{"gene":"RAB12","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2011,"finding":"RAB12 regulates constitutive degradation of transferrin receptor (TfR) via a pathway from recycling endosomes to lysosomes, independently of the conventional EGFR degradation pathway. Constitutively active RAB12 reduced TfR protein levels; siRNA knockdown of RAB12 or its upstream activator DENND3 increased TfR levels. Knockdown had no effect on EGFR degradation.","method":"siRNA knockdown, constitutively active mutant overexpression, colocalization with lysosomes, sequential screening of 60 Rab isoforms","journal":"Traffic","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (knockdown, active mutant, colocalization), replicated conceptually in follow-up addendum (PMID:22279614)","pmids":["21718402","22279614"],"is_preprint":false},{"year":2014,"finding":"DENND3 functions as the physiological guanine nucleotide exchange factor (GEF) for RAB12 in mouse embryonic fibroblasts. DENND3 knockdown phenocopied RAB12 knockdown (increased PAT4 levels, increased intracellular amino acids); DENND3 overexpression reduced mTORC1 activity and promoted autophagy in a RAB12-dependent manner, placing DENND3 upstream of RAB12 in controlling PAT4 trafficking from recycling endosomes to lysosomes.","method":"siRNA knockdown, overexpression, epistasis (Rab12-dependent rescue), amino acid concentration measurements, mTORC1 activity assay","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — epistasis by genetic knockdown and overexpression with multiple functional readouts, single lab but multiple orthogonal methods","pmids":["24719330"],"is_preprint":false},{"year":2013,"finding":"RAB12 physically complexes with the autophagy receptor OPTN, and the M98K-OPTN variant shows enhanced colocalization with RAB12. RAB12 is present in autophagosomes, and knockdown of Rab12 increased TfR levels and reduced M98K-OPTN-induced autolysosomes formation and cell death in retinal ganglion cells (RGC-5).","method":"Co-immunoprecipitation, siRNA knockdown, colocalization (fluorescence microscopy), autophagosome formation assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional knockdown with multiple readouts, single lab","pmids":["23357852"],"is_preprint":false},{"year":2016,"finding":"RAB12 is activated in a stimulus-dependent manner in mast cells and promotes microtubule-dependent retrograde transport of secretory granules (SGs) via interaction with the RILP-dynein complex. RILP was identified as a novel RAB12 effector. RAB12 negatively regulates mast cell degranulation.","method":"Pulldown assay (RILP as effector), live-cell imaging of SG transport, knockdown/overexpression with degranulation readout, colocalization","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — effector identification by pulldown plus functional imaging and degranulation assay with multiple orthogonal approaches, single lab","pmids":["26740112"],"is_preprint":false},{"year":2017,"finding":"LRRK2 phosphorylates human RAB12 at Ser106 in a kinase-dependent manner. This was confirmed in HEK293 cells using the selective LRRK2 inhibitor Lu AF58786 in a phosphoproteomic study, and the phosphorylation was reduced by two distinct LRRK2 inhibitors.","method":"Phosphoproteomics (SILAC), LRRK2 inhibitor treatment (Lu AF58786 and second inhibitor), immunoblot validation in HEK293 and human PBMCs","journal":"Scientific Reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — phosphoproteomics with two distinct inhibitors and validation in multiple cell types; replicated in multiple subsequent studies","pmids":["28860483"],"is_preprint":false},{"year":2017,"finding":"DENND3 GEF activity toward RAB12 is regulated through an intramolecular interaction controlled by tyrosine 940, demonstrated by size-exclusion chromatography, FRET, pulldown, and in vitro GEF assays.","method":"Size-exclusion chromatography, FRET, pulldown assay, in vitro GEF assay, point mutagenesis (Y940)","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro GEF assay with mutagenesis plus multiple orthogonal biophysical methods, single lab","pmids":["28249939"],"is_preprint":false},{"year":2014,"finding":"RAB12 is required for efficient retrograde transport of Shiga toxin from early uptake carriers to the trans-Golgi network. RAB12 localizes to Shiga toxin-induced plasma membrane invaginations (clathrin-independent uptake carriers), and RAB12 depletion reduced toxin reaching TGN membranes and partially protected cells against intoxication. Only TGN46 and CI-M6PR steady-state localization was additionally affected.","method":"SILAC/quantitative mass spectrometry, fluorescence microscopy (GFP-RAB12 colocalization), quantitative biochemical toxin transport assay, siRNA knockdown","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification plus functional knockdown with biochemical transport assay, single lab","pmids":["24703428"],"is_preprint":false},{"year":2018,"finding":"DENND3 contains a PHenn domain with a pleckstrin homology subdomain that binds actin through positively charged residues, and this domain mediates an intramolecular interaction with the DENN domain of DENND3. Both actin binding and DENN domain interaction are required for DENND3 function in autophagy (and thus for RAB12 activation).","method":"Structural domain identification, NMR/crystal analysis (structural), pulldown assay, mutational analysis blocking DENN or actin binding, autophagy functional assay","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — structural domain identification plus mutagenesis and functional autophagy assay, single lab","pmids":["29352104"],"is_preprint":false},{"year":2021,"finding":"RAB12 interacts with RILP, RILP-L1, and RILP-L2 independently of each other. Lysine-71 in mouse RAB12 is critical for interaction with RILP-L1 and RILP-L2 but dispensable for RILP binding. A structural model of the RAB12-RILP complex proposes a RILP homodimer interacting with a single active RAB12 molecule via switch I and switch II regions with RILP's RHD domain and C-terminal threonine. Mutational analyses of RILP RHD confirmed its role in secretory granule transport regulation.","method":"Pulldown assay, molecular dynamics simulation, mutational analysis, peptide inhibition assay","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pulldown and mutagenesis with molecular dynamics modeling, single lab but multiple approaches","pmids":["33986343"],"is_preprint":false},{"year":2023,"finding":"RAB12 is a critical activator of LRRK2 kinase for Rab phosphorylation. Knockout of RAB12 markedly decreased phosphoRab10 levels across multiple cell types and knockout mouse tissues in a LRRK2-dependent and PPM1H-reversible manner. AlphaFold modeling revealed RAB12 binds a novel site in the LRRK2 Armadillo domain; residues at this site influence phosphoRab10 and phosphoRab12 levels distinctly from RAB29-mediated LRRK2 activation. RAB12-driven activation did not require RAB12's own phosphorylation.","method":"CRISPR genome-wide screen (flow cytometry for phosphoRab10), RAB12 knockout in multiple cell types and tissues, AlphaFold structural modeling with mutational validation, PPM1H phosphatase epistasis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased genome-wide CRISPR screen validated in multiple cell types and mouse tissues with structural modeling and mutational follow-up; replicated independently in same year (PMID:37874617)","pmids":["37874635"],"is_preprint":false},{"year":2023,"finding":"RAB12 is recruited to damaged lysosomes and facilitates local LRRK2-dependent phosphorylation of RAB10 (pT73) at the lysosome. PD-linked LRRK2 variants (R1441G, VPS35 D620N) increased LRRK2 recruitment to lysosomes and elevated lysosomal pT73-Rab10. This defines a conserved mechanism by which RAB12 responds to lysosomal damage to activate LRRK2 locally.","method":"siRNA screen, lysosome immunopurification, imaging, immunoblot","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — targeted siRNA screen followed by lysosome immunopurification with imaging and biochemical validation; independently corroborates