{"gene":"RIN1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1997,"finding":"RIN1 binds to the ABL SH3 domain via a proline-rich sequence and is directly tyrosine phosphorylated by c-ABL; RIN1 also encodes a functional SH2 domain. Full-length RIN1 interacts with activated RAS in mammalian cells through its C-terminal effector-binding domain.","method":"In vitro SH3-domain binding assay, co-immunoprecipitation, tyrosine phosphorylation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays and phosphorylation confirmed in vitro and in cells, two orthogonal methods in a single focused study","pmids":["9144171"],"is_preprint":false},{"year":1997,"finding":"RIN1 potentiates BCR-ABL oncogenic activity and accelerates BCR-ABL-induced leukemia; this requires tyrosine phosphorylation of RIN1 and binding to ABL SH2 and SH3 domains. RIN1 is tyrosine phosphorylated and associated with BCR-ABL in human and murine leukemic cells.","method":"Co-immunoprecipitation from leukemic cells, retroviral transformation assay in hematopoietic cells, murine leukemia model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP from primary leukemic cells plus in vivo murine model, multiple orthogonal methods replicated across cell types","pmids":["9208849"],"is_preprint":false},{"year":2001,"finding":"The Vps9-homology domain of RIN1 is necessary and sufficient for binding to GDP-bound Rab5A and Vps21p, and RIN1 stimulates Rab5 guanine nucleotide exchange, Rab5A-dependent endosome fusion, and EGF receptor-mediated endocytosis. Activated RAS potentiates all three of these RIN1-mediated activities.","method":"In vitro GEF assay, endosome fusion assay, EGF receptor endocytosis assay, domain-deletion analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro GEF assay with domain mutagenesis plus functional endosome fusion and receptor endocytosis assays; multiple orthogonal methods","pmids":["11703925"],"is_preprint":false},{"year":2002,"finding":"RIN1 binds activated RAS with Kd ~22 nM, directly competing with RAF1 for RAS binding. RIN1 inhibits RAS-mediated cellular transformation (distinguishing it from other RAS effectors). RIN1 binds 14-3-3 proteins through serine 351, and phosphorylation of S351 by protein kinase D (PKD/PKCmu) in vitro and in vivo controls 14-3-3 binding and RIN1 membrane localization. S351A mutation shifts RIN1 to the plasma membrane and enhances RAS transformation blockade.","method":"Surface plasmon resonance (Kd measurement), competition binding assay, focus formation/transformation assay, co-immunoprecipitation, in vitro kinase assay, subcellular fractionation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative binding measurement, in vitro kinase assay with mutagenesis, and multiple cellular assays in a single rigorous study","pmids":["11784866"],"is_preprint":false},{"year":2003,"finding":"The SH2 domain of RIN1 mediates ligand-dependent binding to tyrosine-phosphorylated EGFR intracellular domain, recruits RIN1 to plasma membrane and endosomes upon EGF stimulation, and is required for EGFR internalization. Expression of the SH2 domain alone substantially impaired EGF internalization without affecting transferrin internalization.","method":"Co-immunoprecipitation, light microscopy/subcellular recruitment, dominant-negative SH2 domain expression, internalization assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain-deletion mutants plus functional internalization assay, two orthogonal methods in a single study","pmids":["12783862"],"is_preprint":false},{"year":2003,"finding":"RIN1 is preferentially expressed in postnatal forebrain neurons where it localizes in dendrites and is physically associated with RAS. Rin1 knockout mice show enhanced amygdala LTP and elevated amygdala-dependent aversive memory, indicating RIN1 is an inhibitory modulator of neuronal plasticity in fear memory formation.","method":"Immunolocalization in neurons, Rin1 gene knockout mice, amygdala LTP electrophysiology, fear conditioning behavioral assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined electrophysiological and behavioral phenotypes, multiple orthogonal