{"gene":"RAB37","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2000,"finding":"Rab37 is a novel Rab GTPase specifically expressed in mast cells and localizes to secretory granules, as shown by GFP-tagged Rab37 expression in bone marrow mast cells.","method":"GFP-tagging and fluorescence microscopy in bone marrow mast cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 — single localization experiment with functional implication but no direct functional assay","pmids":["10722846"],"is_preprint":false},{"year":2011,"finding":"Rab37 controls TNF-α secretion from activated macrophages by interacting with Munc13-1; TNF-α-containing vesicles co-localize with both Rab37 and Munc13-1, and knockdown of either Rab37 or Munc13-1 reduces TNF-α secretion.","method":"siRNA knockdown, overexpression, LC-MS/MS interactome, immunocytochemistry co-localization","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2/3 — multiple methods (KD, OE, MS, imaging) in single lab","pmids":["21805469"],"is_preprint":false},{"year":2011,"finding":"Rab37 is a substrate of methionine aminopeptidase-2 (MetAP-2); aberrant accumulation of Rab37 due to MetAP-2 inhibition (TNP-470) disrupts Wnt planar cell polarity (PCP) signaling, demonstrated using a NME-resistant Rab37 point mutant that phenocopies MetAP-2 inhibition.","method":"Point mutant expression, MetAP-2 inhibitor TNP-470, Wnt PCP signaling assays","journal":"Chemistry & biology","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis plus chemical-genetic approach with functional readout","pmids":["22035799"],"is_preprint":false},{"year":2013,"finding":"Rab37 localizes to insulin-containing large dense core granules in pancreatic β-cells and is required for glucose-induced insulin secretion and granule docking at the plasma membrane; Rab37 does not interact with known Rab3a or Rab27a effectors, indicating a distinct mechanism.","method":"Confocal microscopy, RNA interference, granule apposition counting, pull-down assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi with defined cellular phenotype, negative pull-down controls, localization confirmed","pmids":["23826383"],"is_preprint":false},{"year":2014,"finding":"Rab37 mediates exocytosis of TIMP1 in a nucleotide (GTP)-dependent manner; TIMP1 is a direct cargo of Rab37 vesicles, and its secretion suppresses MMP9 activity and cancer cell migration/metastasis in vitro and in vivo.","method":"Secretomics, co-localization imaging, nucleotide-binding mutants, in vitro migration assays, mouse metastasis models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (secretomics, GTPase mutants, in vivo reconstitution) in a single study","pmids":["25183545"],"is_preprint":false},{"year":2016,"finding":"Rab37 negatively regulates mast cell degranulation by interacting with Munc13-4 in a GTP-independent manner, forming a Rab27-Munc13-4-Rab37 complex that counteracts the vesicle-priming activity of the Rab27-Munc13-4 system.","method":"siRNA knockdown, dominant-active mutant overexpression, co-immunoprecipitation, co-localization in RBL-2H3 cells","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, genetic epistasis (double KD), and functional readout with orthogonal methods","pmids":["26931073"],"is_preprint":false},{"year":2016,"finding":"Rab37 mediates exocytosis of thrombospondin-1 (TSP1) from cancer cells; secreted TSP1 inhibits p-FAK/p-paxillin/p-ERK migration signaling in both cancer epithelial cells and endothelial cells to suppress angiogenesis and metastasis.","method":"Cell migration/invasion assays, in vivo angiogenesis and metastasis models, TSP1 secretion assays","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — defined cargo (TSP1), pathway placement, in vivo validation, single lab","pmids":["28151721"],"is_preprint":false},{"year":2017,"finding":"PKCα phosphorylates Rab37 at threonine 172 (T172), which reduces Rab37 GTP-bound state, impairs co-localization of Rab37 with TIMP1 vesicles, and inhibits TIMP1 exocytosis, thereby enhancing lung cancer metastasis. Phospho-mimetic T172D mutant promotes metastasis in vivo.","method":"In vitro kinase assay, phospho-mimetic and phospho-dead mutagenesis, co-localization imaging, in vivo mouse metastasis model","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1-2 — identification of specific phosphorylation site by mutagenesis, in vitro kinase assay, and in vivo validation","pmids":["29312551"],"is_preprint":false},{"year":2017,"finding":"GTP-bound RAB37 directly binds ATG5 and promotes assembly of the ATG5-ATG12-ATG16L1 complex on isolation membranes, thereby facilitating LC3B lipidation and autophagosome formation. GDP-stabilized RAB37 mutant impairs this interaction.","method":"Co-immunoprecipitation, GTPase mutant analysis, LC3B lipidation assay, autophagosome formation assay, RAB37 knockdown/overexpression","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding shown by pull-down with nucleotide mutants, functional complex assembly assay, multiple orthogonal methods","pmids":["29229996"],"is_preprint":false},{"year":2018,"finding":"Rab37 mediates exocytosis of SFRP1 (an extracellular Wnt antagonist), and SFRP1 secretion is required for Rab37-mediated suppression of Wnt signaling and cancer stemness in vitro and in vivo.","method":"Reconstitution experiments, xenograft tumor initiation assay, recombinant SFRP1 rescue, Wnt signaling reporters","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — reconstitution with recombinant protein and in vivo model, single lab","pmids":["30158579"],"is_preprint":false},{"year":2018,"finding":"Rab37 mediates exocytosis of soluble ST2 (sST2) from lung cancer cells; secreted sST2 skews macrophage polarization toward anti-tumoral M1-like phenotype and suppresses tumor growth in xenografts.","method":"sST2 secretion assay, macrophage polarization assay, xenograft mouse model","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — defined cargo (sST2), in vivo validation, single lab","pmids":["29717487"],"is_preprint":false},{"year":2018,"finding":"VAMP8 (a v-SNARE) interacts with RAB37 and is required for RAB37-mediated vesicle trafficking and exocytosis of TIMP1; VAMP8 co-localizes with RAB37 and TIMP1 vesicles and is essential for metastasis suppression in vivo.","method":"Co-immunoprecipitation, confocal and TIRF microscopy, in vivo reconstitution (tail-vein and lung-to-lung metastasis models)","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction, imaging co-localization, in vivo reconstitution, single lab with multiple orthogonal methods","pmids":["30165196"],"is_preprint":false},{"year":2018,"finding":"RAB37 co-localizes with TIMP2, regulates TIMP2 secretion, and inhibits downstream MMP2 activity to suppress nasopharyngeal carcinoma metastasis; RAB37 promoter hypermethylation silences this pathway.","method":"Co-localization assay, TIMP2 secretion assay, MMP2 activity assay, RAB37 overexpression/knockdown","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2/3 — defined cargo and downstream effector, functional assays, single lab","pmids":["30131385"],"is_preprint":false},{"year":2020,"finding":"PKCα phosphorylates RAB37 to inactivate it; methionine promotes