated by functional loss-of-function studies; highly cited","pmids":["22445341"],"is_preprint":false},{"year":2013,"finding":"NDR2 kinase phosphorylates Rabin8 (RAB3IP) at Ser-272. This phosphorylation is required for ciliogenesis: the non-phosphorylatable S272A mutant causes accumulation of Rabin8/Rab11-containing vesicles at the pericentrosome. Mechanistically, Rabin8 binds GTP-bound Rab11 and phosphatidylserine (PS) on pericentrosomal vesicles, and NDR2-mediated S272 phosphorylation (mimicked by S272E) decreases Rabin8 affinity for PS but increases its affinity for Sec15 (an exocyst component), thereby promoting local Rab8 activation and ciliary membrane formation.","method":"In vitro kinase assay, phospho-mimetic/non-phosphorylatable mutants, lipid-binding assays, Co-IP, live-cell imaging, siRNA knockdown","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay plus mutagenesis plus lipid-binding assay plus functional ciliogenesis readout; multiple orthogonal methods","pmids":["23435566"],"is_preprint":false},{"year":2013,"finding":"Rabin8 (RAB3IP) catalyzes guanine nucleotide exchange on Rab8 through a defined three-step mechanism: formation of a ternary G-protein·GEF·GDP complex, an intermediary nucleotide-free binary G-protein·GEF complex, and a ternary G-protein·GEF·GTP complex. Structural snapshots of each intermediate were obtained and enzyme kinetics were characterized.","method":"In vitro GEF activity assay, structural analysis (crystal snapshots), kinetic characterization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — biochemical reconstitution plus structural snapshots with thorough enzymatic characterization","pmids":["24072714"],"is_preprint":false},{"year":2015,"finding":"The Arf and Rab11 effector FIP3 (RAB11FIP3) coordinates interactions of ASAP1 and Rab11a with Rabin8 (RAB3IP) during ciliary receptor (rhodopsin) trafficking. FIP3 competes with rhodopsin for ASAP1 binding, displacing it from an Arf4-GTP/ASAP1 complex, and shapes a binding pocket for Rabin8 within the ASAP1-Rab11a-FIP3 targeting complex, facilitating assembly of the Rab11-Rabin8-Rab8 cascade during ciliary receptor trafficking.","method":"Co-IP, siRNA knockdown with fluorescence microscopy, competitive binding assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and functional knockdown with defined receptor mislocalization phenotype; single lab","pmids":["25673879"],"is_preprint":false},{"year":2015,"finding":"Rabin8 (RAB3IP) suppresses autophagosome formation independently of its Rab8-GEF catalytic activity. Depletion of Rabin8 promotes nutrient starvation-induced autophagosome formation; depletion of Rab8 does not affect autophagosome formation. A GEF-domain mutant of Rabin8 can revert the Rabin8 depletion-induced increase in autophagosomes, but a non-phosphorylatable S272A mutant cannot, indicating that NDR kinase-mediated phosphorylation at Ser-272 is required for this suppressive function. The suppressive activity is mediated by the non-conserved C-terminal region of Rabin8.","method":"siRNA knockdown, GEF-domain mutants, phospho-mutants, autophagosome quantification by fluorescence microscopy, Western blotting","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mutants tested with defined autophagy phenotype; single lab with orthogonal approaches","pmids":["25787272"],"is_preprint":false},{"year":2019,"finding":"TRAPPC14 (C7orf43/MAP11) directly binds to Rabin8 (RAB3IP) via a region within Rabin8, mediates Rabin8 association with the TRAPPII complex, and is required for Rabin8 centrosome accumulation and ciliogenesis. TRAPPC14 also interacts with distal appendage proteins FBF1 and CEP83, which are required for GFP-Rabin8 centrosomal accumulation, supporting a role for TRAPPII in tethering preciliary vesicles to the mother centriole.","method":"MS-based interaction screen, reciprocal Co-IP, siRNA knockdown, ciliogenesis assays, zebrafish embryo knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — MS interactome plus reciprocal Co-IP, direct binding shown, functional validation in two model systems","pmids":["31467083"],"is_preprint":false},{"year":2019,"finding":"PINK1-dependent phosphorylation of Rab8a at Ser111 impairs Rabin8-mediated nucleotide exchange. Although Ser111 is not at the Rab8a-Rabin8 interface, S111E (phosphomimetic) and pS111 establish an intramolecular interaction with Arg79 in Rab8a that perturbs a favorable Rab8a-Arg79 to Rabin8-Asp187 intermolecular salt bridge, decreasing Rabin8 binding affinity and reducing the nucleotide exchange rate by >80%.","method":"Molecular dynamics simulations, free energy calculations, in vitro GEF activity assay with Rab8a mutants","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 for in vitro assay, but computational mechanism supported by single experimental validation; single lab","pmids":["31361120"],"is_preprint":false},{"year":2023,"finding":"CENTLEIN directly interacts with Rabin8 (RAB3IP) through a 31-amino acid sequence in the 200-230 region of the Rabin8 GEF domain. CENTLEIN depletion causes persistent accumulation of Rabin8 at the pericentrosome and primary cilium loss. Rescue experiments with CENTLEIN lacking the Rabin8-binding site fail to restore ciliogenesis, and expression of activated RAB8A partially reverses cilium loss in CENTLEIN-null cells.","method":"Co-IP, deletion mapping, siRNA/CRISPR knockdown, rescue with mutants, ciliogenesis assays","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — direct interaction mapped to defined domain, functional rescue experiments; single