PMID:37874635","pmids":["37874617"],"is_preprint":false},{"year":2023,"finding":"Pathogenic LRRK2 causes perinuclear lysosomal clustering via RAB12 phosphorylation at Ser106; knockout of RAB12 or its effector RILPL1 abolished clustering. Phosphorylated RAB12 accumulates on clustered lysosomes, and phosphorylation increases RAB12's interaction with RILPL1, thereby disrupting lysosomal transport.","method":"RAB12 knockout, RILPL1 knockout, RAB12 re-expression with phospho-site mutants (Ser106), co-immunoprecipitation of phospho-RAB12 with RILPL1, confocal microscopy","journal":"FASEB Journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO, phospho-site mutagenesis, and co-IP with functional lysosome distribution readout in single study; multiple orthogonal approaches","pmids":["37086089"],"is_preprint":false},{"year":2023,"finding":"LRRK2 phosphorylates RAB12 more efficiently in its GDP-bound form than GTP-bound form in vitro, indicating LRRK2 recognizes the nucleotide-determined structural conformation of RAB12. GDP-bound RAB12 is also more susceptible to heat-induced denaturation, as shown by circular dichroism and differential scanning fluorimetry.","method":"In vitro phosphorylation assay (LRRK2 + GDP- vs GTP-bound RAB12), circular dichroism, differential scanning fluorimetry","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro phosphorylation assay with biophysical characterization, single lab, single study","pmids":["37207563"],"is_preprint":false},{"year":2024,"finding":"RAB12 forms a direct complex with LRRK2 whose cryo-EM structure was solved. RAB12 cooperates with LRRK2 to inhibit primary ciliogenesis and regulate centrosome homeostasis in astrocytes by enhancing RAB10 phosphorylation and recruiting RILPL1. These functions require direct RAB12-LRRK2 interaction and LRRK2 kinase activity. Deletion of RAB12 in astrocytes prevented ciliary and centrosome defects caused by PD-linked LRRK2-G2019S.","method":"Cryo-EM structure determination, phosphoproteomics, RAB12 knockout in astrocytes, RILPL1 recruitment assay, primary cilia and centrosome phenotyping","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus phosphoproteomics, genetic KO with multiple functional readouts; replicated in preprint PMID:39071328","pmids":["39343966"],"is_preprint":false},{"year":2023,"finding":"RAB12 and the AP-1 clathrin adaptor complex interact with EGFR and regulate export of newly synthesized (wild-type) EGFR from the trans-Golgi network to the cell surface. Tyrosine 998 on EGFR is critical for AP-1 binding and TGN export. The constitutively active EGFR-L858R mutant bypasses this requirement.","method":"Gene knockout, siRNA knockdown, streptavidin pulldown, co-immunoprecipitation, cell elongation/proliferation assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — gene KO plus co-IP and pulldown with functional readouts, single lab","pmids":["36739948"],"is_preprint":false},{"year":2017,"finding":"Rare missense variants of RAB12 found in dystonia patients showed increased GTPase activity and altered subcellular (lysosomal) distribution compared to wild-type in patient-derived fibroblasts and overexpression models. Soluble transferrin receptor 1 levels were reduced in blood of p.Ile196Val carriers.","method":"GTPase activity assay, subcellular localization imaging in patient fibroblasts and overexpression models, serum TfR1 measurement","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — enzymatic activity assay plus localization in patient cells, single lab, multiple orthogonal methods","pmids":["29057844"],"is_preprint":false},{"year":2023,"finding":"An activating variant of DENND3 (p.L708V) upregulates RAB12 expression, leading to lysosomal degradation of TFR2 and downregulation of hepcidin via the DENND3/RAB12/TFR2 axis, causing iron overload in a mouse AAV model and in patient hepatocytes.","method":"Cell transfection, in vitro lysosomal degradation assay, adeno-associated virus mouse model, liver iron quantification, hepcidin/pSMAD1/5 signaling","journal":"Hepatology International","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo mechanistic pathway validated with AAV mouse model and patient tissue, single lab","pmids":["36729283"],"is_preprint":false},{"year":2024,"finding":"Loss of REP-1 (Rab escort protein 1) in a CHM iPSC-RPE model causes under-prenylation of RAB12. Rab12 knockdown in control RPE cells reduced autophagic flux and increased mTORC1 signaling, phenocopying CHM cells. Gene replacement restored autophagic flux in CHM cells. This identifies RAB12 under-prenylation as a contributor to RPE dysfunction in choroideremia.","method":"CRISPR/Cas9 CHM knockout iPSC-RPE, TMT mass spectrometry (prenylation screen), siRNA knockdown, AAV gene replacement, mTORC1 and autophagic flux assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model with mass spectrometry, siRNA phenocopy, and rescue by gene replacement, single lab","pmids":["38920696"],"is_preprint":false},{"year":2025,"finding":"In mast cells, LRRK1 (not LRRK2) phosphorylates RAB12 in a PKC-dependent manner upon activation by IgE/antigen or substance P. LRRK1-mediated phosphorylation of RAB12 increases its affinity for RILP-L1 and RILP-L2 while reducing binding to RILP, constituting a phosphorylation-driven effector switch.","method":"Pulldown assay, siRNA knockdown of LRRK1 and LRRK2, PKC inhibitor and LRRK2 inhibitor treatment, mast cell activation assays","journal":"Frontiers in Immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — kinase knockdown with effector pulldowns, multiple inhibitors, single lab","pmids":["41357239"],"is_preprint":false},{"year":2026,"finding":"RAB12 is a negative regulator of synaptic vesicle exocytosis and excitatory neurotransmission in vivo. Rab12 KO mice exhibit increased locomotor activity, enhanced presynaptic release probability and excitatory drive onto striatal medium spiny neurons. Live-cell imaging showed Rab12 deletion facilitates and overexpression inhibits synaptic vesicle exocytosis. RAB12 is biochemically enriched in synaptic vesicle-associated fractions.","method":"Rab12 KO mouse model, electrophysiology (striatal slices), live-cell imaging of synaptic vesicle exocytosis, biochemical fractionation, synaptosome proteomics","journal":"NPJ Parkinson's Disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse with electrophysiology, live imaging, and biochemical fractionation; multiple orthogonal methods in single study","pmids":["42031745"],"is_preprint":false},{"year":2026,"finding":"RAB12 is a negative regulator of mitophagy. siRNA and KO of RAB12 augmented clearance of damaged mitochondria basally and after FCCP-induced depolarization across distinct cell types. RAB12 depletion increased mitochondrial content, lowered mitochondrial membrane potential, and reduced mitochondrial DNA damage.","method":"Family-wide siRNA screen (mt-mKeima/YFP-Parkin HeLa cells), RAB12 KO across multiple cell types, mitochondrial content and membrane potential assays, mitochondrial DNA damage measurement","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated screen hit with KO across multiple cell types and multiple mitochondrial readouts; preprint, single lab","pmids":["41959481"],"is_preprint":true},{"year":1996,"finding":"RAB12 protein is associated with atrial secretory granules, demonstrated by GTP-overlay assay and immunogold electron microscopy, suggesting a role in vesicular traffic in these cells.","method":"[32P]GTP-overlay assay, immunogold electron microscopy, immunoprecipitation/immunoblot","journal":"Circulation Research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — biochemical and ultrastructural co-localization, multiple methods, single lab","pmids":["8575079"],"is_preprint":false},{"year":2005,"finding":"RAB12 is associated with small cytoplasmic vesicles (not the Golgi apparatus) in cultured Sertoli cells and NRK cells. When overexpressed, RAB12-associated vesicles accumulate in the perinuclear centrosome region, suggesting a role in vesicular transport from the cell periphery to the perinuclear centrosome region.","method":"Immunohistochemistry, immunofluorescence localization in cultured cells, overexpression analysis","journal":"Molecular Reproduction and Development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by immunofluorescence and overexpression without functional manipulation, single lab","pmids":["15791598"],"is_preprint":false}],"current_model":"RAB12 is a small GTPase that acts as a critical activator of LRRK2 kinase (binding the LRRK2 Armadillo domain, as revealed by cryo-EM), regulates membrane trafficking from recycling endosomes and the trans-Golgi network to lysosomes (controlling degradation of transferrin receptor, PAT4, and EGFR), is recruited to damaged lysosomes to locally amplify LRRK2-mediated phosphorylation of Rab substrates (Rab10, Rab8A), is itself phosphorylated at Ser106 by LRRK2 and at a similar site by LRRK1 in a PKC-dependent manner—phosphorylation shifting effector preference from RILP to RILPL1/RILPL2—and functions in diverse cellular contexts including mast cell secretory granule retrograde transport, primary ciliogenesis and centrosome homeostasis in astrocytes, synaptic vesicle exocytosis, autophagy initiation (via its GEF DENND3), and mitophagy regulation."