RAB37 methylation and phosphorylation via suppression of the miR-200b/PKCα axis, thereby repressing RAB37-mediated autophagy in gastric cancer stem cells.","method":"Lentiviral methionine-γ-lyase overexpression, miR-200b measurement, PKCα knockdown, autophagy assays, in vivo tumor model","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2/3 — pathway epistasis established with multiple genetic interventions, single lab","pmids":["32926650"],"is_preprint":false},{"year":2021,"finding":"Rab37 regulates IL-6 secretion in a GTPase-dependent manner in macrophages; macrophage-derived IL-6 promotes STAT3-dependent PD-1 mRNA expression in CD8+ T cells, linking Rab37 vesicle trafficking to immunosuppression. This was validated in Rab37 knockout mice and with vesicle isolation.","method":"Rab37 KO mice, vesicle isolation, GTPase mutants, ChIP assay for STAT3 at PD-1 promoter, imaging","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — KO mice, vesicle isolation, ChIP, GTPase mutants, multiple orthogonal methods","pmids":["34093869"],"is_preprint":false},{"year":2021,"finding":"RAB37 directly interacts with TIMP1 and promotes adipogenic differentiation of hADSCs via the TIMP1/CD63/integrin β1 signaling pathway, as shown by proximity ligation assay and FAK phosphorylation.","method":"Proximity ligation assay, TIMP1 ELISA, CD63/integrin β1 knockdown, FAK phosphorylation assay, Oil Red O staining","journal":"Stem cells international","confidence":"Medium","confidence_rationale":"Tier 2/3 — direct interaction shown by PLA, pathway placement via knockdown, single lab","pmids":["34858503"],"is_preprint":false},{"year":2022,"finding":"Rab37 mediates CHI3L1 (chitinase-3-like-1) intracellular vesicle trafficking and exocytosis in a GTP-dependent manner in T cells and macrophages; this was abolished in Rab37 KO mice splenocytes/BMDMs and in cells expressing inactive Rab37.","method":"Rab37 KO mice, vesicle isolation, TIRF and confocal microscopy, GTPase mutants","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — KO mice, vesicle isolation, multiple imaging modalities and GTPase mutants","pmids":["34987649"],"is_preprint":false},{"year":2022,"finding":"Secretory autophagy promotes Rab37-mediated TIMP1 exocytosis; Rab37 and Sec22b co-localize in purified autophagosomes, and silencing of ATG5, ATG7, or Sec22b reduces TIMP1 secretion under starvation-induced autophagy conditions.","method":"Autophagosome purification, co-localization imaging, ATG5/ATG7/Sec22b knockdown, TIMP1 secretion assay, in vivo lung-to-lung metastasis mouse model","journal":"Journal of biomedical science","confidence":"High","confidence_rationale":"Tier 2 — autophagosome purification, multiple genetic KDs, in vivo model, orthogonal methods","pmids":["36457117"],"is_preprint":false},{"year":2023,"finding":"Active (GTP-bound) RAB37 simultaneously regulates autophagy activation and TIMP1 secretion via secretory autophagy; Sec22b (SNARE) is required for this pathway, and starvation-activated RAB37 enhances TIMP1 exocytosis in a Sec22b-dependent manner.","method":"GTPase mutants, Sec22b knockdown, TIMP1 secretion assay, in vivo mouse model, autophagy markers","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — GTPase mutants and genetic KD with functional readout, in vivo validation, single lab","pmids":["37151129"],"is_preprint":false},{"year":2023,"finding":"Rab37 directly binds Hsp90α and TIMP1 (shown by proximity ligation assay) and promotes their secretion from ADSCs; this regulates endothelial differentiation and diabetic wound healing.","method":"LC-MS/MS, ELISA, proximity ligation assay, Hsp90α/TIMP1 knockdown, in vivo diabetic wound model","journal":"Stem cell reviews and reports","confidence":"Medium","confidence_rationale":"Tier 2/3 — direct binding shown by PLA, functional rescue, in vivo model, single lab","pmids":["36627432"],"is_preprint":false},{"year":2024,"finding":"RPGR (retinitis pigmentosa GTPase regulator) is a guanine nucleotide exchange factor (GEF) for RAB37; RPGR directly interacts with RAB37 via its RCC1-like domain and accelerates GDP-to-GTP exchange to promote autophagy. Rpgr KO mice show photoreceptor degeneration due to autophagy impairment, rescued by AAV-mediated RPGR re-expression.","method":"GEF activity assay (GDP-to-GTP exchange kinetics), co-immunoprecipitation, Rpgr KO mice, AAV rescue, autophagy markers","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — in vitro GEF activity assay with direct binding, KO mouse model, and in vivo genetic rescue","pmids":["38536817"],"is_preprint":false},{"year":2024,"finding":"Rab37 mediates trafficking and plasma membrane presentation of PD-1 in T cells in a GTP-dependent manner; glycosylation-deficient PD-1 mutant delays recruitment to Rab37 vesicles, stalling membrane presentation. Rab37 KO mice show increased T cell activity in tumors.","method":"GTPase mutants, co-localization imaging, glycosylation mutant, Rab37 KO mice, T cell functional assays","journal":"Journal of biomedical science","confidence":"High","confidence_rationale":"Tier 2 — GTPase and glycosylation mutants with mechanistic imaging, KO mice with defined immune phenotype","pmids":["38321486"],"is_preprint":false},{"year":2024,"finding":"RAB37-mediated autophagy is required for ovarian homeostasis and follicular development; conditional knockout of Rab37 in oocytes impairs autophagy, disrupts follicular homeostasis, and causes ovarian dysfunction in mice. E2F1 and EGR2 transcription factors synergistically activate Rab37 transcription.","method":"Conditional KO mice (oocyte-specific), autophagy markers, transcription factor ChIP/reporter assays, flunarizine rescue","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO with defined cellular phenotype and pharmacological rescue, single lab","pmids":["39113565"],"is_preprint":false},{"year":2024,"finding":"RAB37 promotes autophagic degradation of β-catenin by strengthening the interaction between p62 and β-catenin; this suppresses EMT, migration and invasion of gastric cancer cells in a GTPase activity-dependent manner, reversed by autophagy inhibitor chloroquine.","method":"Co-immunoprecipitation, autophagy inhibitor rescue (chloroquine), GTPase activity mutants, wound healing/transwell assays, in vivo pulmonary metastasis model","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP, chemical rescue, GTPase mutants, in vivo model, single lab","pmids":["39699800"],"is_preprint":false},{"year":2025,"finding":"GDP-bound (inactive) Rab37 interacts with the nuclear localization sequence of STAT1 in the cytosol, sequestering it from nuclear translocation and transcription, thereby downregulating type I IFN pathway genes and promoting M2-like TAM polarization.","method":"cDNA microarray (Rab37 KO vs WT BMDMs), co-immunoprecipitation with NLS of STAT1, STAT1 nuclear translocation assay, in vitro/in vivo assays","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — KO transcriptomics, co-IP mapping to NLS domain, nuclear translocation functional assay, single lab","pmids":["39984679"],"is_preprint":false},{"year":2026,"finding":"Rab37 promotes OPN (osteopontin) secretion in macrophages, which activates STAT3 signaling in an autocrine loop to sustain Spp1+ TAM polarization and paracrine promotion of lung cancer cell proliferation/invasion.","method":"Single-cell RNA sequencing, Rab37 KO mice, OPN secretion assay, STAT3 signaling assay, in vivo tumor models","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — scRNA-seq, KO mice, defined cargo and signaling pathway, single lab","pmids":["41535255"],"is_preprint":false}],"current_model":"RAB37 is a small GTPase that cycles between inactive GDP-bound and active GTP-bound states to regulate vesicle trafficking and exocytosis of multiple secreted cargos (TIMP1, TIMP2, TSP1, SFRP1, sST2, IL-6, CHI3L1, OPN, PD-1, Hsp90α) as well as autophagosome biogenesis via direct interaction with ATG5 to promote ATG5-ATG12-ATG16L1 complex assembly; its activity is regulated by the GEF RPGR (which catalyzes GDP-to-GTP exchange) and is negatively modulated by PKCα-mediated phosphorylation at T172, while in its GDP-bound form it additionally sequesters STAT1 in the cytosol to suppress type I IFN signaling."