lab","pmids":["37475549"],"is_preprint":false},{"year":2024,"finding":"Rabin8 (RAB3IP) acts as the guanine exchange factor activating Rab8 at the cell contact area downstream of low-affinity LFA1 outside-in signaling, independent of Rap1. Activated Rab8 then promotes intracellular transport and accumulation of LFA1 at contact membranes, increasing LFA1 avidity (density/frequency of ICAM1 interactions) rather than affinity.","method":"Super-resolution microscopy, GTP-bound Rab8 overexpression, Rab8 inactivation, single-molecule imaging on supported lipid bilayer","journal":"PNAS nexus","confidence":"Medium","confidence_rationale":"Tier 2 — live imaging with functional Rab8 manipulation and single-molecule readout; single lab","pmids":["39170909"],"is_preprint":false},{"year":2025,"finding":"In Xenopus rod photoreceptors, Rabin8 (RAB3IP) accumulates at Golgi exit sites (TGN) through Rab11 binding-dependent membrane association, where it is phosphorylated at S272 by NDR2 kinase. NDR2 and Rabin8 both interact with the RTC-associated R-SNARE VAMP7 at the TGN. Phosphomimetic S272E-Rabin8 integrates into rhodopsin transport carriers (RTCs) and is subsequently functionalized by Rabin8's Rab8-GEF activity; non-phosphorylatable S272A-Rabin8 causes GES enlargement, suggesting bypass of RTCs and dysfunctional rhodopsin Golgi-to-cilia trafficking.","method":"Xenopus transgenic photoreceptors, GFP-tagged wild-type and mutant Rabin8 expression, Co-IP with VAMP7, live imaging","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — transgenic animal model with mutant rescue and Co-IP; single lab, single paper","pmids":["39774853"],"is_preprint":false}],"current_model":"RAB3IP (Rabin8) is a guanine nucleotide exchange factor (GEF) that activates Rab8 GTPase through a three-step mechanism, and is itself regulated by a multi-step pathway in which Rab11-GTP recruits Rabin8 to pericentrosomal vesicles (via its C-terminal region), the TRAPPII complex (linked by TRAPPC14) tethers Rabin8-bearing vesicles to the mother centriole, NDR2 kinase phosphorylates Rabin8 at Ser-272 to switch its binding from phosphatidylserine to the exocyst component Sec15, thereby enabling local Rab8 activation and ciliary membrane assembly; additionally, Rabin8 independently suppresses autophagosome formation via its C-terminal region and NDR-mediated S272 phosphorylation, interacts with Rheb to modulate mTORC1 signaling, mediates Rab8-dependent LFA1 avidity in lymphocytes, and can be relocalized to the nucleus by SSX2."},"narrative":{"teleology":[{"year":1995,"claim":"The initial identification of Rabin3 as a Rab3A/3D-interacting protein with Sec2p homology established RAB3IP as a potential Rab-regulatory factor, defining the effector-domain dependence of the interaction.","evidence":"Yeast two-hybrid and GST pulldown with Rab3A effector-domain point mutants","pmids":["7532276"],"confidence":"High","gaps":["GEF activity was not tested","Physiological function of the Rab3A interaction remained unclear","Endogenous localization not determined"]},{"year":2005,"claim":"Demonstration that Rabin8 functions as a GEF for Rab8 (not Rab3A or Rab5) redefined the protein's enzymatic identity and linked it to Rab8-dependent actin-associated membrane dynamics.","evidence":"In vitro nucleotide exchange assay with substrate specificity panel, live-cell imaging of cortical actin colocalization","pmids":["16473595"],"confidence":"High","gaps":["Catalytic mechanism and kinetic parameters unknown","Upstream regulation of GEF activity not addressed"]},{"year":2011,"claim":"Establishing that Rab11-GTP recruits Rabin8 to pericentrosomal vesicles and that the TRAPPII complex targets Rabin8 to the centrosome solved how a cytoplasmic GEF is spatially restricted for ciliogenesis, defining the Rab11→Rabin8→Rab8 cascade.","evidence":"Live-cell microscopy, TAP-MS, Co-IP, siRNA knockdown, zebrafish genetic epistasis","pmids":["21273506"],"confidence":"High","gaps":["Phosphoregulation of Rabin8 not yet known","Molecular link between TRAPPII and mother centriole unresolved","Role of NDR kinases not yet established"]},{"year":2012,"claim":"Identification of Rabin8 as an NDR1/2 kinase substrate placed it downstream of a signaling kinase in dendritic spine development, revealing a neuronal function beyond ciliogenesis.","evidence":"Chemical genetics with analog-sensitive NDR kinase allele and mass spectrometry substrate identification, validated by siRNA","pmids":["22445341"],"confidence":"High","gaps":["Specific phosphorylation site(s) not mapped in this study","Mechanism linking phosphorylation to spine morphogenesis unclear"]},{"year":2013,"claim":"Mapping NDR2 phosphorylation to Ser-272 and showing it switches Rabin8 binding from phosphatidylserine to Sec15 provided a mechanistic explanation for how kinase signaling licenses vesicle-to-ciliary-membrane transition, while structural characterization of the three-step GEF mechanism defined the catalytic cycle.","evidence":"In vitro kinase assay, phosphomimetic/non-phosphorylatable mutants, lipid-binding assays, structural snapshots of GEF intermediates, enzyme kinetics","pmids":["23435566","24072714"],"confidence":"High","gaps":["In vivo structural intermediates not captured","Whether other kinases phosphorylate additional sites unknown"]},{"year":2015,"claim":"Discovery that Rabin8 suppresses autophagosome formation independently of its Rab8-GEF activity—requiring NDR-mediated S272 phosphorylation and the C-terminal region—revealed a non-canonical function, while the FIP3-ASAP1-Rab11a complex was shown to assemble and deliver Rabin8 during ciliary