readouts","pmids":["12574403"],"is_preprint":false},{"year":2005,"finding":"RIN1 is a direct activator of ABL tyrosine kinases: it binds ABL SH3 and SH2 domains, stimulates ABL2 catalytic activity in immune complexes and in a defined-component in vitro assay with purified ABL-binding domain (ABD), leading to increased phosphorylation of CRK and CRKL. Activated RAS forms a stable RAS-RIN1-ABL2 complex and enhances ABL2 activation. Deletion of the RAS-binding domain (RBD) strongly increases ABL2 activation, suggesting RAS relieves RIN1 autoinhibition. Rin1-/- mammary epithelial cells show accelerated adhesion and increased motility.","method":"In vitro ABL2 kinase assay with purified proteins, co-immunoprecipitation, Rin1 knockout mouse cells, cell adhesion and migration assay, RNAi knockdown","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase reconstitution with purified components, mutagenesis, co-IP, and Rin1 KO cellular phenotype — multiple orthogonal methods","pmids":["15886098"],"is_preprint":false},{"year":2006,"finding":"RIN1 regulates insulin receptor internalization and signaling: RIN1 expression enhances insulin receptor-mediated and fluid-phase insulin-stimulated endocytosis via its Rab5-GEF and Ras-binding domains; the SH2 domain of RIN1 associates with tyrosine-phosphorylated insulin receptor. RIN1 expression selectively blocks ERK1/2 and Akt1 activation without affecting JNK or p38.","method":"Retroviral expression of RIN1 deletion mutants, receptor internalization assay, co-immunoprecipitation, kinase activity assays, confocal microscopy co-localization","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mutants plus functional endocytosis and signaling assays, single lab","pmids":["16457816"],"is_preprint":false},{"year":2007,"finding":"RIN1 interacts with STAM2 (signal-transducing adaptor molecule 2) via its proline-rich domain (PRD) and STAM2's SH3 domain. This interaction is required for RIN1-accelerated EGFR degradation following EGF stimulation; a RIN1 mutant lacking the PRD (RIN1ΔPRD) neither binds STAM2 nor accelerates EGFR degradation.","method":"Co-immunoprecipitation, RNAi knockdown, confocal co-localization (GFP-Rin1 and HA-STAM2), domain-deletion mutagenesis, EGFR degradation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain mutants plus RNAi rescue and functional EGFR degradation assay, multiple orthogonal methods","pmids":["17403676"],"is_preprint":false},{"year":2008,"finding":"RIN1 (Rin1), expressed specifically in postnatal brain excitatory neurons, interacts with EphA4 receptor tyrosine kinase in synaptosomal fractions via its SH2 domain, mediates EphA4 endocytosis in amygdala neurons following ephrinB3 engagement, and suppresses synaptic plasticity in the amygdala.","method":"Co-immunoprecipitation from synaptosomal fractions, EphA4 endocytosis assay in amygdala neurons, Rin1 knockout mice, amygdala LTP electrophysiology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP from native synaptosomal fractions, functional endocytosis assay, and KO electrophysiology in a single study with multiple orthogonal methods","pmids":["18723684"],"is_preprint":false},{"year":2010,"finding":"RIN1 silencing decreases BCR-ABL1 kinase activity; RIN1 overexpression increases it. Rin1-/- bone marrow cells are not transformed by BCR-ABL1, ETV6-ABL1, or drug-resistant BCR-ABL1(T315I); rescue by ectopic RIN1 confirms cell-autonomous mechanism. RIN1 silencing increases imatinib sensitivity, consistent with RIN1 stabilizing an activated BCR-ABL1 conformation with reduced drug affinity.","method":"RNAi knockdown, Rin1 knockout bone marrow transformation assay, ectopic RIN1 rescue, BCR-ABL1 kinase activity assay, imatinib sensitivity assay","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with ectopic rescue plus RNAi and kinase activity measurements, multiple orthogonal methods confirming cell-autonomous mechanism","pmids":["21102429"],"is_preprint":false},{"year":2012,"finding":"RIN1 orchestrates EGFR fate by activating RAB5 GTPases (favoring EGFR degradation over recycling) and ABL tyrosine kinases (stabilizing EGFR and inhibiting macropinocytosis). A RIN1(QM) mutant that blocks ABL activation causes