},"narrative":{"mechanistic_narrative":"RAB12 is a small GTPase that governs membrane trafficking from recycling endosomes and the trans-Golgi network to lysosomes, controlling the degradation and surface delivery of cargoes including the transferrin receptor, the amino-acid transporter PAT4, and EGFR, and thereby coupling endolysosomal flux to mTORC1 signaling and autophagy [PMID:21718402, PMID:22279614, PMID:24719330, PMID:36739948]. Its activation cycle is driven by the GEF DENND3, which is itself autoregulated by an intramolecular interaction between its DENN and actin-binding PHenn domains and acts upstream of RAB12 to promote autophagy and PAT4 trafficking [PMID:24719330, PMID:28249939, PMID:29352104]. Active RAB12 engages the RILP family of effectors—RILP, RILPL1, and RILPL2—to direct microtubule- and dynein-dependent retrograde transport, with RILP binding underlying secretory granule transport and negative regulation of mast cell degranulation [PMID:26740112, PMID:33986343]. RAB12 is a direct, critical activator of LRRK2 kinase: it binds a distinct site on the LRRK2 Armadillo domain (resolved by cryo-EM), and RAB12 loss markedly reduces LRRK2-mediated phosphorylation of Rab10 and Rab8A in a PPM1H-reversible manner independent of RAB12's own phosphorylation [PMID:37874635, PMID:39343966]. RAB12 is recruited to damaged lysosomes where it locally amplifies LRRK2 activity, and pathogenic LRRK2 phosphorylates RAB12 at Ser106, which increases RILPL1 binding and drives perinuclear lysosomal clustering and centrosome/ciliogenesis defects [PMID:37874617, PMID:37086089, PMID:39343966]. Phosphorylation thus acts as an effector switch shifting RAB12 preference from RILP toward RILPL1/RILPL2, a switch also executed by LRRK1 in a PKC-dependent manner in mast cells [PMID:41357239]. RAB12 additionally functions as a negative regulator of synaptic vesicle exocytosis in vivo and of mitophagy [PMID:42031745, PMID:41959481]. Disease-linked variants connect RAB12 to dystonia, while DENND3-driven RAB12 upregulation drives TFR2 degradation and iron overload [PMID:29057844, PMID:36729283].","teleology":[{"year":1996,"claim":"Before any functional assignment, it was unknown whether RAB12 associated with a defined membrane compartment; localizing it to secretory granules established a candidate role in vesicular traffic.","evidence":"GTP-overlay assay and immunogold electron microscopy in atrial cells","pmids":["8575079"],"confidence":"Medium","gaps":["No functional manipulation","Compartment identity in other cell types unresolved"]},{"year":2011,"claim":"The cargo and pathway specificity of RAB12 were unknown; identifying it as a regulator of transferrin receptor degradation from recycling endosomes to lysosomes, distinct from EGFR degradation, defined a dedicated trafficking route.","evidence":"siRNA knockdown, constitutively active mutant, lysosomal colocalization, Rab isoform screen","pmids":["21718402","22279614"],"confidence":"High","gaps":["Effector linking RAB12 to lysosomal delivery not yet identified","Mechanism of cargo selection unknown"]},{"year":2014,"claim":"How RAB12 is activated and integrated with nutrient signaling was unclear; identifying DENND3 as its GEF placed RAB12 in a pathway controlling PAT4 trafficking, mTORC1 activity, and autophagy.","evidence":"siRNA epistasis, overexpression, mTORC1 and amino-acid readouts in MEFs","pmids":["24719330"],"confidence":"High","gaps":["Direct in vitro GEF kinetics not shown here","How DENND3 activity is triggered unresolved"]},{"year":2014,"claim":"RAB12's role beyond endolysosomal degradation was untested; it was shown to be required for retrograde Shiga toxin transport to the TGN, broadening its trafficking remit.","evidence":"SILAC mass spectrometry, GFP-RAB12 imaging, biochemical toxin transport assay, knockdown","pmids":["24703428"],"confidence":"Medium","gaps":["Effector mediating TGN-directed transport not identified","Single-lab finding"]},{"year":2016,"claim":"RAB12 effectors and a physiological context were unknown; identifying RILP as an effector linked RAB12 to dynein-dependent retrograde secretory granule transport and negative control of mast cell degranulation.","evidence":"Pulldown effector identification, live-cell SG imaging, degranulation assay","pmids":["26740112"],"confidence":"High","gaps":["Structural basis of RAB12-RILP binding not yet defined","Stimulus-to-activation signaling incomplete"]},{"year":2017,"claim":"It was unknown whether RAB12 is a kinase substrate; phosphoproteomics established LRRK2 phosphorylates human RAB12 at Ser106, embedding it in the LRRK2 Rab-substrate network.","evidence":"SILAC phosphoproteomics with two LRRK2 inhibitors, immunoblot validation in HEK293 and PBMCs","pmids":["28860483"],"confidence":"High","gaps":["Functional consequence of Ser106 phosphorylation not yet defined","Directionality (RAB12 as activator vs substrate) unresolved"]},{"year":2017,"claim":"How DENND3 GEF activity is controlled was unknown; an intramolecular interaction gated by tyrosine 940 was shown to regulate its activity toward RAB12.","evidence":"SEC, FRET, pulldown, in vitro GEF assay, Y940 mutagenesis","pmids":["28249939"],"confidence":"High","gaps":["Upstream signal regulating Y940 unknown","Physiological trigger for relief of autoinhibition unclear"]},{"year":2017,"claim":"Whether RAB12 variants cause disease was untested; rare missense variants in dystonia patients were found to increase GTPase activity and alter lysosomal distribution, linking RAB12 dysfunction to a human phenotype.","evidence":"GTPase activity assay, patient fibroblast localization, serum TfR1 measurement","pmids":["29057844"],"confidence":"Medium","gaps":["Causality not established by family genetics or rescue","Mechanism connecting variant to dystonia unclear"]},{"year":2018,"claim":"The structural mechanism of DENND3 function was incomplete; a PHenn domain binding actin and the DENN domain was shown to be required for autophagy and thus RAB12 activation.","evidence":"Structural domain analysis, pulldown, mutagenesis, autophagy assay","pmids":["29352104"],"confidence":"Medium","gaps":["Role of actin binding in nucleotide exchange kinetics unresolved","Single-lab structural model"]},{"year":2021,"claim":"How RAB12 selects among RILP-family effectors was unknown; pulldown and modeling showed RILP, RILPL1, and RILPL2 bind independently, with Lys71 critical for RILPL1/L2 but not RILP, defining the structural basis of effector choice.","evidence":"Pulldown, molecular dynamics modeling, mutagenesis, peptide inhibition","pmids":["33986343"],"confidence":"Medium","gaps":["Model not validated by experimental structure","Determinants of in vivo effector switching not addressed"]},{"year":2023,"claim":"Whether RAB12 merely is a LRRK2 substrate or actively regulates LRRK2 was unresolved; an unbiased CRISPR screen established RAB12 as a critical activator binding a novel Armadillo-domain site, distinct from RAB29-mediated activation and independent of RAB12 phosphorylation.","evidence":"Genome-wide