receptor (rhodopsin) trafficking.","evidence":"siRNA with GEF-domain mutants and phospho-mutants for autophagy; Co-IP and competitive binding assays for FIP3/ASAP1 complex","pmids":["25787272","25673879"],"confidence":"Medium","gaps":["Direct target of autophagy suppression unknown","Whether FIP3 mechanism operates beyond photoreceptors not tested","Autophagy suppression not validated in vivo"]},{"year":2019,"claim":"TRAPPC14 was identified as the direct link between Rabin8 and the TRAPPII complex, connecting Rabin8-bearing vesicles to distal appendage proteins FBF1/CEP83 at the mother centriole, while PINK1-dependent phosphorylation of Rab8a at Ser111 was shown to impair Rabin8-mediated nucleotide exchange by disrupting an intermolecular salt bridge.","evidence":"MS interaction screen with reciprocal Co-IP, ciliogenesis assays in cells and zebrafish for TRAPPC14; molecular dynamics plus in vitro GEF assay for PINK1/Rab8a","pmids":["31467083","31361120"],"confidence":"High","gaps":["Whether PINK1-Rab8a phosphorylation modulates ciliogenesis in vivo not tested","Structural basis of TRAPPC14-Rabin8 interaction not resolved"]},{"year":2023,"claim":"CENTLEIN was shown to directly bind the Rabin8 GEF domain (residues 200–230) and is required for Rabin8 release from the pericentrosome, adding a new regulatory step to pericentrosomal Rab8 activation during ciliogenesis.","evidence":"Co-IP, deletion mapping, CRISPR knockout with rescue and ciliogenesis assays","pmids":["37475549"],"confidence":"Medium","gaps":["Mechanism by which CENTLEIN promotes Rabin8 release not defined","Whether CENTLEIN competes with or cooperates with TRAPPC14 unknown"]},{"year":2024,"claim":"Rabin8 was established as the GEF activating Rab8 downstream of LFA1 outside-in signaling in lymphocytes, driving integrin avidity rather than affinity—extending Rabin8 function to immune cell adhesion.","evidence":"Super-resolution and single-molecule imaging on supported lipid bilayers with Rab8 manipulation","pmids":["39170909"],"confidence":"Medium","gaps":["Upstream signal connecting LFA1 to Rabin8 activation not identified","In vivo immune phenotype of Rabin8 loss not assessed"]},{"year":2025,"claim":"In Xenopus photoreceptors, Rabin8 accumulates at TGN Golgi exit sites through Rab11-dependent recruitment, interacts with VAMP7 on rhodopsin transport carriers, and requires S272 phosphorylation for proper RTC integration, providing an in vivo trafficking itinerary for Rabin8 during Golgi-to-cilia transport.","evidence":"Xenopus transgenic photoreceptors expressing WT and mutant GFP-Rabin8, Co-IP with VAMP7, live imaging","pmids":["39774853"],"confidence":"Medium","gaps":["Whether VAMP7 interaction is direct or bridged not determined","Mammalian in vivo validation lacking"]},{"year":null,"claim":"Key unresolved questions include the molecular target through which Rabin8 suppresses autophagy independently of Rab8, the structural basis of the TRAPPC14–Rabin8 and CENTLEIN–Rabin8 interactions, whether PINK1-mediated Rab8a phosphorylation is physiologically relevant for ciliogenesis or neurodegeneration, and the in vivo consequences of Rabin8 loss in immune function.","evidence":"","pmids":[],"confidence":"Low","gaps":["Direct autophagy target of Rabin8 unidentified","No high-resolution structure of Rabin8 in complex with TRAPPC14 or CENTLEIN","No genetic model linking Rabin8 to a Mendelian ciliopathy"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[2,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,7,6]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3,6,10,12]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,6,14]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,6,10,14]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[3,6,10,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,13]}],"complexes":["TRAPPII complex (via TRAPPC14)"],"partners":["RAB8A","RAB11A","TRAPPC14","SEC15","NDR2","CENTLEIN","FIP3","VAMP7"],"other_free_text":[]},"mechanistic_narrative":"RAB3IP (Rabin8) is a guanine nucleotide exchange factor (GEF) for Rab8 that operates at the nexus of vesicle trafficking, ciliogenesis, and membrane remodeling. Rabin8 catalyzes Rab8 nucleotide exchange through a three-step mechanism involving sequential ternary and binary intermediates, and is recruited to pericentrosomal Rab11-positive vesicles via its C-terminal region, where the TRAPPII complex (linked through TRAPPC14) tethers these vesicles to the mother centriole for ciliary membrane assembly [PMID:24072714, PMID:21273506, PMID:31467083]. NDR2 kinase phosphorylates Rabin8 at Ser-272, switching its binding from phosphatidylserine to the exocyst subunit Sec15, thereby licensing local Rab8 activation and ciliary membrane growth; this same phosphorylation event is required for Rabin8's GEF-independent suppression of autophagosome formation [PMID:23435566, PMID:25787272]. Beyond ciliogenesis, Rabin8-activated Rab8 drives LFA1 accumulation at lymphocyte contact membranes to increase integrin avidity and mediates rhodopsin transport carrier formation at the trans-Golgi network in photoreceptors [PMID:39170909, PMID:39774853]."},"prefetch_data":{"uniprot":{"accession":"Q96QF0","full_name":"Rab-3A-interacting protein","aliases":["Rabin-3","Rabin8","SSX2-interacting protein"],"length_aa":476,"mass_kda":53.0,"function":"Guanine nucleotide exchange factor (GEF) which may activate RAB8A and RAB8B (PubMed:12221131, PubMed:26824392). Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form (PubMed:12221131, PubMed:26824392). Mediates the release of GDP from RAB8A and RAB8B but not from RAB3A or RAB5 (PubMed:20937701, PubMed:26824392). Modulates actin organization and promotes polarized transport of RAB8A-specific vesicles to the cell surface (PubMed:12221131). Together with RAB11A, RAB8A, the exocyst complex, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis (PubMed:20890297). Part of the ciliary targeting complex containing Rab11, ASAP1, RAB3IP and RAB11FIP3 and ARF4 that promotes RAB3IP preciliary vesicle trafficking to mother centriole and ciliogenesis initiation (PubMed:25673879, PubMed:31204173)","subcellular_location":"Cytoplasm; Nucleus; Cytoplasm, cytoskeleton; Cell projection, lamellipodium; Vesicle; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q96QF0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB3IP","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SF3A1","stoichiometry":0.2},{"gene":"SF3B1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RAB3IP","total_profiled":1310},"omim":[{"mim_id":"608690","title":"SSX2-INTERACTING PROTEIN; SSX2IP","url":"https://www.omim.org/entry/608690"},{"mim_id":"608686","title":"RAB3A-INTERACTING PROTEIN; RAB3IP","url":"https://www.omim.org/entry/608686"},{"mim_id":"608132","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 8; TTC8","url":"https://www.omim.org/entry/608132"},{"mim_id":"607968","title":"PARATHYROID HORMONE-RESPONSIVE B1 GENE","url":"https://www.omim.org/entry/607968"},{"mim_id":"607590","title":"BBS7 GENE; BBS7","url":"https://www.omim.org/entry/607590"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Centrosome","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"choroid plexus","ntpm":109.6}],"url":"https://www.proteinatlas.org/search/RAB3IP"},"hgnc":{"alias_symbol":["RABIN3","FLJ22548","RABIN8"],"prev_symbol":[]},"alphafold":{"accession":"Q96QF0","domains":[{"cath_id":"-","chopping":"328-377_386-470","consensus_level":"medium","plddt":94.6587,"start":328,"end":470},{"cath_id":"1.20.5","chopping":"167-258","consensus_level":"medium","plddt":96.0387,"start":167,"end":258}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QF0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QF0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QF0-F1-predicted_aligned_error_v6.png","plddt_mean":70.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB3IP","jax_strain_url":"https://www.jax.org/strain/search?query=RAB3IP"},"sequence":{"accession":"Q96QF0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96QF0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96QF0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QF0"}},"corpus_meta":[{"pmid":"21273506","id":"PMC_21273506","title":"Primary cilia membrane assembly is initiated by Rab11 and transport protein particle II (TRAPPII) complex-dependent trafficking of Rabin8 to the centrosome.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21273506","citation_count":346,"is_preprint":false},{"pmid":"22445341","id":"PMC_22445341","title":"Chemical genetic identification of NDR1/2 kinase substrates AAK1 and Rabin8 Uncovers their roles in dendrite arborization and spine development.","date":"2012","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/22445341","citation_count":114,"is_preprint":false},{"pmid":"30738012","id":"PMC_30738012","title":"LncRNA HOTAIR targets miR-126-5p to promote the progression of Parkinson's disease through RAB3IP.","date":"2019","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30738012","citation_count":85,"is_preprint":false},{"pmid":"23435566","id":"PMC_23435566","title":"NDR2-mediated Rabin8 phosphorylation is crucial for ciliogenesis by switching binding specificity from phosphatidylserine to Sec15.","date":"2013","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/23435566","citation_count":83,"is_preprint":false},{"pmid":"7532276","id":"PMC_7532276","title":"Interaction cloning of Rabin3, a novel protein that associates with the Ras-like GTPase Rab3A.","date":"1995","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7532276","citation_count":71,"is_preprint":false},{"pmid":"24072714","id":"PMC_24072714","title":"Intermediates in the guanine nucleotide exchange reaction of Rab8 protein catalyzed by guanine nucleotide exchange factors Rabin8 and GRAB.","date":"2013","source":"The Journal of biological 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Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30519341","citation_count":35,"is_preprint":false},{"pmid":"34935056","id":"PMC_34935056","title":"MicroRNA‑126 protects SH‑SY5Y cells from ischemia/reperfusion injury‑induced apoptosis by inhibiting RAB3IP.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/34935056","citation_count":34,"is_preprint":false},{"pmid":"32442477","id":"PMC_32442477","title":"Long noncoding RNA NEAT1 knockdown inhibits MPP+-induced apoptosis, inflammation and cytotoxicity in SK-N-SH cells by regulating miR-212-5p/RAB3IP axis.","date":"2020","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/32442477","citation_count":31,"is_preprint":false},{"pmid":"31467083","id":"PMC_31467083","title":"The C7orf43/TRAPPC14 component links the TRAPPII complex to Rabin8 for preciliary vesicle tethering at the mother centriole during ciliogenesis.