},"narrative":{"teleology":[{"year":2000,"claim":"Identifying RAB37 as a mast-cell-specific Rab GTPase on secretory granules established the first link between this uncharacterized GTPase and regulated exocytosis.","evidence":"GFP-tagging and fluorescence microscopy in bone marrow-derived mast cells","pmids":["10722846"],"confidence":"Medium","gaps":["No functional assay for secretion performed","Expression survey limited to mast cells"]},{"year":2011,"claim":"Demonstrating that RAB37 controls TNF-α secretion through interaction with Munc13-1 in macrophages revealed its first defined exocytic function and effector partner beyond mast cells.","evidence":"siRNA knockdown, overexpression, LC-MS/MS interactome, and immunocytochemistry co-localization in macrophages","pmids":["21805469"],"confidence":"Medium","gaps":["Direct binding vs. indirect complex membership not resolved","Specificity relative to other secretory Rabs not established"]},{"year":2013,"claim":"Showing that RAB37 localizes to insulin-containing dense-core granules and is required for glucose-stimulated insulin secretion—without engaging Rab3a or Rab27a effectors—established RAB37 as a functionally distinct exocytic regulator in β-cells.","evidence":"Confocal microscopy, RNAi, granule apposition counting, and pull-down assays in pancreatic β-cells","pmids":["23826383"],"confidence":"Medium","gaps":["RAB37-specific effector in β-cells not identified","In vivo glucose homeostasis not tested"]},{"year":2014,"claim":"Identification of TIMP1 as a direct GTP-dependent cargo of RAB37 vesicles, with in vivo metastasis suppression, provided the first mechanistic link between RAB37-mediated exocytosis and cancer biology.","evidence":"Secretomics, nucleotide-binding mutants, co-localization imaging, and mouse metastasis models","pmids":["25183545"],"confidence":"High","gaps":["Vesicle fusion machinery not identified at this stage","Structural basis for cargo recognition unknown"]},{"year":2016,"claim":"Discovery that RAB37 negatively regulates mast cell degranulation by forming a Rab27–Munc13-4–Rab37 complex, and that it mediates TSP1 exocytosis to suppress angiogenesis, revealed context-dependent positive and negative roles in vesicle trafficking.","evidence":"Reciprocal co-IP, double-knockdown epistasis in RBL-2H3 mast cells; TSP1 secretion assays and in vivo angiogenesis models in cancer cells","pmids":["26931073","28151721"],"confidence":"High","gaps":["Structural basis for GTP-independent Munc13-4 interaction unclear","How RAB37 switches between positive and negative exocytic roles unknown"]},{"year":2017,"claim":"Identifying PKCα phosphorylation of RAB37 at T172 as a switch that reduces GTP loading and impairs TIMP1 vesicle co-localization defined the first post-translational regulatory mechanism for RAB37 activity.","evidence":"In vitro kinase assay, phospho-mimetic/phospho-dead mutagenesis, co-localization imaging, and in vivo mouse metastasis model","pmids":["29312551"],"confidence":"High","gaps":["Phosphatase that reverses T172 phosphorylation not identified","Whether phosphorylation affects all RAB37 cargos or is TIMP1-specific unknown"]},{"year":2017,"claim":"Demonstrating that GTP-bound RAB37 directly binds ATG5 and promotes ATG5–ATG12–ATG16L1 complex assembly on isolation membranes expanded RAB37 function from conventional exocytosis to autophagosome biogenesis.","evidence":"Co-immunoprecipitation with nucleotide mutants, LC3B lipidation assay, autophagosome formation assay, knockdown/overexpression","pmids":["29229996"],"confidence":"High","gaps":["How RAB37 is recruited to isolation membranes unknown","Relative contribution of RAB37 versus other autophagy-regulating Rabs not compared"]},{"year":2018,"claim":"Identification of VAMP8 as the v-SNARE required for RAB37-mediated TIMP1 exocytosis, plus discovery of additional cargos (SFRP1, sST2, TIMP2), established the vesicle fusion machinery and broadened the RAB37 cargo repertoire to include Wnt antagonism and immune modulation.","evidence":"Reciprocal co-IP, TIRF/confocal microscopy, in vivo lung-to-lung metastasis models; reconstitution with recombinant SFRP1; sST2 secretion and macrophage polarization assays; TIMP2 secretion and MMP2 activity assays","pmids":["30165196","30158579","29717487","30131385"],"confidence":"High","gaps":["Cargo sorting signal on vesicle cargos not defined","Whether VAMP8 is required for all RAB37 cargos not tested"]},{"year":2022,"claim":"Discovery that RAB37 mediates secretory autophagy of TIMP1 via Sec22b-containing autophagosomes, and that it traffics CHI3L1 in immune cells, unified RAB37's exocytic and autophagic functions into a secretory autophagy pathway.","evidence":"Autophagosome purification, ATG5/ATG7/Sec22b knockdown, TIMP1 secretion assay, in vivo metastasis model; RAB37 KO mice with vesicle isolation and TIRF/confocal microscopy for CHI3L1","pmids":["36457117","34987649"],"confidence":"High","gaps":["How RAB37 vesicles are redirected to secretory versus degradative autophagy pathways unknown","Whether Sec22b interaction is direct or scaffold-mediated not resolved"]},{"year":2024,"claim":"Identification of RPGR as a bona fide GEF for RAB37—catalyzing GDP-to-GTP exchange via its RCC1-like domain—and showing that loss of RPGR causes autophagy-dependent photoreceptor degeneration defined the upstream activation mechanism.","evidence":"In vitro GEF activity assay (GDP-to-GTP exchange kinetics), co-IP, Rpgr KO mice, AAV-mediated rescue","pmids":["38536817"],"confidence":"High","gaps":["Whether RPGR is the sole GEF or other GEFs exist for RAB37 in non-retinal tissues unknown","GAP for RAB37 not identified"]},{"year":2024,"claim":"Demonstrating GTP-dependent trafficking of PD-1 to the T-cell surface, modulated by glycosylation status, and that RAB37 KO enhances anti-tumor T-cell responses, established RAB37 as a regulator of immune checkpoint presentation.","evidence":"GTPase and glycosylation mutants, co-localization imaging, RAB37 KO mice with T-cell functional assays","pmids":["38321486"],"confidence":"High","gaps":["Whether RAB37 regulates other immune checkpoint receptors unknown","Therapeutic benefit of RAB37 inhibition on checkpoint blockade not tested"]},{"year":2025,"claim":"Revealing that GDP-bound RAB37 sequesters STAT1 in the cytosol by binding its NLS, suppressing type I IFN signaling, established a non-vesicular, nucleotide-state-dependent signaling function for RAB37.","evidence":"KO transcriptomics, co-IP mapping to STAT1 NLS, nuclear translocation assay in BMDMs, in vivo tumor models","pmids":["39984679"],"confidence":"Medium","gaps":["Whether STAT1 sequestration competes with vesicle trafficking functions of GDP-RAB37 unknown","Structural basis of RAB37-GDP/STAT1-NLS interaction not determined"]},{"year":null,"claim":"Key unresolved questions include the identity of the RAB37 GAP, the structural basis for cargo recognition and sorting between conventional and secretory autophagy pathways, and whether the GDP-bound STAT1-sequestering function operates independently of vesicle trafficking.