EGF-stimulated membrane ruffling, actin remodeling, macropinocytosis (dextran uptake), and EGFR degradation. EGFR activation also promotes RIN1 interaction with BIN1, a membrane-bending protein.","method":"RNAi silencing and overexpression of RIN1/mutants, EGFR degradation assay, macropinocytosis (dextran uptake) assay, ABL kinase inhibitor treatment, co-immunoprecipitation (RIN1-BIN1), actin remodeling imaging","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays with structure-function mutants and pharmacological validation in a single study","pmids":["22976291"],"is_preprint":false},{"year":2014,"finding":"RIN1's RAB5-GEF activity is required for efficient Listeria monocytogenes invasion of intestinal epithelial cells (RIN1 is rapidly engaged post-infection) and subsequently facilitates phagosome-lysosome fusion to promote bacterial clearance, performing counterbalancing roles at early and late infection stages.","method":"RIN1 RNAi knockdown, L. monocytogenes invasion assay, phagosome-lysosome fusion assay in epithelial cells","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with defined invasion and phagosome fusion phenotypes, single lab, two functional readouts","pmids":["25082076"],"is_preprint":false},{"year":2015,"finding":"An engineered ABL SH3 mutant (T79Y) blocks the RIN1–BCR-ABL SH3 interaction via PxxP motifs, represses BCR-ABL autophosphorylation and downstream signaling pathways, and increases imatinib sensitivity in resistant CML cell lines in vitro and in vivo.","method":"Co-immunoprecipitation (SH3-RIN1 interaction), BCR-ABL kinase activity assay, cell proliferation assay, xenograft mouse model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with engineered SH3 mutant plus kinase activity and in vivo tumor assay, single lab","pmids":["26321052"],"is_preprint":false},{"year":2015,"finding":"A TR-FRET-based HTS identified small molecules that disrupt RIN1 binding to ABL, blocking RIN1-dependent stimulation of ABL kinase. Five confirmed compounds decrease MAPK1/3 phosphorylation (a RIN1-dependent ABL signaling indicator) in CML K562 cells and lower BCR-ABL1 kinase activity.","method":"TR-FRET binding assay, HTS of 444,743 compounds, cellular MAPK1/3 phosphorylation assay, BCR-ABL kinase activity assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical binding assay plus cellular signaling validation, single lab, two orthogonal methods","pmids":["25811598"],"is_preprint":false},{"year":2016,"finding":"Smad2 forms a cytoplasmic complex with RIN1 and MFN2 (mitofusin2). Inactive cytoplasmic Smad2 recruits RIN1 to act as a GEF for MFN2-GTPase, promoting mitochondrial fusion, ATP synthesis, and suppression of superoxide production. This is distinct from TGF-β-induced nuclear Smad2/3 transcriptional activity.","method":"Co-immunoprecipitation (Smad2-RIN1-MFN2 complex), GTP exchange assay for MFN2, mitochondrial morphology imaging, ATP and ROS measurements, RNAi knockdown","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro GEF assay for MFN2, co-IP of complex, and functional mitochondrial assays with RNAi, multiple orthogonal methods in a single focused study","pmids":["27184078"],"is_preprint":false},{"year":2016,"finding":"PGE2-dependent PKA phosphorylation of RIN1 at Ser291 and Ser292 promotes RIN1 binding to activated RAS and abrogates TGF-β-induced RAS/RAF/ERK signaling activation and downstream cellular migration. Ser291/292Ala mutant RIN1 fails to bind activated RAS and fails to block TGF-β-induced migration.","method":"Global phosphoproteomics, in vitro PKA phosphorylation, co-immunoprecipitation/pull-down with RAS, RIN1 mutant overexpression, cell migration assay, siRNA knockdown","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics identification confirmed by mutagenesis and RAS pull-down with functional migration readout, single lab","pmids":["27137893"],"is_preprint":false},{"year":2016,"finding":"RIN1 interacts with RAB25 GTPase and activates EGFR signaling in clear cell renal cell carcinoma; knockdown of RAB25 eliminates RIN1-driven increases in cell proliferation, migration, and invasion.","method":"Co-immunoprecipitation (RIN1-RAB25), RIN1 gain- and