CRISPR screen, RAB12 KO in cells and mouse tissues, AlphaFold modeling, PPM1H epistasis","pmids":["37874635"],"confidence":"High","gaps":["Experimental structure of the interaction not yet solved here","How RAB12 nucleotide state couples to activation unclear"]},{"year":2023,"claim":"The subcellular trigger for RAB12-LRRK2 activation was unknown; RAB12 was shown to be recruited to damaged lysosomes to drive local LRRK2-dependent Rab10 phosphorylation, with PD variants enhancing recruitment.","evidence":"siRNA screen, lysosome immunopurification, imaging, immunoblot","pmids":["37874617"],"confidence":"High","gaps":["Sensor mechanism for lysosomal damage unidentified","Link between local activation and downstream pathology incomplete"]},{"year":2023,"claim":"The downstream consequence of RAB12 Ser106 phosphorylation was undefined; it was shown to increase RILPL1 binding and drive pathogenic perinuclear lysosomal clustering, connecting phosphorylation to an effector switch and trafficking defect.","evidence":"RAB12 and RILPL1 KO, Ser106 phospho-mutant re-expression, phospho-RAB12 co-IP, confocal imaging","pmids":["37086089"],"confidence":"High","gaps":["Physiological (non-pathogenic) role of the switch unclear","Quantitative contribution of RILPL2 not addressed"]},{"year":2023,"claim":"Whether LRRK2 reads RAB12 nucleotide state was untested; in vitro phosphorylation showed GDP-bound RAB12 is the preferred substrate, indicating conformational recognition.","evidence":"In vitro phosphorylation of GDP- vs GTP-RAB12, circular dichroism, differential scanning fluorimetry","pmids":["37207563"],"confidence":"Medium","gaps":["In vivo relevance of GDP-state preference unestablished","Single in vitro study"]},{"year":2023,"claim":"RAB12's role in biosynthetic EGFR trafficking was unknown; it was shown to act with the AP-1 adaptor to export newly synthesized EGFR from the TGN, with EGFR Y998 governing AP-1 binding.","evidence":"Gene KO, siRNA, streptavidin pulldown, co-IP, proliferation assays","pmids":["36739948"],"confidence":"Medium","gaps":["Direct RAB12-AP-1 interaction mechanism unclear","Single-lab finding"]},{"year":2023,"claim":"A disease mechanism via the DENND3/RAB12 axis was untested; a DENND3 activating variant was shown to upregulate RAB12, driving TFR2 lysosomal degradation, hepcidin downregulation, and iron overload.","evidence":"Transfection, lysosomal degradation assay, AAV mouse model, liver iron and hepcidin signaling, patient hepatocytes","pmids":["36729283"],"confidence":"Medium","gaps":["Direct RAB12-TFR2 trafficking step not structurally defined","Generality beyond the DENND3 variant unclear"]},{"year":2024,"claim":"The RAB12-LRRK2 interaction lacked an experimental structure and a cellular phenotype; cryo-EM resolved the direct complex and RAB12 was shown to cooperate with LRRK2 to inhibit ciliogenesis and disrupt centrosome homeostasis in astrocytes via Rab10 phosphorylation and RILPL1 recruitment.","evidence":"Cryo-EM, phosphoproteomics, RAB12 KO in astrocytes, cilia/centrosome phenotyping","pmids":["39343966"],"confidence":"High","gaps":["Whether these defects translate to neuronal pathology unaddressed","Stoichiometry of the in-cell complex not resolved"]},{"year":2024,"claim":"Whether RAB12 prenylation contributes to retinal disease was unknown; loss of REP-1 was shown to under-prenylate RAB12, and RAB12 knockdown phenocopied choroideremia RPE dysfunction (reduced autophagic flux, increased mTORC1).","evidence":"CRISPR CHM iPSC-RPE, TMT prenylation proteomics, siRNA, AAV rescue, autophagy/mTORC1 assays","pmids":["38920696"],"confidence":"Medium","gaps":["Specific contribution of RAB12 among under-prenylated Rabs unclear","Mechanistic link from prenylation to autophagy flux incomplete"]},{"year":2025,"claim":"Whether a kinase other than LRRK2 phosphorylates RAB12 was unknown; LRRK1 was shown to phosphorylate RAB12 in a PKC-dependent manner in activated mast cells, executing the RILP-to-RILPL1/L2 effector switch.","evidence":"Pulldown, LRRK1/LRRK2 siRNA, PKC and LRRK2 inhibitors, mast cell activation assays","pmids":["41357239"],"confidence":"Medium","gaps":["Phosphosite for LRRK1 not definitively mapped here","Single-lab finding"]},{"year":2026,"claim":"A neuronal in vivo function was undefined; Rab12 KO mice revealed RAB12 as a negative regulator of synaptic vesicle exocytosis and excitatory striatal transmission, with enrichment in synaptic vesicle fractions.","evidence":"Rab12 KO mouse, striatal electrophysiology, live-cell SV exocytosis imaging, biochemical fractionation, synaptosome proteomics","pmids":["42031745"],"confidence":"High","gaps":["Effector mediating SV exocytosis control unidentified","Relationship to LRRK2 activity in neurons unresolved"]},{"year":2026,"claim":"A role in mitochondrial quality control was untested; a family-wide screen and KO across cell types identified RAB12 as a negative regulator of mitophagy.","evidence":"mt-mKeima/YFP-Parkin siRNA screen, RAB12 KO, mitochondrial content/potential and mtDNA damage assays (preprint)","pmids":["41959481"],"confidence":"Medium","gaps":["Mechanism linking RAB12 to mitophagy suppression unknown","Preprint, awaiting peer review"]},{"year":null,"claim":"The unifying logic connecting RAB12's trafficking roles, its LRRK2-activating function, and its negative regulation of synaptic vesicle exocytosis and mitophagy remains to be integrated into a single mechanistic framework.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No common effector tying endolysosomal, synaptic, and mitophagy roles together","How nucleotide state, phosphorylation, and effector choice are coordinated in vivo is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[9,12,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,10,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,8]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,10,11,15]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[6,14]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[21,22]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[13,22]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,6,14]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,2,17,20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,10,13]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[19]}],"complexes":[],"partners":["LRRK2","DENND3","RILP","RILPL1","RILPL2","OPTN","LRRK1","EGFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6IQ22","full_name":"Ras-related protein Rab-12","aliases":[],"length_aa":244,"mass_kda":27.2,"function":"The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion (By similarity). RAB12 may play a role in protein transport from recycling endosomes to lysosomes regulating, for instance, the degradation of the transferrin receptor. Involved in autophagy (By similarity)","subcellular_location":"Recycling endosome membrane; Lysosome membrane; Golgi apparatus membrane; Cytoplasmic vesicle, autophagosome","url":"https://www.uniprot.org/uniprotkb/Q6IQ22/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB12","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CHM","stoichiometry":0.2},{"gene":"GDI1","stoichiometry":0.2},{"gene":"GDI2","stoichiometry":0.2},{"gene":"LSS","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RAB12","total_profiled":1310},"omim":[{"mim_id":"617503","title":"DENN DOMAIN-CONTAINING PROTEIN 3; DENND3","url":"https://www.omim.org/entry/617503"},{"mim_id":"616448","title":"RAS-ASSOCIATED PROTEIN RAB12; RAB12","url":"https://www.omim.org/entry/616448"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":180.3}],"url":"https://www.proteinatlas.org/search/RAB12"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q6IQ22","domains":[{"cath_id":"3.40.50.300","chopping":"40-100_107-220","consensus_level":"high","plddt":88.0418,"start":40,"end":220}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6IQ22","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6IQ22-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6IQ22-F1-predicted_aligned_error_v6.png","plddt_mean":78.