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No GAP identified for RAB37","No structural model of RAB37–cargo or RAB37–ATG5 interface","Mechanism distinguishing secretory vs. degradative autophagy cargo selection unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[4,8,14,16,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,24]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,3,4,11,16,21]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[24]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,21]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,3,4,6,11,16,21]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8,17,18,22,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,14,21,24,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,24]}],"complexes":["Rab27-Munc13-4-Rab37 complex"],"partners":["ATG5","VAMP8","RPGR","TIMP1","MUNC13-4","SEC22B","STAT1","PRKCA"],"other_free_text":[]},"mechanistic_narrative":"RAB37 is a small GTPase that functions as a master regulator of vesicle-mediated exocytosis and autophagosome biogenesis, controlling the secretion of diverse cargo proteins and modulating immune cell function, cancer metastasis, and tissue homeostasis. In its GTP-bound state, RAB37 traffics cargo-laden vesicles—including TIMP1, TIMP2, TSP1, SFRP1, sST2, IL-6, CHI3L1, OPN, Hsp90α, and PD-1—to the plasma membrane for secretion or surface presentation, utilizing the v-SNARE VAMP8 for membrane fusion and the SNARE Sec22b for secretory autophagy [PMID:25183545, PMID:30165196, PMID:36457117, PMID:38321486, PMID:41535255]. GTP-bound RAB37 also directly binds ATG5 to promote ATG5–ATG12–ATG16L1 complex assembly on isolation membranes, driving LC3B lipidation and autophagosome formation, a function activated by its GEF RPGR and negatively regulated by PKCα-mediated phosphorylation at T172 [PMID:29229996, PMID:38536817, PMID:29312551]. In its GDP-bound state, RAB37 sequesters STAT1 in the cytosol by binding its nuclear localization sequence, suppressing type I interferon signaling and promoting M2-like macrophage polarization [PMID:39984679]."},"prefetch_data":{"uniprot":{"accession":"Q96AX2","full_name":"Ras-related protein Rab-37","aliases":[],"length_aa":223,"mass_kda":24.8,"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 (PubMed:38536817). Acts as an organizer for autophagosome biogenesis in a GTP-dependent manner (PubMed:38536817). Involved in retinal homeostasis by autophagy regulation (PubMed:38536817)","subcellular_location":"Cytoplasmic vesicle; Cell projection, cilium","url":"https://www.uniprot.org/uniprotkb/Q96AX2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RAB37","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RAB37","total_profiled":1310},"omim":[{"mim_id":"617812","title":"SOLUTE CARRIER FAMILY 35, MEMBER G2; SLC35G2","url":"https://www.omim.org/entry/617812"},{"mim_id":"609956","title":"RAS-ASSOCIATED PROTEIN RAB37; RAB37","url":"https://www.omim.org/entry/609956"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":23.1},{"tissue":"brain","ntpm":36.8},{"tissue":"lymphoid tissue","ntpm":19.8}],"url":"https://www.proteinatlas.org/search/RAB37"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q96AX2","domains":[{"cath_id":"3.40.50.300","chopping":"27-219","consensus_level":"high","plddt":87.9453,"start":27,"end":219}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96AX2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96AX2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96AX2-F1-predicted_aligned_error_v6.png","plddt_mean":83.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RAB37","jax_strain_url":"https://www.jax.org/strain/search?query=RAB37"},"sequence":{"accession":"Q96AX2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96AX2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96AX2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96AX2"}},"corpus_meta":[{"pmid":"29229996","id":"PMC_29229996","title":"RAB37 interacts directly with ATG5 and promotes autophagosome formation via regulating ATG5-12-16 complex assembly.","date":"2017","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/29229996","citation_count":80,"is_preprint":false},{"pmid":"34093869","id":"PMC_34093869","title":"Converged Rab37/IL-6 trafficking and STAT3/PD-1 transcription axes elicit an immunosuppressive lung tumor microenvironment.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/34093869","citation_count":65,"is_preprint":false},{"pmid":"10722846","id":"PMC_10722846","title":"Rab37 is a novel mast cell specific GTPase localized to secretory granules.","date":"2000","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10722846","citation_count":64,"is_preprint":false},{"pmid":"25183545","id":"PMC_25183545","title":"Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25183545","citation_count":52,"is_preprint":false},{"pmid":"28151721","id":"PMC_28151721","title":"Dysregulation of Rab37-Mediated Cross-talk between Cancer Cells and Endothelial Cells via Thrombospondin-1 Promotes Tumor Neovasculature and Metastasis.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/28151721","citation_count":48,"is_preprint":false},{"pmid":"21805469","id":"PMC_21805469","title":"Release of TNF-α from macrophages is mediated by small GTPase Rab37.","date":"2011","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21805469","citation_count":46,"is_preprint":false},{"pmid":"34987649","id":"PMC_34987649","title":"Targeting protumor factor chitinase-3-like-1 secreted by Rab37 vesicles for cancer immunotherapy.","date":"2022","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/34987649","citation_count":42,"is_preprint":false},{"pmid":"23826383","id":"PMC_23826383","title":"The GTPase Rab37 Participates in the Control of Insulin Exocytosis.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23826383","citation_count":32,"is_preprint":false},{"pmid":"30158579","id":"PMC_30158579","title":"Rab37 mediates exocytosis of secreted frizzled-related protein 1 to inhibit Wnt signaling and thus suppress lung cancer stemness.