loss-of-function, RAB25 knockdown rescue assay, in vitro cell growth/migration/invasion, in vivo xenograft","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with functional rescue experiments, single lab, in vitro and in vivo but mechanistic depth limited","pmids":["28612496"],"is_preprint":false},{"year":2023,"finding":"In Costello syndrome keratinocytes expressing HRAS(Gly12Ser), RIN1 is the quantitatively most prominent high-affinity effector of active HRAS. HRASGly12Ser strongly increases RIN1-dependent RAB5A activation and HRAS-RIN1-ABL1/2 signaling, redirects β1 integrin to RAB5/EEA1-positive early endosomes, impairs integrin recycling, and reduces β1 integrin surface distribution. RIN1 disruption reverses β1 integrin intracellular accumulation.","method":"Co-immunoprecipitation (HRAS-RIN1), RAB5A activation assay, confocal co-localization of β1 integrin with endosomal markers, RIN1 siRNA/disruption, integrin surface distribution assay, cell spreading assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with activity assay and functional integrin trafficking readouts, single lab, multiple orthogonal methods","pmids":["35981076"],"is_preprint":false},{"year":2025,"finding":"RIN1 dictates synaptic NMDAR subunit composition in spinal cord SOM+ neurons by differentially regulating synaptic trafficking of GluN2B- and GluN2A-containing NMDARs. RIN1 protein levels increase with synapse maturation and drive the developmental GluN2B-to-GluN2A switch; nerve injury-induced RIN1 increase drives a new round of this switch and alters the analgesic efficacy of NMDAR subunit antagonists.","method":"Conditional RIN1 knockout in spinal SOM+ neurons, synaptic NMDAR subunit composition analysis, immunofluorescence, behavioral nociception assays, pharmacological NMDAR antagonist sensitivity testing","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined synaptic trafficking and pharmacological phenotypes, single lab, multiple readouts","pmids":["41329672"],"is_preprint":false},{"year":2025,"finding":"RIN1 in dorsal root ganglion neurons interacts with TRPV1 and promotes TRPV1 endocytosis via its Rab5-GEF activity, limiting TRPV1 plasma membrane levels and the duration/magnitude of TRPV1-dependent acute pain responses. Conditional RIN1 knockout in DRG neurons enhances TRPV1 surface accumulation and nociceptive sensitization; AAV-mediated RIN1 re-expression rescues this.","method":"Co-immunoprecipitation (RIN1-TRPV1), conditional DRG-specific RIN1 knockout, TRPV1 endocytosis assay, TRPV1 surface distribution assay, nociceptive behavioral assays, AAV rescue experiment","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus conditional KO with AAV rescue and TRPV1 surface trafficking readouts, single lab, multiple orthogonal methods","pmids":["42186385"],"is_preprint":false}],"current_model":"RIN1 is a multidomain RAS effector that directly competes with RAF for activated RAS binding; upon RAS activation (potentiated by growth factor receptor stimulation via its SH2 domain binding to phosphorylated receptors such as EGFR and EphA4), RIN1 activates RAB5 GTPases through its Vps9-homology GEF domain to drive receptor endocytosis and endosomal trafficking, activates ABL tyrosine kinases through its SH3/SH2-binding ABL-activation domain to remodel actin and regulate cell adhesion/migration, and can additionally act as a GEF for MFN2 when scaffolded by cytoplasmic Smad2 to promote mitochondrial fusion; RIN1 activity and localization are regulated by PKD-mediated phosphorylation of S351 (controlling 14-3-3 binding and membrane targeting) and by PKA-mediated phosphorylation of S291/S292, and RIN1 autoinhibition is relieved by RAS binding."