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB12","jax_strain_url":"https://www.jax.org/strain/search?query=RAB12"},"sequence":{"accession":"Q6IQ22","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6IQ22.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6IQ22/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6IQ22"}},"corpus_meta":[{"pmid":"21718402","id":"PMC_21718402","title":"Small GTPase Rab12 regulates 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Constitutively active RAB12 reduced TfR protein levels; siRNA knockdown of RAB12 or its upstream activator DENND3 increased TfR levels. Knockdown had no effect on EGFR degradation.\",\n      \"method\": \"siRNA knockdown, constitutively active mutant overexpression, colocalization with lysosomes, sequential screening of 60 Rab isoforms\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (knockdown, active mutant, colocalization), replicated conceptually in follow-up addendum (PMID:22279614)\",\n      \"pmids\": [\"21718402\", \"22279614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DENND3 functions as the physiological guanine nucleotide exchange factor (GEF) for RAB12 in mouse embryonic fibroblasts. DENND3 knockdown phenocopied RAB12 knockdown (increased PAT4 levels, increased intracellular amino acids); DENND3 overexpression reduced mTORC1 activity and promoted autophagy in a RAB12-dependent manner, placing DENND3 upstream of RAB12 in controlling PAT4 trafficking from recycling endosomes to lysosomes.\",\n      \"method\": \"siRNA knockdown, overexpression, epistasis (Rab12-dependent rescue), amino acid concentration measurements, mTORC1 activity assay\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by genetic knockdown and overexpression with multiple functional readouts, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24719330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RAB12 physically complexes with the autophagy receptor OPTN, and the M98K-OPTN variant shows enhanced colocalization with RAB12. RAB12 is present in autophagosomes, and knockdown of Rab12 increased TfR levels and reduced M98K-OPTN-induced autolysosomes formation and cell death in retinal ganglion cells (RGC-5).\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, colocalization (fluorescence microscopy), autophagosome formation assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional knockdown with multiple readouts, single lab\",\n      \"pmids\": [\"23357852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RAB12 is activated in a stimulus-dependent manner in mast cells and promotes microtubule-dependent retrograde transport of secretory granules (SGs) via interaction with the RILP-dynein complex. RILP was identified as a novel RAB12 effector. RAB12 negatively regulates mast cell degranulation.\",\n      \"method\": \"Pulldown assay (RILP as effector), live-cell imaging of SG transport, knockdown/overexpression with degranulation readout, colocalization\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — effector identification by pulldown plus functional imaging and degranulation assay with multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"26740112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LRRK2 phosphorylates human RAB12 at Ser106 in a kinase-dependent manner. This was confirmed in HEK293 cells using the selective LRRK2 inhibitor Lu AF58786 in a phosphoproteomic study, and the phosphorylation was reduced by two distinct LRRK2 inhibitors.\",\n      \"method\": \"Phosphoproteomics (SILAC), LRRK2 inhibitor treatment (Lu AF58786 and second inhibitor), immunoblot validation in HEK293 and human PBMCs\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — phosphoproteomics with two distinct inhibitors and validation in multiple cell types; replicated in multiple subsequent studies\",\n      \"pmids\": [\"28860483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DENND3 GEF activity toward RAB12 is regulated through an intramolecular interaction controlled by tyrosine 940, demonstrated by size-exclusion chromatography, FRET, pulldown, and in vitro GEF assays.\",\n      \"method\": \"Size-exclusion chromatography, FRET, pulldown assay, in vitro GEF assay, point mutagenesis (Y940)\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro GEF assay with mutagenesis plus multiple orthogonal biophysical methods, single lab\",\n      \"pmids\": [\"28249939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RAB12 is required for efficient retrograde transport of Shiga toxin from early uptake carriers to the trans-Golgi network. RAB12 localizes to Shiga toxin-induced plasma membrane invaginations (clathrin-independent uptake carriers), and RAB12 depletion reduced toxin reaching TGN membranes and partially protected cells against intoxication. Only TGN46 and CI-M6PR steady-state localization was additionally affected.\",\n      \"method\": \"SILAC/quantitative mass spectrometry, fluorescence microscopy (GFP-RAB12 colocalization), quantitative biochemical toxin transport assay, siRNA knockdown\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification plus functional knockdown with biochemical transport assay, single lab\",\n      \"pmids\": [\"24703428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DENND3 contains a PHenn domain with a pleckstrin homology subdomain that binds actin through positively charged residues, and this domain mediates an intramolecular interaction with the DENN domain of DENND3. Both actin binding and DENN domain interaction are required for DENND3 function in autophagy (and thus for RAB12 activation).\",\n      \"method\": \"Structural domain identification, NMR/crystal analysis (structural), pulldown assay, mutational analysis blocking DENN or actin binding, autophagy functional assay\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structural domain identification plus mutagenesis and functional autophagy assay, single lab\",\n      \"pmids\": [\"29352104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RAB12 interacts with RILP, RILP-L1, and RILP-L2 independently of each other. Lysine-71 in mouse RAB12 is critical for interaction with RILP-L1 and RILP-L2 but dispensable for RILP binding. A structural model of the RAB12-RILP complex proposes a RILP homodimer interacting with a single active RAB12 molecule via switch I and switch II regions with RILP's RHD domain and C-terminal threonine. Mutational analyses of RILP RHD confirmed its role in secretory granule transport regulation.\",\n      \"method\": \"Pulldown assay, molecular dynamics simulation, mutational analysis, peptide inhibition assay\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pulldown and mutagenesis with molecular dynamics modeling, single lab but multiple approaches\",\n      \"pmids\": [\"33986343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RAB12 is a critical activator of LRRK2 kinase for Rab phosphorylation. Knockout of RAB12 markedly decreased phosphoRab10 levels across multiple cell types and knockout mouse tissues in a LRRK2-dependent and PPM1H-reversible manner. AlphaFold modeling revealed RAB12 binds a novel site in the LRRK2 Armadillo domain; residues at this site influence phosphoRab10 and phosphoRab12 levels distinctly from RAB29-mediated LRRK2 activation. RAB12-driven activation did not require RAB12's own phosphorylation.\",\n      \"method\": \"CRISPR genome-wide screen (flow cytometry for phosphoRab10), RAB12 knockout in multiple cell types and tissues, AlphaFold structural modeling with mutational validation, PPM1H phosphatase epistasis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased genome-wide CRISPR screen validated in multiple cell types and mouse tissues with structural modeling and mutational follow-up; replicated independently in same year (PMID:37874617)\",\n      \"pmids\": [\"37874635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RAB12 is recruited to damaged lysosomes and facilitates local LRRK2-dependent phosphorylation of RAB10 (pT73) at the lysosome. PD-linked LRRK2 variants (R1441G, VPS35 D620N) increased LRRK2 recruitment to lysosomes and elevated lysosomal pT73-Rab10. This defines a conserved mechanism by which RAB12 responds to lysosomal damage to activate LRRK2 locally.