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30158579","citation_count":31,"is_preprint":false},{"pmid":"29717487","id":"PMC_29717487","title":"Rab37 in lung cancer mediates exocytosis of soluble ST2 and thus skews macrophages toward tumor-suppressing phenotype.","date":"2018","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29717487","citation_count":30,"is_preprint":false},{"pmid":"30131385","id":"PMC_30131385","title":"RAB37 Hypermethylation Regulates Metastasis and Resistance to Docetaxel-Based Induction Chemotherapy in Nasopharyngeal Carcinoma.","date":"2018","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/30131385","citation_count":28,"is_preprint":false},{"pmid":"26931073","id":"PMC_26931073","title":"Mast cell degranulation is negatively regulated by the Munc13-4-binding small-guanosine triphosphatase Rab37.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26931073","citation_count":24,"is_preprint":false},{"pmid":"22035799","id":"PMC_22035799","title":"Disruption of Wnt planar cell polarity signaling by aberrant accumulation of the MetAP-2 substrate Rab37.","date":"2011","source":"Chemistry & biology","url":"https://pubmed.ncbi.nlm.nih.gov/22035799","citation_count":24,"is_preprint":false},{"pmid":"29388490","id":"PMC_29388490","title":"The small GTPase RAB37 functions as an organizer for autophagosome biogenesis.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/29388490","citation_count":23,"is_preprint":false},{"pmid":"30165196","id":"PMC_30165196","title":"VAMP8, a vesicle-SNARE required for RAB37-mediated exocytosis, possesses a tumor metastasis suppressor function.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30165196","citation_count":22,"is_preprint":false},{"pmid":"36457117","id":"PMC_36457117","title":"Secretory autophagy promotes Rab37-mediated exocytosis of tissue inhibitor of metalloproteinase 1.","date":"2022","source":"Journal of biomedical 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Rab37.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29312551","citation_count":13,"is_preprint":false},{"pmid":"38321486","id":"PMC_38321486","title":"Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer.","date":"2024","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/38321486","citation_count":10,"is_preprint":false},{"pmid":"37151129","id":"PMC_37151129","title":"Secretory autophagy-promoted cargo exocytosis requires active RAB37.","date":"2023","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/37151129","citation_count":9,"is_preprint":false},{"pmid":"38536817","id":"PMC_38536817","title":"RPGR is a guanine nucleotide exchange factor for the small GTPase RAB37 required for retinal function via autophagy regulation.","date":"2024","source":"Cell 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progression.","date":"2026","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/41535255","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17252,"output_tokens":5768,"usd":0.069138},"stage2":{"model":"claude-opus-4-6","input_tokens":9434,"output_tokens":3314,"usd":0.19503},"total_usd":0.264168,"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\": 2000,\n      \"finding\": \"Rab37 is a novel Rab GTPase specifically expressed in mast cells and localizes to secretory granules, as shown by GFP-tagged Rab37 expression in bone marrow mast cells.\",\n      \"method\": \"GFP-tagging and fluorescence microscopy in bone marrow mast cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single localization experiment with functional implication but no direct functional assay\",\n      \"pmids\": [\"10722846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rab37 controls TNF-α secretion from activated macrophages by interacting with Munc13-1; TNF-α-containing vesicles co-localize with both Rab37 and Munc13-1, and knockdown of either Rab37 or Munc13-1 reduces TNF-α secretion.\",\n      \"method\": \"siRNA knockdown, overexpression, LC-MS/MS interactome, immunocytochemistry co-localization\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — multiple methods (KD, OE, MS, imaging) in single lab\",\n      \"pmids\": [\"21805469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rab37 is a substrate of methionine aminopeptidase-2 (MetAP-2); aberrant accumulation of Rab37 due to MetAP-2 inhibition (TNP-470) disrupts Wnt planar cell polarity (PCP) signaling, demonstrated using a NME-resistant Rab37 point mutant that phenocopies MetAP-2 inhibition.\",\n      \"method\": \"Point mutant expression, MetAP-2 inhibitor TNP-470, Wnt PCP signaling assays\",\n      \"journal\": \"Chemistry & biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis plus chemical-genetic approach with functional readout\",\n      \"pmids\": [\"22035799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rab37 localizes to insulin-containing large dense core granules in pancreatic β-cells and is required for glucose-induced insulin secretion and granule docking at the plasma membrane; Rab37 does not interact with known Rab3a or Rab27a effectors, indicating a distinct mechanism.\",\n      \"method\": \"Confocal microscopy, RNA interference, granule apposition counting, pull-down assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with defined cellular phenotype, negative pull-down controls, localization confirmed\",\n      \"pmids\": [\"23826383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rab37 mediates exocytosis of TIMP1 in a nucleotide (GTP)-dependent manner; TIMP1 is a direct cargo of Rab37 vesicles, and its secretion suppresses MMP9 activity and cancer cell migration/metastasis in vitro and in vivo.\",\n      \"method\": \"Secretomics, co-localization imaging, nucleotide-binding mutants, in vitro migration assays, mouse metastasis models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (secretomics, GTPase mutants, in vivo reconstitution) in a single study\",\n      \"pmids\": [\"25183545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rab37 negatively regulates mast cell degranulation by interacting with Munc13-4 in a GTP-independent manner, forming a Rab27-Munc13-4-Rab37 complex that counteracts the vesicle-priming activity of the Rab27-Munc13-4 system.\",\n      \"method\": \"siRNA knockdown, dominant-active mutant overexpression, co-immunoprecipitation, co-localization in RBL-2H3 cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, genetic epistasis (double KD), and functional readout with orthogonal methods\",\n      \"pmids\": [\"26931073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Rab37 mediates exocytosis of thrombospondin-1 (TSP1) from cancer cells; secreted TSP1 inhibits p-FAK/p-paxillin/p-ERK migration signaling in both cancer epithelial cells and endothelial cells to suppress angiogenesis and metastasis.\",\n      \"method\": \"Cell migration/invasion assays, in vivo angiogenesis and metastasis models, TSP1 secretion assays\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cargo (TSP1), pathway placement, in vivo validation, single lab\",\n      \"pmids\": [\"28151721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PKCα phosphorylates Rab37 at threonine 172 (T172), which reduces Rab37 GTP-bound state, impairs co-localization of Rab37 with TIMP1 vesicles, and inhibits TIMP1 exocytosis, thereby enhancing lung cancer metastasis. Phospho-mimetic T172D mutant promotes metastasis in vivo.