},"narrative":{"mechanistic_narrative":"RIN1 is a multidomain RAS effector that couples activated RAS to membrane trafficking and tyrosine-kinase signaling, thereby controlling receptor endocytosis, cytoskeletal remodeling, and cell adhesion/migration [PMID:11784866, PMID:11703925, PMID:15886098]. It binds activated RAS with high affinity (~22 nM) and competes directly with RAF1, and unlike canonical proliferative effectors it inhibits RAS-mediated transformation [PMID:11784866]. Through its Vps9-homology domain, RIN1 acts as a guanine-nucleotide exchange factor for RAB5, stimulating Rab5-dependent endosome fusion and driving internalization of activated receptors including EGFR; activated RAS potentiates this GEF activity [PMID:11703925, PMID:12783862]. In parallel, RIN1 directly activates ABL tyrosine kinases by binding their SH3 and SH2 domains and stimulating catalytic activity toward CRK/CRKL, with RAS forming a stable RAS–RIN1–ABL2 complex that relieves RIN1 autoinhibition; loss of RIN1 accelerates cell adhesion and motility [PMID:15886098, PMID:9144171]. These two outputs are integrated at the receptor level: RIN1 dictates EGFR fate by routing it toward RAB5-driven degradation while ABL activation stabilizes the receptor and restrains macropinocytosis, with degradation requiring the RIN1 PRD–STAM2 interaction [PMID:22976291, PMID:17403676]. RIN1 is recruited to ligand-engaged receptors through its SH2 domain binding to phosphorylated EGFR, insulin receptor, and EphA4, and its activity and membrane localization are tuned by PKD phosphorylation of S351 (controlling 14-3-3 binding) and PKA phosphorylation of S291/S292 (promoting RAS binding and blocking TGF-β–induced migration) [PMID:12783862, PMID:16457816, PMID:18723684, PMID:11784866, PMID:27137893]. Beyond receptor trafficking, RIN1 acts as a GEF for the mitofusin MFN2 when scaffolded by cytoplasmic Smad2 to promote mitochondrial fusion [PMID:27184078]. In the nervous system RIN1 is an inhibitory modulator of neuronal plasticity: it is enriched in forebrain and excitatory neurons, mediates EphA4 endocytosis, and its knockout enhances amygdala LTP and aversive memory, while in sensory and spinal neurons it controls NMDAR subunit switching and TRPV1 surface levels to shape nociception [PMID:12574403, PMID:18723684, PMID:41329672, PMID:42186385]. In disease, RIN1 potentiates BCR-ABL oncogenic signaling and is required for BCR-ABL-driven leukemic transformation, with its silencing increasing imatinib sensitivity [PMID:9208849, PMID:21102429].","teleology":[{"year":1997,"claim":"Established RIN1 as a bifunctional adaptor that physically and enzymatically links ABL tyrosine kinase to activated RAS, defining its core domain architecture.","evidence":"In vitro SH3 binding, co-IP, and tyrosine phosphorylation assays in mammalian cells","pmids":["9144171"],"confidence":"High","gaps":["Functional consequence of ABL–RIN1 binding not yet defined","Did not establish how RAS binding regulates RIN1 activity"]},{"year":1997,"claim":"Showed RIN1 is a functional partner of oncogenic BCR-ABL, providing the first disease context by demonstrating it accelerates BCR-ABL-induced leukemia.","evidence":"Co-IP from leukemic cells, retroviral transformation, and murine leukemia model","pmids":["9208849"],"confidence":"High","gaps":["Mechanism by which RIN1 potentiates kinase activity not resolved","Whether RIN1 is required (not just sufficient) for transformation untested"]},{"year":2001,"claim":"Identified RIN1's enzymatic activity as a RAB5 GEF, explaining how a RAS effector drives receptor endocytosis and endosome fusion.","evidence":"In vitro GEF assay with domain deletions plus endosome fusion and EGFR endocytosis assays","pmids":["11703925"],"confidence":"High","gaps":["How RAS potentiation of GEF activity is achieved structurally unknown","Receptor specificity of RIN1-driven endocytosis not delineated"]},{"year":2002,"claim":"Quantified RIN1–RAS binding and showed it competes with RAF and inhibits transformation, plus identified PKD/14-3-3 control of localization—distinguishing RIN1 from proliferative RAS effectors.","evidence":"Surface plasmon resonance, competition and transformation assays, in vitro PKD kinase assay, fractionation","pmids":["11784866"],"confidence":"High","gaps":["Upstream signals controlling PKD-mediated S351 phosphorylation in vivo unclear","Link between membrane localization and effector output not mechanistically dissected"]},{"year":2003,"claim":"Defined the SH2 domain as the receptor-recruitment module, explaining how growth factor stimulation localizes RIN1 to drive EGFR internalization.","evidence":"Co-IP, recruitment