\",\n      \"method\": \"siRNA screen, lysosome immunopurification, imaging, immunoblot\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — targeted siRNA screen followed by lysosome immunopurification with imaging and biochemical validation; independently corroborates PMID:37874635\",\n      \"pmids\": [\"37874617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Pathogenic LRRK2 causes perinuclear lysosomal clustering via RAB12 phosphorylation at Ser106; knockout of RAB12 or its effector RILPL1 abolished clustering. Phosphorylated RAB12 accumulates on clustered lysosomes, and phosphorylation increases RAB12's interaction with RILPL1, thereby disrupting lysosomal transport.\",\n      \"method\": \"RAB12 knockout, RILPL1 knockout, RAB12 re-expression with phospho-site mutants (Ser106), co-immunoprecipitation of phospho-RAB12 with RILPL1, confocal microscopy\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO, phospho-site mutagenesis, and co-IP with functional lysosome distribution readout in single study; multiple orthogonal approaches\",\n      \"pmids\": [\"37086089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LRRK2 phosphorylates RAB12 more efficiently in its GDP-bound form than GTP-bound form in vitro, indicating LRRK2 recognizes the nucleotide-determined structural conformation of RAB12. GDP-bound RAB12 is also more susceptible to heat-induced denaturation, as shown by circular dichroism and differential scanning fluorimetry.\",\n      \"method\": \"In vitro phosphorylation assay (LRRK2 + GDP- vs GTP-bound RAB12), circular dichroism, differential scanning fluorimetry\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro phosphorylation assay with biophysical characterization, single lab, single study\",\n      \"pmids\": [\"37207563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RAB12 forms a direct complex with LRRK2 whose cryo-EM structure was solved. RAB12 cooperates with LRRK2 to inhibit primary ciliogenesis and regulate centrosome homeostasis in astrocytes by enhancing RAB10 phosphorylation and recruiting RILPL1. These functions require direct RAB12-LRRK2 interaction and LRRK2 kinase activity. Deletion of RAB12 in astrocytes prevented ciliary and centrosome defects caused by PD-linked LRRK2-G2019S.\",\n      \"method\": \"Cryo-EM structure determination, phosphoproteomics, RAB12 knockout in astrocytes, RILPL1 recruitment assay, primary cilia and centrosome phenotyping\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus phosphoproteomics, genetic KO with multiple functional readouts; replicated in preprint PMID:39071328\",\n      \"pmids\": [\"39343966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RAB12 and the AP-1 clathrin adaptor complex interact with EGFR and regulate export of newly synthesized (wild-type) EGFR from the trans-Golgi network to the cell surface. Tyrosine 998 on EGFR is critical for AP-1 binding and TGN export. The constitutively active EGFR-L858R mutant bypasses this requirement.\",\n      \"method\": \"Gene knockout, siRNA knockdown, streptavidin pulldown, co-immunoprecipitation, cell elongation/proliferation assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — gene KO plus co-IP and pulldown with functional readouts, single lab\",\n      \"pmids\": [\"36739948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Rare missense variants of RAB12 found in dystonia patients showed increased GTPase activity and altered subcellular (lysosomal) distribution compared to wild-type in patient-derived fibroblasts and overexpression models. Soluble transferrin receptor 1 levels were reduced in blood of p.Ile196Val carriers.\",\n      \"method\": \"GTPase activity assay, subcellular localization imaging in patient fibroblasts and overexpression models, serum TfR1 measurement\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — enzymatic activity assay plus localization in patient cells, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29057844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"An activating variant of DENND3 (p.L708V) upregulates RAB12 expression, leading to lysosomal degradation of TFR2 and downregulation of hepcidin via the DENND3/RAB12/TFR2 axis, causing iron overload in a mouse AAV model and in patient hepatocytes.\",\n      \"method\": \"Cell transfection, in vitro lysosomal degradation assay, adeno-associated virus mouse model, liver iron quantification, hepcidin/pSMAD1/5 signaling\",\n      \"journal\": \"Hepatology International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo mechanistic pathway validated with AAV mouse model and patient tissue, single lab\",\n      \"pmids\": [\"36729283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of REP-1 (Rab escort protein 1) in a CHM iPSC-RPE model causes under-prenylation of RAB12. Rab12 knockdown in control RPE cells reduced autophagic flux and increased mTORC1 signaling, phenocopying CHM cells. Gene replacement restored autophagic flux in CHM cells. This identifies RAB12 under-prenylation as a contributor to RPE dysfunction in choroideremia.\",\n      \"method\": \"CRISPR/Cas9 CHM knockout iPSC-RPE, TMT mass spectrometry (prenylation screen), siRNA knockdown, AAV gene replacement, mTORC1 and autophagic flux assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model with mass spectrometry, siRNA phenocopy, and rescue by gene replacement, single lab\",\n      \"pmids\": [\"38920696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In mast cells, LRRK1 (not LRRK2) phosphorylates RAB12 in a PKC-dependent manner upon activation by IgE/antigen or substance P. LRRK1-mediated phosphorylation of RAB12 increases its affinity for RILP-L1 and RILP-L2 while reducing binding to RILP, constituting a phosphorylation-driven effector switch.\",\n      \"method\": \"Pulldown assay, siRNA knockdown of LRRK1 and LRRK2, PKC inhibitor and LRRK2 inhibitor treatment, mast cell activation assays\",\n      \"journal\": \"Frontiers in Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — kinase knockdown with effector pulldowns, multiple inhibitors, single lab\",\n      \"pmids\": [\"41357239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RAB12 is a negative regulator of synaptic vesicle exocytosis and excitatory neurotransmission in vivo. Rab12 KO mice exhibit increased locomotor activity, enhanced presynaptic release probability and excitatory drive onto striatal medium spiny neurons. Live-cell imaging showed Rab12 deletion facilitates and overexpression inhibits synaptic vesicle exocytosis. RAB12 is biochemically enriched in synaptic vesicle-associated fractions.\",\n      \"method\": \"Rab12 KO mouse model, electrophysiology (striatal slices), live-cell imaging of synaptic vesicle exocytosis, biochemical fractionation, synaptosome proteomics\",\n      \"journal\": \"NPJ Parkinson's Disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with electrophysiology, live imaging, and biochemical fractionation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"42031745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RAB12 is a negative regulator of mitophagy. siRNA and KO of RAB12 augmented clearance of damaged mitochondria basally and after FCCP-induced depolarization across distinct cell types. RAB12 depletion increased mitochondrial content, lowered mitochondrial membrane potential, and reduced mitochondrial DNA damage.\",\n      \"method\": \"Family-wide siRNA screen (mt-mKeima/YFP-Parkin HeLa cells), RAB12 KO across multiple cell types, mitochondrial content and membrane potential assays, mitochondrial DNA damage measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated screen hit with KO across multiple cell types and multiple mitochondrial readouts; preprint, single lab\",\n      \"pmids\": [\"41959481\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"RAB12 protein is associated with atrial secretory granules, demonstrated by GTP-overlay assay and immunogold electron microscopy, suggesting a role in vesicular traffic in these cells.