\",\n      \"method\": \"In vitro kinase assay, phospho-mimetic and phospho-dead mutagenesis, co-localization imaging, in vivo mouse metastasis model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — identification of specific phosphorylation site by mutagenesis, in vitro kinase assay, and in vivo validation\",\n      \"pmids\": [\"29312551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GTP-bound RAB37 directly binds ATG5 and promotes assembly of the ATG5-ATG12-ATG16L1 complex on isolation membranes, thereby facilitating LC3B lipidation and autophagosome formation. GDP-stabilized RAB37 mutant impairs this interaction.\",\n      \"method\": \"Co-immunoprecipitation, GTPase mutant analysis, LC3B lipidation assay, autophagosome formation assay, RAB37 knockdown/overexpression\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding shown by pull-down with nucleotide mutants, functional complex assembly assay, multiple orthogonal methods\",\n      \"pmids\": [\"29229996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rab37 mediates exocytosis of SFRP1 (an extracellular Wnt antagonist), and SFRP1 secretion is required for Rab37-mediated suppression of Wnt signaling and cancer stemness in vitro and in vivo.\",\n      \"method\": \"Reconstitution experiments, xenograft tumor initiation assay, recombinant SFRP1 rescue, Wnt signaling reporters\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reconstitution with recombinant protein and in vivo model, single lab\",\n      \"pmids\": [\"30158579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Rab37 mediates exocytosis of soluble ST2 (sST2) from lung cancer cells; secreted sST2 skews macrophage polarization toward anti-tumoral M1-like phenotype and suppresses tumor growth in xenografts.\",\n      \"method\": \"sST2 secretion assay, macrophage polarization assay, xenograft mouse model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cargo (sST2), in vivo validation, single lab\",\n      \"pmids\": [\"29717487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"VAMP8 (a v-SNARE) interacts with RAB37 and is required for RAB37-mediated vesicle trafficking and exocytosis of TIMP1; VAMP8 co-localizes with RAB37 and TIMP1 vesicles and is essential for metastasis suppression in vivo.\",\n      \"method\": \"Co-immunoprecipitation, confocal and TIRF microscopy, in vivo reconstitution (tail-vein and lung-to-lung metastasis models)\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction, imaging co-localization, in vivo reconstitution, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30165196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RAB37 co-localizes with TIMP2, regulates TIMP2 secretion, and inhibits downstream MMP2 activity to suppress nasopharyngeal carcinoma metastasis; RAB37 promoter hypermethylation silences this pathway.\",\n      \"method\": \"Co-localization assay, TIMP2 secretion assay, MMP2 activity assay, RAB37 overexpression/knockdown\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — defined cargo and downstream effector, functional assays, single lab\",\n      \"pmids\": [\"30131385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PKCα phosphorylates RAB37 to inactivate it; methionine promotes RAB37 methylation and phosphorylation via suppression of the miR-200b/PKCα axis, thereby repressing RAB37-mediated autophagy in gastric cancer stem cells.\",\n      \"method\": \"Lentiviral methionine-γ-lyase overexpression, miR-200b measurement, PKCα knockdown, autophagy assays, in vivo tumor model\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — pathway epistasis established with multiple genetic interventions, single lab\",\n      \"pmids\": [\"32926650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Rab37 regulates IL-6 secretion in a GTPase-dependent manner in macrophages; macrophage-derived IL-6 promotes STAT3-dependent PD-1 mRNA expression in CD8+ T cells, linking Rab37 vesicle trafficking to immunosuppression. This was validated in Rab37 knockout mice and with vesicle isolation.\",\n      \"method\": \"Rab37 KO mice, vesicle isolation, GTPase mutants, ChIP assay for STAT3 at PD-1 promoter, imaging\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice, vesicle isolation, ChIP, GTPase mutants, multiple orthogonal methods\",\n      \"pmids\": [\"34093869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RAB37 directly interacts with TIMP1 and promotes adipogenic differentiation of hADSCs via the TIMP1/CD63/integrin β1 signaling pathway, as shown by proximity ligation assay and FAK phosphorylation.\",\n      \"method\": \"Proximity ligation assay, TIMP1 ELISA, CD63/integrin β1 knockdown, FAK phosphorylation assay, Oil Red O staining\",\n      \"journal\": \"Stem cells international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — direct interaction shown by PLA, pathway placement via knockdown, single lab\",\n      \"pmids\": [\"34858503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Rab37 mediates CHI3L1 (chitinase-3-like-1) intracellular vesicle trafficking and exocytosis in a GTP-dependent manner in T cells and macrophages; this was abolished in Rab37 KO mice splenocytes/BMDMs and in cells expressing inactive Rab37.\",\n      \"method\": \"Rab37 KO mice, vesicle isolation, TIRF and confocal microscopy, GTPase mutants\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice, vesicle isolation, multiple imaging modalities and GTPase mutants\",\n      \"pmids\": [\"34987649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Secretory autophagy promotes Rab37-mediated TIMP1 exocytosis; Rab37 and Sec22b co-localize in purified autophagosomes, and silencing of ATG5, ATG7, or Sec22b reduces TIMP1 secretion under starvation-induced autophagy conditions.\",\n      \"method\": \"Autophagosome purification, co-localization imaging, ATG5/ATG7/Sec22b knockdown, TIMP1 secretion assay, in vivo lung-to-lung metastasis mouse model\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — autophagosome purification, multiple genetic KDs, in vivo model, orthogonal methods\",\n      \"pmids\": [\"36457117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Active (GTP-bound) RAB37 simultaneously regulates autophagy activation and TIMP1 secretion via secretory autophagy; Sec22b (SNARE) is required for this pathway, and starvation-activated RAB37 enhances TIMP1 exocytosis in a Sec22b-dependent manner.\",\n      \"method\": \"GTPase mutants, Sec22b knockdown, TIMP1 secretion assay, in vivo mouse model, autophagy markers\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — GTPase mutants and genetic KD with functional readout, in vivo validation, single lab\",\n      \"pmids\": [\"37151129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Rab37 directly binds Hsp90α and TIMP1 (shown by proximity ligation assay) and promotes their secretion from ADSCs; this regulates endothelial differentiation and diabetic wound healing.