microscopy, dominant-negative SH2 expression, internalization assay","pmids":["12783862"],"confidence":"High","gaps":["Phosphotyrosine specificity of the SH2 domain not mapped","Whether SH2 binding feeds into GEF or ABL output untested here"]},{"year":2003,"claim":"Revealed an in vivo physiological role: RIN1 restrains neuronal plasticity and fear memory, moving it beyond cell-line biochemistry.","evidence":"Neuronal immunolocalization, Rin1 knockout mice, amygdala LTP, fear conditioning","pmids":["12574403"],"confidence":"High","gaps":["Which RIN1 effector activity (RAB5 vs ABL) underlies the plasticity phenotype not separated","Synaptic substrate/receptor unknown at this stage"]},{"year":2005,"claim":"Reconstituted RIN1 as a direct ABL activator and showed RAS relieves RIN1 autoinhibition, unifying the RAS, ABL, and adhesion outputs into one regulatory logic.","evidence":"In vitro ABL2 kinase assay with purified proteins, co-IP, Rin1 KO cells, migration assays, RNAi","pmids":["15886098"],"confidence":"High","gaps":["Structural basis of RBD-mediated autoinhibition not resolved","How RAS binding allosterically opens RIN1 unknown"]},{"year":2006,"claim":"Extended RIN1 receptor regulation to the insulin receptor and showed it selectively dampens ERK and Akt signaling, indicating pathway-selective control.","evidence":"Retroviral expression of deletion mutants, internalization, co-IP, kinase assays, confocal","pmids":["16457816"],"confidence":"Medium","gaps":["Single-lab study without independent confirmation","Basis for selective ERK/Akt versus JNK/p38 effects not mechanistically explained"]},{"year":2007,"claim":"Identified STAM2 as the PRD partner required to route EGFR to degradation, connecting RIN1 to the ESCRT/endosomal sorting machinery.","evidence":"Reciprocal co-IP, RNAi, confocal co-localization, PRD deletion, EGFR degradation assay","pmids":["17403676"],"confidence":"High","gaps":["Whether STAM2 recruitment requires concurrent RAB5 activation untested","Generality across other receptors not examined"]},{"year":2008,"claim":"Provided the synaptic substrate for RIN1's plasticity role by showing SH2-mediated EphA4 binding and ephrin-triggered EphA4 endocytosis in amygdala neurons.","evidence":"Co-IP from synaptosomes, EphA4 endocytosis assay, Rin1 KO, amygdala LTP","pmids":["18723684"],"confidence":"High","gaps":["Downstream signaling from internalized EphA4 not traced","Contribution of ABL versus RAB5 activity to LTP suppression unresolved"]},{"year":2010,"claim":"Demonstrated RIN1 is required for BCR-ABL1 transformation and stabilizes a drug-resistant kinase conformation, establishing it as a determinant of imatinib sensitivity.","evidence":"RNAi, Rin1 KO bone marrow transformation with ectopic rescue, kinase activity and imatinib sensitivity assays","pmids":["21102429"],"confidence":"High","gaps":["Structural model of the stabilized BCR-ABL1 conformation not determined","Whether RIN1 targeting is therapeutically tractable not yet tested"]},{"year":2012,"claim":"Integrated RIN1's dual outputs by showing RAB5 and ABL arms oppositely control EGFR degradation versus macropinocytosis, defining RIN1 as a switch governing receptor fate.","evidence":"RNAi/overexpression of mutants, EGFR degradation and macropinocytosis assays, ABL inhibitor, RIN1-BIN1 co-IP, actin imaging","pmids":["22976291"],"confidence":"High","gaps":["How the balance between the two arms is set in different cell types unclear","Role of BIN1 in membrane bending mechanistically undefined"]},{"year":2014,"claim":"Showed RIN1's RAB5-GEF activity is exploited and used during bacterial infection, broadening its trafficking role to host–pathogen interactions.","evidence":"RNAi, Listeria invasion assay, phagosome-lysosome fusion assay in epithelial cells","pmids":["25082076"],"confidence":"Medium","gaps":["Single-lab study; counterbalancing early/late roles need independent confirmation","Host signal triggering RIN1 engagement post-infection unknown"]},{"year":2015,"claim":"Validated the RIN1–ABL interface as a druggable node by showing both engineered and small-molecule disruption of the interaction suppress BCR-ABL signaling