\",\n      \"method\": \"[32P]GTP-overlay assay, immunogold electron microscopy, immunoprecipitation/immunoblot\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — biochemical and ultrastructural co-localization, multiple methods, single lab\",\n      \"pmids\": [\"8575079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RAB12 is associated with small cytoplasmic vesicles (not the Golgi apparatus) in cultured Sertoli cells and NRK cells. When overexpressed, RAB12-associated vesicles accumulate in the perinuclear centrosome region, suggesting a role in vesicular transport from the cell periphery to the perinuclear centrosome region.\",\n      \"method\": \"Immunohistochemistry, immunofluorescence localization in cultured cells, overexpression analysis\",\n      \"journal\": \"Molecular Reproduction and Development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization by immunofluorescence and overexpression without functional manipulation, single lab\",\n      \"pmids\": [\"15791598\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB12 is a small GTPase that acts as a critical activator of LRRK2 kinase (binding the LRRK2 Armadillo domain, as revealed by cryo-EM), regulates membrane trafficking from recycling endosomes and the trans-Golgi network to lysosomes (controlling degradation of transferrin receptor, PAT4, and EGFR), is recruited to damaged lysosomes to locally amplify LRRK2-mediated phosphorylation of Rab substrates (Rab10, Rab8A), is itself phosphorylated at Ser106 by LRRK2 and at a similar site by LRRK1 in a PKC-dependent manner—phosphorylation shifting effector preference from RILP to RILPL1/RILPL2—and functions in diverse cellular contexts including mast cell secretory granule retrograde transport, primary ciliogenesis and centrosome homeostasis in astrocytes, synaptic vesicle exocytosis, autophagy initiation (via its GEF DENND3), and mitophagy regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAB12 is a small GTPase that governs membrane trafficking from recycling endosomes and the trans-Golgi network to lysosomes, controlling the degradation and surface delivery of cargoes including the transferrin receptor, the amino-acid transporter PAT4, and EGFR, and thereby coupling endolysosomal flux to mTORC1 signaling and autophagy [#0, #1, #14]. Its activation cycle is driven by the GEF DENND3, which is itself autoregulated by an intramolecular interaction between its DENN and actin-binding PHenn domains and acts upstream of RAB12 to promote autophagy and PAT4 trafficking [#1, #5, #7]. Active RAB12 engages the RILP family of effectors—RILP, RILPL1, and RILPL2—to direct microtubule- and dynein-dependent retrograde transport, with RILP binding underlying secretory granule transport and negative regulation of mast cell degranulation [#3, #8]. RAB12 is a direct, critical activator of LRRK2 kinase: it binds a distinct site on the LRRK2 Armadillo domain (resolved by cryo-EM), and RAB12 loss markedly reduces LRRK2-mediated phosphorylation of Rab10 and Rab8A in a PPM1H-reversible manner independent of RAB12's own phosphorylation [#9, #13]. RAB12 is recruited to damaged lysosomes where it locally amplifies LRRK2 activity, and pathogenic LRRK2 phosphorylates RAB12 at Ser106, which increases RILPL1 binding and drives perinuclear lysosomal clustering and centrosome/ciliogenesis defects [#10, #11, #13]. Phosphorylation thus acts as an effector switch shifting RAB12 preference from RILP toward RILPL1/RILPL2, a switch also executed by LRRK1 in a PKC-dependent manner in mast cells [#18]. RAB12 additionally functions as a negative regulator of synaptic vesicle exocytosis in vivo and of mitophagy [#19, #20]. Disease-linked variants connect RAB12 to dystonia, while DENND3-driven RAB12 upregulation drives TFR2 degradation and iron overload [#15, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Before any functional assignment, it was unknown whether RAB12 associated with a defined membrane compartment; localizing it to secretory granules established a candidate role in vesicular traffic.\",\n      \"evidence\": \"GTP-overlay assay and immunogold electron microscopy in atrial cells\",\n      \"pmids\": [\"8575079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional manipulation\", \"Compartment identity in other cell types unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The cargo and pathway specificity of RAB12 were unknown; identifying it as a regulator of transferrin receptor degradation from recycling endosomes to lysosomes, distinct from EGFR degradation, defined a dedicated trafficking route.\",\n      \"evidence\": \"siRNA knockdown, constitutively active mutant, lysosomal colocalization, Rab isoform screen\",\n      \"pmids\": [\"21718402\", \"22279614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effector linking RAB12 to lysosomal delivery not yet identified\", \"Mechanism of cargo selection unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"How RAB12 is activated and integrated with nutrient signaling was unclear; identifying DENND3 as its GEF placed RAB12 in a pathway controlling PAT4 trafficking, mTORC1 activity, and autophagy.\",\n      \"evidence\": \"siRNA epistasis, overexpression, mTORC1 and amino-acid readouts in MEFs\",\n      \"pmids\": [\"24719330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct in vitro GEF kinetics not shown here\", \"How DENND3 activity is triggered unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"RAB12's role beyond endolysosomal degradation was untested; it was shown to be required for retrograde Shiga toxin transport to the TGN, broadening its trafficking remit.\",\n      \"evidence\": \"SILAC mass spectrometry, GFP-RAB12 imaging, biochemical toxin transport assay, knockdown\",\n      \"pmids\": [\"24703428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effector mediating TGN-directed transport not identified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"RAB12 effectors and a physiological context were unknown; identifying RILP as an effector linked RAB12 to dynein-dependent retrograde secretory granule transport and negative control of mast cell degranulation.\",\n      \"evidence\": \"Pulldown effector identification, live-cell SG imaging, degranulation assay\",\n      \"pmids\": [\"26740112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RAB12-RILP binding not yet defined\", \"Stimulus-to-activation signaling incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"It was unknown whether RAB12 is a kinase substrate; phosphoproteomics established LRRK2 phosphorylates human RAB12 at Ser106, embedding it in the LRRK2 Rab-substrate network.\",\n      \"evidence\": \"SILAC phosphoproteomics with two LRRK2 inhibitors, immunoblot validation in HEK293 and PBMCs\",\n      \"pmids\": [\"28860483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Ser106 phosphorylation not yet defined\", \"Directionality (RAB12 as activator vs substrate) unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"How DENND3 GEF activity is controlled was unknown; an intramolecular interaction gated by tyrosine 940 was shown to regulate its activity toward RAB12.\",\n      \"evidence\": \"SEC, FRET, pulldown, in vitro GEF assay, Y940 mutagenesis\",\n      \"pmids\": [\"28249939\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signal regulating Y940 unknown\", \"Physiological trigger for relief of autoinhibition unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Whether RAB12 variants cause disease was untested; rare missense variants in dystonia patients were found to increase GTPase activity and alter lysosomal distribution, linking RAB12 dysfunction to a human phenotype.\",\n      \"evidence\": \"GTPase activity assay, patient fibroblast localization, serum TfR1 measurement\",\n      \"pmids\": [\"29057844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality not established by family genetics or rescue\", \"Mechanism connecting variant to dystonia unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The structural mechanism of DENND3 function was incomplete; a PHenn domain binding actin and the DENN domain was shown to be required for autophagy and thus RAB12 activation.