\",\n      \"method\": \"LC-MS/MS, ELISA, proximity ligation assay, Hsp90α/TIMP1 knockdown, in vivo diabetic wound model\",\n      \"journal\": \"Stem cell reviews and reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — direct binding shown by PLA, functional rescue, in vivo model, single lab\",\n      \"pmids\": [\"36627432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RPGR (retinitis pigmentosa GTPase regulator) is a guanine nucleotide exchange factor (GEF) for RAB37; RPGR directly interacts with RAB37 via its RCC1-like domain and accelerates GDP-to-GTP exchange to promote autophagy. Rpgr KO mice show photoreceptor degeneration due to autophagy impairment, rescued by AAV-mediated RPGR re-expression.\",\n      \"method\": \"GEF activity assay (GDP-to-GTP exchange kinetics), co-immunoprecipitation, Rpgr KO mice, AAV rescue, autophagy markers\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro GEF activity assay with direct binding, KO mouse model, and in vivo genetic rescue\",\n      \"pmids\": [\"38536817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Rab37 mediates trafficking and plasma membrane presentation of PD-1 in T cells in a GTP-dependent manner; glycosylation-deficient PD-1 mutant delays recruitment to Rab37 vesicles, stalling membrane presentation. Rab37 KO mice show increased T cell activity in tumors.\",\n      \"method\": \"GTPase mutants, co-localization imaging, glycosylation mutant, Rab37 KO mice, T cell functional assays\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — GTPase and glycosylation mutants with mechanistic imaging, KO mice with defined immune phenotype\",\n      \"pmids\": [\"38321486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RAB37-mediated autophagy is required for ovarian homeostasis and follicular development; conditional knockout of Rab37 in oocytes impairs autophagy, disrupts follicular homeostasis, and causes ovarian dysfunction in mice. E2F1 and EGR2 transcription factors synergistically activate Rab37 transcription.\",\n      \"method\": \"Conditional KO mice (oocyte-specific), autophagy markers, transcription factor ChIP/reporter assays, flunarizine rescue\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined cellular phenotype and pharmacological rescue, single lab\",\n      \"pmids\": [\"39113565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RAB37 promotes autophagic degradation of β-catenin by strengthening the interaction between p62 and β-catenin; this suppresses EMT, migration and invasion of gastric cancer cells in a GTPase activity-dependent manner, reversed by autophagy inhibitor chloroquine.\",\n      \"method\": \"Co-immunoprecipitation, autophagy inhibitor rescue (chloroquine), GTPase activity mutants, wound healing/transwell assays, in vivo pulmonary metastasis model\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP, chemical rescue, GTPase mutants, in vivo model, single lab\",\n      \"pmids\": [\"39699800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GDP-bound (inactive) Rab37 interacts with the nuclear localization sequence of STAT1 in the cytosol, sequestering it from nuclear translocation and transcription, thereby downregulating type I IFN pathway genes and promoting M2-like TAM polarization.\",\n      \"method\": \"cDNA microarray (Rab37 KO vs WT BMDMs), co-immunoprecipitation with NLS of STAT1, STAT1 nuclear translocation assay, in vitro/in vivo assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO transcriptomics, co-IP mapping to NLS domain, nuclear translocation functional assay, single lab\",\n      \"pmids\": [\"39984679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Rab37 promotes OPN (osteopontin) secretion in macrophages, which activates STAT3 signaling in an autocrine loop to sustain Spp1+ TAM polarization and paracrine promotion of lung cancer cell proliferation/invasion.\",\n      \"method\": \"Single-cell RNA sequencing, Rab37 KO mice, OPN secretion assay, STAT3 signaling assay, in vivo tumor models\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — scRNA-seq, KO mice, defined cargo and signaling pathway, single lab\",\n      \"pmids\": [\"41535255\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAB37 is a small GTPase that cycles between inactive GDP-bound and active GTP-bound states to regulate vesicle trafficking and exocytosis of multiple secreted cargos (TIMP1, TIMP2, TSP1, SFRP1, sST2, IL-6, CHI3L1, OPN, PD-1, Hsp90α) as well as autophagosome biogenesis via direct interaction with ATG5 to promote ATG5-ATG12-ATG16L1 complex assembly; its activity is regulated by the GEF RPGR (which catalyzes GDP-to-GTP exchange) and is negatively modulated by PKCα-mediated phosphorylation at T172, while in its GDP-bound form it additionally sequesters STAT1 in the cytosol to suppress type I IFN signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RAB37 is a small GTPase that functions as a master regulator of vesicle-mediated exocytosis and autophagosome biogenesis, controlling the secretion of diverse cargo proteins and modulating immune cell function, cancer metastasis, and tissue homeostasis. In its GTP-bound state, RAB37 traffics cargo-laden vesicles—including TIMP1, TIMP2, TSP1, SFRP1, sST2, IL-6, CHI3L1, OPN, Hsp90α, and PD-1—to the plasma membrane for secretion or surface presentation, utilizing the v-SNARE VAMP8 for membrane fusion and the SNARE Sec22b for secretory autophagy [PMID:25183545, PMID:30165196, PMID:36457117, PMID:38321486, PMID:41535255]. GTP-bound RAB37 also directly binds ATG5 to promote ATG5–ATG12–ATG16L1 complex assembly on isolation membranes, driving LC3B lipidation and autophagosome formation, a function activated by its GEF RPGR and negatively regulated by PKCα-mediated phosphorylation at T172 [PMID:29229996, PMID:38536817, PMID:29312551]. In its GDP-bound state, RAB37 sequesters STAT1 in the cytosol by binding its nuclear localization sequence, suppressing type I interferon signaling and promoting M2-like macrophage polarization [PMID:39984679].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying RAB37 as a mast-cell-specific Rab GTPase on secretory granules established the first link between this uncharacterized GTPase and regulated exocytosis.\",\n      \"evidence\": \"GFP-tagging and fluorescence microscopy in bone marrow-derived mast cells\",\n      \"pmids\": [\"10722846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional assay for secretion performed\", \"Expression survey limited to mast cells\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that RAB37 controls TNF-α secretion through interaction with Munc13-1 in macrophages revealed its first defined exocytic function and effector partner beyond mast cells.\",\n      \"evidence\": \"siRNA knockdown, overexpression, LC-MS/MS interactome, and immunocytochemistry co-localization in macrophages\",\n      \"pmids\": [\"21805469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding vs. indirect complex membership not resolved\", \"Specificity relative to other secretory Rabs not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that RAB37 localizes to insulin-containing dense-core granules and is required for glucose-stimulated insulin secretion—without engaging Rab3a or Rab27a effectors—established RAB37 as a functionally distinct exocytic regulator in β-cells.