and restore imatinib sensitivity.","evidence":"Co-IP with engineered SH3 mutant and TR-FRET HTS, kinase activity, MAPK assays, proliferation, xenograft","pmids":["26321052","25811598"],"confidence":"Medium","gaps":["Compound selectivity and in vivo efficacy beyond initial models unestablished","Single-lab validation of each approach"]},{"year":2016,"claim":"Uncovered a non-trafficking role: Smad2-scaffolded RIN1 acts as a MFN2 GEF to promote mitochondrial fusion and metabolic output, expanding its GEF repertoire beyond RAB5.","evidence":"Co-IP of Smad2-RIN1-MFN2 complex, MFN2 GTP-exchange assay, mitochondrial imaging, ATP/ROS measurements, RNAi","pmids":["27184078"],"confidence":"High","gaps":["How RIN1 selects RAB5 versus MFN2 substrates not resolved","Physiological trigger redirecting RIN1 to mitochondria unclear"]},{"year":2016,"claim":"Defined PKA phosphorylation of S291/S292 as a regulatory input that enhances RAS binding and blocks TGF-β-driven migration, adding a second phospho-control layer atop PKD/S351.","evidence":"Phosphoproteomics, in vitro PKA assay, RAS pull-down, mutagenesis, migration assay, siRNA","pmids":["27137893"],"confidence":"Medium","gaps":["Single-lab study","Interplay between S291/292 and S351 phosphorylation not examined"]},{"year":2017,"claim":"Showed a context where RIN1 promotes (rather than inhibits) oncogenic signaling, acting via RAB25 to drive EGFR signaling and tumor cell aggressiveness in renal carcinoma.","evidence":"RIN1-RAB25 co-IP, gain/loss-of-function, RAB25 knockdown rescue, growth/migration/invasion, xenograft","pmids":["28612496"],"confidence":"Medium","gaps":["Mechanistic depth limited; how RAB25 alters EGFR fate unclear","Reconciliation with RIN1's transformation-inhibitory role elsewhere not addressed"]},{"year":2023,"claim":"Implicated RIN1 in RASopathy pathology by showing it is the dominant HRAS(G12S) effector in Costello syndrome keratinocytes, mislocalizing β1 integrin and impairing its recycling.","evidence":"HRAS-RIN1 co-IP, RAB5A activation assay, integrin endosomal co-localization, RIN1 disruption, surface distribution and spreading assays","pmids":["35981076"],"confidence":"Medium","gaps":["Single-lab study","Whether RIN1 targeting ameliorates Costello syndrome phenotypes untested"]},{"year":2025,"claim":"Established RIN1 as a regulator of nociceptive signaling by controlling NMDAR subunit composition in spinal neurons and TRPV1 surface levels in DRG neurons.","evidence":"Conditional RIN1 knockouts, synaptic NMDAR composition and TRPV1 surface trafficking assays, RIN1-TRPV1 co-IP, AAV rescue, behavioral nociception","pmids":["41329672","42186385"],"confidence":"Medium","gaps":["Single-lab studies","Which RIN1 effector arm drives NMDAR subunit switching not separated from RAB5-GEF activity"]},{"year":null,"claim":"How RIN1 partitions its GEF activity among RAB5, MFN2, and other targets, and how phosphorylation, RAS binding, and partner scaffolds combinatorially select among its receptor-degradation, ABL-activation, and metabolic outputs in a given cell, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of full-length autoinhibited versus RAS-bound RIN1","Cell-type rules governing inhibitory versus oncogenic RIN1 outputs undefined","Integration of S351 and S291/292 phospho-control not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,4,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15,16]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,4,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,6,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,10,18]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[5,9,19,20]}],"complexes":["RAS-RIN1-ABL2 complex","Smad2-RIN1-MFN2 complex"],"partners":["ABL1","ABL2","HRAS","RAB5A","EGFR","STAM2","MFN2","SMAD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13671","full_name":"Ras and Rab interactor 1","aliases":["Ras inhibitor JC99","Ras interaction/interference protein 1"],"length_aa":783,"mass_kda":84.1,"function":"Ras effector protein, which may serve as an inhibitory modulator of neuronal plasticity in aversive memory formation. Can affect Ras signaling at different levels. First, by