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31467083","citation_count":25,"is_preprint":false},{"pmid":"33208053","id":"PMC_33208053","title":"LINC00943 knockdown attenuates MPP+-induced neuronal damage via miR-15b-5p/RAB3IP axis in SK-N-SH cells.","date":"2020","source":"Neurological research","url":"https://pubmed.ncbi.nlm.nih.gov/33208053","citation_count":21,"is_preprint":false},{"pmid":"25787272","id":"PMC_25787272","title":"Rabin8 suppresses autophagosome formation independently of its guanine nucleotide-exchange activity towards Rab8.","date":"2015","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25787272","citation_count":11,"is_preprint":false},{"pmid":"16473595","id":"PMC_16473595","title":"Purification and functional properties of a Rab8-specific GEF (Rabin3) in action remodeling and polarized transport.","date":"2005","source":"Methods in 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elegans</i>","date":"2025-06-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.09.658633","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13596,"output_tokens":4316,"usd":0.052764},"stage2":{"model":"claude-opus-4-6","input_tokens":7729,"output_tokens":3024,"usd":0.171368},"total_usd":0.224132,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Rabin3 (RAB3IP) was identified as a novel protein that specifically interacts with Rab3A and Rab3D (but not Rab3C, Rab2, Ran, or Ras) via the effector domain of Rab3A, as shown by yeast two-hybrid and GST pulldown. The interaction requires the Rab3A effector domain (mutations F51L, V55E, G56D abolish binding). The protein contains a coiled-coil domain and a region with similarity to yeast Sec2p.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, point mutagenesis of Rab3A effector domain\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assay with mutagenesis, original discovery paper\",\n      \"pmids\": [\"7532276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RAB3IP (human homolog of Rabin3) interacts directly with the cancer-related protein SSX2 via SSX2's N-terminal moiety, as shown by yeast two-hybrid and GST pulldown. Coexpression of RAB3IP and SSX2 causes relocalization of normally cytoplasmic RAB3IP to the nucleus.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, immunofluorescence of transfected cells\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal yeast two-hybrid plus in vitro GST pulldown confirming direct interaction; single lab\",\n      \"pmids\": [\"12007189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Rabin8 (human) and Rabin3 (rat equivalent, RAB3IP orthologs) function as guanine nucleotide exchange factors (GEFs) for Rab8 but not for Rab3A or Rab5. Endogenous and ectopic Rabin8 colocalizes with cortical actin, and this association is increased by cytochalasin D and phorbol esters, which also induce translocation of both Rabin8 and Rab8 to lamellipodia-like structures. Coexpression with dominant-negative Rab8 causes Rabin8 to accumulate on vesicular structures in cell protrusions.\",\n      \"method\": \"Nucleotide exchange assay, live-cell imaging, yeast two-hybrid, dominant-negative expression\",\n      \"journal\": \"Methods in enzymology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro GEF activity assay with substrate specificity determination, functional localization studies\",\n      \"pmids\": [\"16473595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Upon serum withdrawal, Rabin8 relocalizes to Rab11-positive vesicles that are transported to the centrosome to initiate ciliogenesis. Rab11-GTP associates with the Rabin8 C-terminal region and is required for Rabin8 preciliary membrane trafficking to the centrosome. The TRAPPII complex associates with the Rabin8 N-terminal domain, colocalizes with centrosomal Rabin8, and is required for Rabin8 preciliary targeting and ciliogenesis.\",\n      \"method\": \"Live-cell microscopy, tandem affinity purification/mass spectrometry, Co-IP, siRNA knockdown, zebrafish epistasis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (live imaging, TAP-MS, Co-IP, genetic epistasis in zebrafish), highly cited foundational paper\",\n      \"pmids\": [\"21273506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rabin8 (RAB3IP) interacts with the GTPase Rheb by co-immunoprecipitation, and overexpression of Rabin8 suppresses phosphorylation of Ser235/Ser236 in ribosomal protein S6 (a downstream readout of mTORC1), while Rabin8 siRNA knockdown increases this phosphorylation, suggesting Rabin8 negatively regulates mTORC1 signaling.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, Western blotting\",\n      \"journal\": \"Acta naturae\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP without reciprocal validation; single lab, single methods\",\n      \"pmids\": [\"22649696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NDR1/2 kinases phosphorylate Rabin8 (RAB3IP) in the brain, as identified by chemical genetics (analog-sensitive kinase allele plus mass spectrometry). NDR1/2 activity promotes dendritic spine development, and Rabin8 was shown to regulate spine development downstream of NDR1/2.\",\n      \"method\": \"Chemical genetics (analog-sensitive kinase), mass spectrometry substrate identification, dominant-negative/constitutively active expression, siRNA\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — chemical genetic substrate identification with MS, validated by functional loss-of-function studies; highly cited\",\n      \"pmids\": [\"22445341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NDR2 kinase phosphorylates Rabin8 (RAB3IP) at Ser-272. This phosphorylation is required for ciliogenesis: the non-phosphorylatable S272A mutant causes accumulation of Rabin8/Rab11-containing vesicles at the pericentrosome. Mechanistically, Rabin8 binds GTP-bound Rab11 and phosphatidylserine (PS) on pericentrosomal vesicles, and NDR2-mediated S272 phosphorylation (mimicked by S272E) decreases Rabin8 affinity for PS but increases its affinity for Sec15 (an exocyst component), thereby promoting local Rab8 activation and ciliary membrane formation.