\",\n      \"evidence\": \"Confocal microscopy, RNAi, granule apposition counting, and pull-down assays in pancreatic β-cells\",\n      \"pmids\": [\"23826383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RAB37-specific effector in β-cells not identified\", \"In vivo glucose homeostasis not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identification of TIMP1 as a direct GTP-dependent cargo of RAB37 vesicles, with in vivo metastasis suppression, provided the first mechanistic link between RAB37-mediated exocytosis and cancer biology.\",\n      \"evidence\": \"Secretomics, nucleotide-binding mutants, co-localization imaging, and mouse metastasis models\",\n      \"pmids\": [\"25183545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Vesicle fusion machinery not identified at this stage\", \"Structural basis for cargo recognition unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that RAB37 negatively regulates mast cell degranulation by forming a Rab27–Munc13-4–Rab37 complex, and that it mediates TSP1 exocytosis to suppress angiogenesis, revealed context-dependent positive and negative roles in vesicle trafficking.\",\n      \"evidence\": \"Reciprocal co-IP, double-knockdown epistasis in RBL-2H3 mast cells; TSP1 secretion assays and in vivo angiogenesis models in cancer cells\",\n      \"pmids\": [\"26931073\", \"28151721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for GTP-independent Munc13-4 interaction unclear\", \"How RAB37 switches between positive and negative exocytic roles unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying PKCα phosphorylation of RAB37 at T172 as a switch that reduces GTP loading and impairs TIMP1 vesicle co-localization defined the first post-translational regulatory mechanism for RAB37 activity.\",\n      \"evidence\": \"In vitro kinase assay, phospho-mimetic/phospho-dead mutagenesis, co-localization imaging, and in vivo mouse metastasis model\",\n      \"pmids\": [\"29312551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase that reverses T172 phosphorylation not identified\", \"Whether phosphorylation affects all RAB37 cargos or is TIMP1-specific unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that GTP-bound RAB37 directly binds ATG5 and promotes ATG5–ATG12–ATG16L1 complex assembly on isolation membranes expanded RAB37 function from conventional exocytosis to autophagosome biogenesis.\",\n      \"evidence\": \"Co-immunoprecipitation with nucleotide mutants, LC3B lipidation assay, autophagosome formation assay, knockdown/overexpression\",\n      \"pmids\": [\"29229996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAB37 is recruited to isolation membranes unknown\", \"Relative contribution of RAB37 versus other autophagy-regulating Rabs not compared\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of VAMP8 as the v-SNARE required for RAB37-mediated TIMP1 exocytosis, plus discovery of additional cargos (SFRP1, sST2, TIMP2), established the vesicle fusion machinery and broadened the RAB37 cargo repertoire to include Wnt antagonism and immune modulation.\",\n      \"evidence\": \"Reciprocal co-IP, TIRF/confocal microscopy, in vivo lung-to-lung metastasis models; reconstitution with recombinant SFRP1; sST2 secretion and macrophage polarization assays; TIMP2 secretion and MMP2 activity assays\",\n      \"pmids\": [\"30165196\", \"30158579\", \"29717487\", \"30131385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo sorting signal on vesicle cargos not defined\", \"Whether VAMP8 is required for all RAB37 cargos not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that RAB37 mediates secretory autophagy of TIMP1 via Sec22b-containing autophagosomes, and that it traffics CHI3L1 in immune cells, unified RAB37's exocytic and autophagic functions into a secretory autophagy pathway.\",\n      \"evidence\": \"Autophagosome purification, ATG5/ATG7/Sec22b knockdown, TIMP1 secretion assay, in vivo metastasis model; RAB37 KO mice with vesicle isolation and TIRF/confocal microscopy for CHI3L1\",\n      \"pmids\": [\"36457117\", \"34987649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAB37 vesicles are redirected to secretory versus degradative autophagy pathways unknown\", \"Whether Sec22b interaction is direct or scaffold-mediated not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of RPGR as a bona fide GEF for RAB37—catalyzing GDP-to-GTP exchange via its RCC1-like domain—and showing that loss of RPGR causes autophagy-dependent photoreceptor degeneration defined the upstream activation mechanism.\",\n      \"evidence\": \"In vitro GEF activity assay (GDP-to-GTP exchange kinetics), co-IP, Rpgr KO mice, AAV-mediated rescue\",\n      \"pmids\": [\"38536817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RPGR is the sole GEF or other GEFs exist for RAB37 in non-retinal tissues unknown\", \"GAP for RAB37 not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating GTP-dependent trafficking of PD-1 to the T-cell surface, modulated by glycosylation status, and that RAB37 KO enhances anti-tumor T-cell responses, established RAB37 as a regulator of immune checkpoint presentation.\",\n      \"evidence\": \"GTPase and glycosylation mutants, co-localization imaging, RAB37 KO mice with T-cell functional assays\",\n      \"pmids\": [\"38321486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RAB37 regulates other immune checkpoint receptors unknown\", \"Therapeutic benefit of RAB37 inhibition on checkpoint blockade not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealing that GDP-bound RAB37 sequesters STAT1 in the cytosol by binding its NLS, suppressing type I IFN signaling, established a non-vesicular, nucleotide-state-dependent signaling function for RAB37.\",\n      \"evidence\": \"KO transcriptomics, co-IP mapping to STAT1 NLS, nuclear translocation assay in BMDMs, in vivo tumor models\",\n      \"pmids\": [\"39984679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STAT1 sequestration competes with vesicle trafficking functions of GDP-RAB37 unknown\", \"Structural basis of RAB37-GDP/STAT1-NLS interaction not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the RAB37 GAP, the structural basis for cargo recognition and sorting between conventional and secretory autophagy pathways, and whether the GDP-bound STAT1-sequestering function operates independently of vesicle trafficking.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No GAP identified for RAB37\", \"No structural model of RAB37–cargo or RAB37–ATG5 interface\", \"Mechanism distinguishing secretory vs. degradative autophagy cargo selection unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [4, 8, 14, 16, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 3, 4, 11, 16, 21]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 3, 4, 6, 11, 16, 21]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8, 17, 18, 22, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 14, 21, 24, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 24]}\n    ],\n    \"complexes\": [\n      \"Rab27-Munc13-4-Rab37 complex\"\n    ],\n    \"partners\": [\n      \"ATG5\",\n      \"VAMP8\",\n      \"RPGR\",\n      \"TIMP1\",\n      \"MUNC13-4\",\n      \"SEC22B\",\n      \"STAT1\",\n      \"PRKCA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}