\",\n      \"evidence\": \"Structural domain analysis, pulldown, mutagenesis, autophagy assay\",\n      \"pmids\": [\"29352104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of actin binding in nucleotide exchange kinetics unresolved\", \"Single-lab structural model\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"How RAB12 selects among RILP-family effectors was unknown; pulldown and modeling showed RILP, RILPL1, and RILPL2 bind independently, with Lys71 critical for RILPL1/L2 but not RILP, defining the structural basis of effector choice.\",\n      \"evidence\": \"Pulldown, molecular dynamics modeling, mutagenesis, peptide inhibition\",\n      \"pmids\": [\"33986343\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Model not validated by experimental structure\", \"Determinants of in vivo effector switching not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether RAB12 merely is a LRRK2 substrate or actively regulates LRRK2 was unresolved; an unbiased CRISPR screen established RAB12 as a critical activator binding a novel Armadillo-domain site, distinct from RAB29-mediated activation and independent of RAB12 phosphorylation.\",\n      \"evidence\": \"Genome-wide CRISPR screen, RAB12 KO in cells and mouse tissues, AlphaFold modeling, PPM1H epistasis\",\n      \"pmids\": [\"37874635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Experimental structure of the interaction not yet solved here\", \"How RAB12 nucleotide state couples to activation unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The subcellular trigger for RAB12-LRRK2 activation was unknown; RAB12 was shown to be recruited to damaged lysosomes to drive local LRRK2-dependent Rab10 phosphorylation, with PD variants enhancing recruitment.\",\n      \"evidence\": \"siRNA screen, lysosome immunopurification, imaging, immunoblot\",\n      \"pmids\": [\"37874617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sensor mechanism for lysosomal damage unidentified\", \"Link between local activation and downstream pathology incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The downstream consequence of RAB12 Ser106 phosphorylation was undefined; it was shown to increase RILPL1 binding and drive pathogenic perinuclear lysosomal clustering, connecting phosphorylation to an effector switch and trafficking defect.\",\n      \"evidence\": \"RAB12 and RILPL1 KO, Ser106 phospho-mutant re-expression, phospho-RAB12 co-IP, confocal imaging\",\n      \"pmids\": [\"37086089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological (non-pathogenic) role of the switch unclear\", \"Quantitative contribution of RILPL2 not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether LRRK2 reads RAB12 nucleotide state was untested; in vitro phosphorylation showed GDP-bound RAB12 is the preferred substrate, indicating conformational recognition.\",\n      \"evidence\": \"In vitro phosphorylation of GDP- vs GTP-RAB12, circular dichroism, differential scanning fluorimetry\",\n      \"pmids\": [\"37207563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of GDP-state preference unestablished\", \"Single in vitro study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"RAB12's role in biosynthetic EGFR trafficking was unknown; it was shown to act with the AP-1 adaptor to export newly synthesized EGFR from the TGN, with EGFR Y998 governing AP-1 binding.\",\n      \"evidence\": \"Gene KO, siRNA, streptavidin pulldown, co-IP, proliferation assays\",\n      \"pmids\": [\"36739948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RAB12-AP-1 interaction mechanism unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A disease mechanism via the DENND3/RAB12 axis was untested; a DENND3 activating variant was shown to upregulate RAB12, driving TFR2 lysosomal degradation, hepcidin downregulation, and iron overload.\",\n      \"evidence\": \"Transfection, lysosomal degradation assay, AAV mouse model, liver iron and hepcidin signaling, patient hepatocytes\",\n      \"pmids\": [\"36729283\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RAB12-TFR2 trafficking step not structurally defined\", \"Generality beyond the DENND3 variant unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The RAB12-LRRK2 interaction lacked an experimental structure and a cellular phenotype; cryo-EM resolved the direct complex and RAB12 was shown to cooperate with LRRK2 to inhibit ciliogenesis and disrupt centrosome homeostasis in astrocytes via Rab10 phosphorylation and RILPL1 recruitment.\",\n      \"evidence\": \"Cryo-EM, phosphoproteomics, RAB12 KO in astrocytes, cilia/centrosome phenotyping\",\n      \"pmids\": [\"39343966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these defects translate to neuronal pathology unaddressed\", \"Stoichiometry of the in-cell complex not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether RAB12 prenylation contributes to retinal disease was unknown; loss of REP-1 was shown to under-prenylate RAB12, and RAB12 knockdown phenocopied choroideremia RPE dysfunction (reduced autophagic flux, increased mTORC1).\",\n      \"evidence\": \"CRISPR CHM iPSC-RPE, TMT prenylation proteomics, siRNA, AAV rescue, autophagy/mTORC1 assays\",\n      \"pmids\": [\"38920696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific contribution of RAB12 among under-prenylated Rabs unclear\", \"Mechanistic link from prenylation to autophagy flux incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether a kinase other than LRRK2 phosphorylates RAB12 was unknown; LRRK1 was shown to phosphorylate RAB12 in a PKC-dependent manner in activated mast cells, executing the RILP-to-RILPL1/L2 effector switch.\",\n      \"evidence\": \"Pulldown, LRRK1/LRRK2 siRNA, PKC and LRRK2 inhibitors, mast cell activation assays\",\n      \"pmids\": [\"41357239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosite for LRRK1 not definitively mapped here\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A neuronal in vivo function was undefined; Rab12 KO mice revealed RAB12 as a negative regulator of synaptic vesicle exocytosis and excitatory striatal transmission, with enrichment in synaptic vesicle fractions.\",\n      \"evidence\": \"Rab12 KO mouse, striatal electrophysiology, live-cell SV exocytosis imaging, biochemical fractionation, synaptosome proteomics\",\n      \"pmids\": [\"42031745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effector mediating SV exocytosis control unidentified\", \"Relationship to LRRK2 activity in neurons unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A role in mitochondrial quality control was untested; a family-wide screen and KO across cell types identified RAB12 as a negative regulator of mitophagy.\",\n      \"evidence\": \"mt-mKeima/YFP-Parkin siRNA screen, RAB12 KO, mitochondrial content/potential and mtDNA damage assays (preprint)\",\n      \"pmids\": [\"41959481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking RAB12 to mitophagy suppression unknown\", \"Preprint, awaiting peer review\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying logic connecting RAB12's trafficking roles, its LRRK2-activating function, and its negative regulation of synaptic vesicle exocytosis and mitophagy remains to be integrated into a single mechanistic framework.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No common effector tying endolysosomal, synaptic, and mitophagy roles together\", \"How nucleotide state, phosphorylation, and effector choice are coordinated in vivo is unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [9, 12, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 10, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 10, 11, 15]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [6, 14]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [21, 22]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [13, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 6, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 2, 17, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 10, 13]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LRRK2\", \"DENND3\", \"RILP\", \"RILPL1\", \"RILPL2\", \"OPTN\", \"LRRK1\", \"EGFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}