\",\n      \"method\": \"In vitro kinase assay, phospho-mimetic/non-phosphorylatable mutants, lipid-binding assays, Co-IP, live-cell imaging, siRNA knockdown\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus mutagenesis plus lipid-binding assay plus functional ciliogenesis readout; multiple orthogonal methods\",\n      \"pmids\": [\"23435566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rabin8 (RAB3IP) catalyzes guanine nucleotide exchange on Rab8 through a defined three-step mechanism: formation of a ternary G-protein·GEF·GDP complex, an intermediary nucleotide-free binary G-protein·GEF complex, and a ternary G-protein·GEF·GTP complex. Structural snapshots of each intermediate were obtained and enzyme kinetics were characterized.\",\n      \"method\": \"In vitro GEF activity assay, structural analysis (crystal snapshots), kinetic characterization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical reconstitution plus structural snapshots with thorough enzymatic characterization\",\n      \"pmids\": [\"24072714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The Arf and Rab11 effector FIP3 (RAB11FIP3) coordinates interactions of ASAP1 and Rab11a with Rabin8 (RAB3IP) during ciliary receptor (rhodopsin) trafficking. FIP3 competes with rhodopsin for ASAP1 binding, displacing it from an Arf4-GTP/ASAP1 complex, and shapes a binding pocket for Rabin8 within the ASAP1-Rab11a-FIP3 targeting complex, facilitating assembly of the Rab11-Rabin8-Rab8 cascade during ciliary receptor trafficking.\",\n      \"method\": \"Co-IP, siRNA knockdown with fluorescence microscopy, competitive binding assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and functional knockdown with defined receptor mislocalization phenotype; single lab\",\n      \"pmids\": [\"25673879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rabin8 (RAB3IP) suppresses autophagosome formation independently of its Rab8-GEF catalytic activity. Depletion of Rabin8 promotes nutrient starvation-induced autophagosome formation; depletion of Rab8 does not affect autophagosome formation. A GEF-domain mutant of Rabin8 can revert the Rabin8 depletion-induced increase in autophagosomes, but a non-phosphorylatable S272A mutant cannot, indicating that NDR kinase-mediated phosphorylation at Ser-272 is required for this suppressive function. The suppressive activity is mediated by the non-conserved C-terminal region of Rabin8.\",\n      \"method\": \"siRNA knockdown, GEF-domain mutants, phospho-mutants, autophagosome quantification by fluorescence microscopy, Western blotting\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mutants tested with defined autophagy phenotype; single lab with orthogonal approaches\",\n      \"pmids\": [\"25787272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRAPPC14 (C7orf43/MAP11) directly binds to Rabin8 (RAB3IP) via a region within Rabin8, mediates Rabin8 association with the TRAPPII complex, and is required for Rabin8 centrosome accumulation and ciliogenesis. TRAPPC14 also interacts with distal appendage proteins FBF1 and CEP83, which are required for GFP-Rabin8 centrosomal accumulation, supporting a role for TRAPPII in tethering preciliary vesicles to the mother centriole.\",\n      \"method\": \"MS-based interaction screen, reciprocal Co-IP, siRNA knockdown, ciliogenesis assays, zebrafish embryo knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS interactome plus reciprocal Co-IP, direct binding shown, functional validation in two model systems\",\n      \"pmids\": [\"31467083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PINK1-dependent phosphorylation of Rab8a at Ser111 impairs Rabin8-mediated nucleotide exchange. Although Ser111 is not at the Rab8a-Rabin8 interface, S111E (phosphomimetic) and pS111 establish an intramolecular interaction with Arg79 in Rab8a that perturbs a favorable Rab8a-Arg79 to Rabin8-Asp187 intermolecular salt bridge, decreasing Rabin8 binding affinity and reducing the nucleotide exchange rate by >80%.\",\n      \"method\": \"Molecular dynamics simulations, free energy calculations, in vitro GEF activity assay with Rab8a mutants\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 for in vitro assay, but computational mechanism supported by single experimental validation; single lab\",\n      \"pmids\": [\"31361120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CENTLEIN directly interacts with Rabin8 (RAB3IP) through a 31-amino acid sequence in the 200-230 region of the Rabin8 GEF domain. CENTLEIN depletion causes persistent accumulation of Rabin8 at the pericentrosome and primary cilium loss. Rescue experiments with CENTLEIN lacking the Rabin8-binding site fail to restore ciliogenesis, and expression of activated RAB8A partially reverses cilium loss in CENTLEIN-null cells.\",\n      \"method\": \"Co-IP, deletion mapping, siRNA/CRISPR knockdown, rescue with mutants, ciliogenesis assays\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction mapped to defined domain, functional rescue experiments; single lab\",\n      \"pmids\": [\"37475549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Rabin8 (RAB3IP) acts as the guanine exchange factor activating Rab8 at the cell contact area downstream of low-affinity LFA1 outside-in signaling, independent of Rap1. Activated Rab8 then promotes intracellular transport and accumulation of LFA1 at contact membranes, increasing LFA1 avidity (density/frequency of ICAM1 interactions) rather than affinity.\",\n      \"method\": \"Super-resolution microscopy, GTP-bound Rab8 overexpression, Rab8 inactivation, single-molecule imaging on supported lipid bilayer\",\n      \"journal\": \"PNAS nexus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging with functional Rab8 manipulation and single-molecule readout; single lab\",\n      \"pmids\": [\"39170909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Xenopus rod photoreceptors, Rabin8 (RAB3IP) accumulates at Golgi exit sites (TGN) through Rab11 binding-dependent membrane association, where it is phosphorylated at S272 by NDR2 kinase. NDR2 and Rabin8 both interact with the RTC-associated R-SNARE VAMP7 at the TGN. Phosphomimetic S272E-Rabin8 integrates into rhodopsin transport carriers (RTCs) and is subsequently functionalized by Rabin8's Rab8-GEF activity; non-phosphorylatable S272A-Rabin8 causes GES enlargement, suggesting bypass of RTCs and dysfunctional rhodopsin Golgi-to-cilia trafficking.\",\n      \"method\": \"Xenopus transgenic photoreceptors, GFP-tagged wild-type and mutant Rabin8 expression, Co-IP with VAMP7, live imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic animal model with mutant rescue and Co-IP; single lab, single paper\",\n      \"pmids\": [\"39774853\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB3IP (Rabin8) is a guanine nucleotide exchange factor (GEF) that activates Rab8 GTPase through a three-step mechanism, and is itself regulated by a multi-step pathway in which Rab11-GTP recruits Rabin8 to pericentrosomal vesicles (via its C-terminal region), the TRAPPII complex (linked by TRAPPC14) tethers Rabin8-bearing vesicles to the mother centriole, NDR2 kinase phosphorylates Rabin8 at Ser-272 to switch its binding from phosphatidylserine to the exocyst component Sec15, thereby enabling local Rab8 activation and ciliary membrane assembly; additionally, Rabin8 independently suppresses autophagosome formation via its C-terminal region and NDR-mediated S272 phosphorylation, interacts with Rheb to modulate mTORC1 signaling, mediates Rab8-dependent LFA1 avidity in lymphocytes, and can be relocalized to the nucleus by SSX2.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RAB3IP (Rabin8) is a guanine nucleotide exchange factor (GEF) for Rab8 that operates at the nexus of vesicle trafficking, ciliogenesis, and membrane remodeling. Rabin8 catalyzes Rab8 nucleotide exchange through a three-step mechanism involving sequential ternary and binary intermediates, and is recruited to pericentrosomal Rab11-positive vesicles via its C-terminal region, where the TRAPPII complex (linked through TRAPPC14) tethers these vesicles to the mother centriole for ciliary membrane assembly [PMID:24072714, PMID:21273506, PMID:31467083]. NDR2 kinase phosphorylates Rabin8 at Ser-272, switching its binding from phosphatidylserine to the exocyst subunit Sec15, thereby licensing local Rab8 activation and ciliary membrane growth; this same phosphorylation event is required for Rabin8's GEF-independent suppression of autophagosome formation [PMID:23435566, PMID:25787272]. Beyond ciliogenesis, Rabin8-activated Rab8 drives LFA1 accumulation at lymphocyte contact membranes to increase integrin avidity and mediates rhodopsin transport carrier formation at the trans-Golgi network in photoreceptors [PMID:39170909, PMID:39774853].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"The initial identification of Rabin3 as a Rab3A/3D-interacting protein with Sec2p homology established RAB3IP as a potential Rab-regulatory factor, defining the effector-domain dependence of the interaction.\",\n      \"evidence\": \"Yeast two-hybrid and GST pulldown with Rab3A effector-domain point mutants\",\n      \"pmids\": [\"7532276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GEF activity was not tested\", \"Physiological function of the Rab3A interaction remained unclear\", \"Endogenous localization not determined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that Rabin8 functions as a GEF for Rab8 (not Rab3A or Rab5) redefined the protein's enzymatic identity and linked it to Rab8-dependent actin-associated membrane dynamics.\",\n      \"evidence\": \"In vitro nucleotide exchange assay with substrate specificity panel, live-cell imaging of cortical actin colocalization\",\n      \"pmids\": [\"16473595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism and kinetic parameters unknown\", \"Upstream regulation of GEF activity not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that Rab11-GTP recruits Rabin8 to pericentrosomal vesicles and that the TRAPPII complex targets Rabin8 to the centrosome solved how a cytoplasmic GEF is spatially restricted for ciliogenesis, defining the Rab11→Rabin8→Rab8 cascade.\",\n      \"evidence\": \"Live-cell microscopy, TAP-MS, Co-IP, siRNA knockdown, zebrafish genetic epistasis\",\n      \"pmids\": [\"21273506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphoregulation of Rabin8 not yet known\", \"Molecular link between TRAPPII and mother centriole unresolved\", \"Role of NDR kinases not yet established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of Rabin8 as an NDR1/2 kinase substrate placed it downstream of a signaling kinase in dendritic spine development, revealing a neuronal function beyond ciliogenesis.\",\n      \"evidence\": \"Chemical genetics with analog-sensitive NDR kinase allele and mass spectrometry substrate identification, validated by siRNA\",\n      \"pmids\": [\"22445341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphorylation site(s) not mapped in this study\", \"Mechanism linking phosphorylation to spine morphogenesis unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping NDR2 phosphorylation to Ser-272 and showing it switches Rabin8 binding from phosphatidylserine to Sec15 provided a mechanistic explanation for how kinase signaling licenses vesicle-to-ciliary-membrane transition, while structural characterization of the three-step GEF mechanism defined the catalytic cycle.\",\n      \"evidence\": \"In vitro kinase assay, phosphomimetic/non-phosphorylatable mutants, lipid-binding assays, structural snapshots of GEF intermediates, enzyme kinetics\",\n      \"pmids\": [\"23435566\", \"24072714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo structural intermediates not captured\", \"Whether other kinases phosphorylate additional sites unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that Rabin8 suppresses autophagosome formation independently of its Rab8-GEF activity—requiring NDR-mediated S272 phosphorylation and the C-terminal region—revealed a non-canonical function, while the FIP3-ASAP1-Rab11a complex was shown to assemble and deliver Rabin8 during ciliary receptor (rhodopsin) trafficking.\",\n      \"evidence\": \"siRNA with GEF-domain mutants and phospho-mutants for autophagy; Co-IP and competitive binding assays for FIP3/ASAP1 complex\",\n      \"pmids\": [\"25787272\", \"25673879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct target of autophagy suppression unknown\", \"Whether FIP3 mechanism operates beyond photoreceptors not tested\", \"Autophagy suppression not validated in vivo\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"TRAPPC14 was identified as the direct link between Rabin8 and the TRAPPII complex, connecting Rabin8-bearing vesicles to distal appendage proteins FBF1/CEP83 at the mother centriole, while PINK1-dependent phosphorylation of Rab8a at Ser111 was shown to impair Rabin8-mediated nucleotide exchange by disrupting an intermolecular salt bridge.\",\n      \"evidence\": \"MS interaction screen with reciprocal Co-IP, ciliogenesis assays in cells and zebrafish for TRAPPC14; molecular dynamics plus in vitro GEF assay for PINK1/Rab8a\",\n      \"pmids\": [\"31467083\", \"31361120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PINK1-Rab8a phosphorylation modulates ciliogenesis in vivo not tested\", \"Structural basis of TRAPPC14-Rabin8 interaction not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"CENTLEIN was shown to directly bind the Rabin8 GEF domain (residues 200–230) and is required for Rabin8 release from the pericentrosome, adding a new regulatory step to pericentrosomal Rab8 activation during ciliogenesis.\",\n      \"evidence\": \"Co-IP, deletion mapping, CRISPR knockout with rescue and ciliogenesis assays\",\n      \"pmids\": [\"37475549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CENTLEIN promotes Rabin8 release not defined\", \"Whether CENTLEIN competes with or cooperates with TRAPPC14 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Rabin8 was established as the GEF activating Rab8 downstream of LFA1 outside-in signaling in lymphocytes, driving integrin avidity rather than affinity—extending Rabin8 function to immune cell adhesion.\",\n      \"evidence\": \"Super-resolution and single-molecule imaging on supported lipid bilayers with Rab8 manipulation\",\n      \"pmids\": [\"39170909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signal connecting LFA1 to Rabin8 activation not identified\", \"In vivo immune phenotype of Rabin8 loss not assessed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In Xenopus photoreceptors, Rabin8 accumulates at TGN Golgi exit sites through Rab11-dependent recruitment, interacts with VAMP7 on rhodopsin transport carriers, and requires S272 phosphorylation for proper RTC integration, providing an in vivo trafficking itinerary for Rabin8 during Golgi-to-cilia transport.\",\n      \"evidence\": \"Xenopus transgenic photoreceptors expressing WT and mutant GFP-Rabin8, Co-IP with VAMP7, live imaging\",\n      \"pmids\": [\"39774853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether VAMP7 interaction is direct or bridged not determined\", \"Mammalian in vivo validation lacking\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the molecular target through which Rabin8 suppresses autophagy independently of Rab8, the structural basis of the TRAPPC14–Rabin8 and CENTLEIN–Rabin8 interactions, whether PINK1-mediated Rab8a phosphorylation is physiologically relevant for ciliogenesis or neurodegeneration, and the in vivo consequences of Rabin8 loss in immune function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct autophagy target of Rabin8 unidentified\", \"No high-resolution structure of Rabin8 in complex with TRAPPC14 or CENTLEIN\", \"No genetic model linking Rabin8 to a Mendelian ciliopathy\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 7, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3, 6, 10, 12]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 6, 14]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 6, 10, 14]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [3, 6, 10, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 13]}\n    ],\n    \"complexes\": [\n      \"TRAPPII complex (via TRAPPC14)\"\n    ],\n    \"partners\": [\n      \"RAB8A\",\n      \"RAB11A\",\n      \"TRAPPC14\",\n      \"SEC15\",\n      \"NDR2\",\n      \"CENTLEIN\",\n      \"FIP3\",\n      \"VAMP7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}