competing with RAF1 protein for binding to activated Ras. Second, by enhancing signaling from ABL1 and ABL2, which regulate cytoskeletal remodeling. Third, by activating RAB5A, possibly by functioning as a guanine nucleotide exchange factor (GEF) for RAB5A, by exchanging bound GDP for free GTP, and facilitating Ras-activated receptor endocytosis","subcellular_location":"Cytoplasm; Membrane; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q13671/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RIN1","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RIN1","total_profiled":1310},"omim":[{"mim_id":"610223","title":"RAS AND RAB INTERACTOR 3; RIN3","url":"https://www.omim.org/entry/610223"},{"mim_id":"609592","title":"RIC-LIKE PROTEIN WITHOUT CAAX MOTIF 2; 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1","ntpm":9.0}],"url":"https://www.proteinatlas.org/search/RIN1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q13671","domains":[{"cath_id":"3.30.505.10","chopping":"57-194","consensus_level":"high","plddt":88.1236,"start":57,"end":194},{"cath_id":"1.20.1050.80","chopping":"477-595","consensus_level":"high","plddt":89.5726,"start":477,"end":595},{"cath_id":"3.10.20.90","chopping":"623-702","consensus_level":"high","plddt":80.4554,"start":623,"end":702},{"cath_id":"1.10.246","chopping":"358-444","consensus_level":"high","plddt":86.916,"start":358,"end":444}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13671","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13671-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13671-F1-predicted_aligned_error_v6.png","plddt_mean":66.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RIN1","jax_strain_url":"https://www.jax.org/strain/search?query=RIN1"},"sequence":{"accession":"Q13671","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13671.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13671/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13671"}},"corpus_meta":[{"pmid":"11703925","id":"PMC_11703925","title":"Ras-activated 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Full-length RIN1 interacts with activated RAS in mammalian cells through its C-terminal effector-binding domain.\",\n      \"method\": \"In vitro SH3-domain binding assay, co-immunoprecipitation, tyrosine phosphorylation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays and phosphorylation confirmed in vitro and in cells, two orthogonal methods in a single focused study\",\n      \"pmids\": [\"9144171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"RIN1 potentiates BCR-ABL oncogenic activity and accelerates BCR-ABL-induced leukemia; this requires tyrosine phosphorylation of RIN1 and binding to ABL SH2 and SH3 domains. RIN1 is tyrosine phosphorylated and associated with BCR-ABL in human and murine leukemic cells.\",\n      \"method\": \"Co-immunoprecipitation from leukemic cells, retroviral transformation assay in hematopoietic cells, murine leukemia model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP from primary leukemic cells plus in vivo murine model, multiple orthogonal methods replicated across cell types\",\n      \"pmids\": [\"9208849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The Vps9-homology domain of RIN1 is necessary and sufficient for binding to GDP-bound Rab5A and Vps21p, and RIN1 stimulates Rab5 guanine nucleotide exchange, Rab5A-dependent endosome fusion, and EGF receptor-mediated endocytosis. Activated RAS potentiates all three of these RIN1-mediated activities.\",\n      \"method\": \"In vitro GEF assay, endosome fusion assay, EGF receptor endocytosis assay, domain-deletion analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro GEF assay with domain mutagenesis plus functional endosome fusion and receptor endocytosis assays; multiple orthogonal methods\",\n      \"pmids\": [\"11703925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RIN1 binds activated RAS with Kd ~22 nM, directly competing with RAF1 for RAS binding. RIN1 inhibits RAS-mediated cellular transformation (distinguishing it from other RAS effectors). RIN1 binds 14-3-3 proteins through serine 351, and phosphorylation of S351 by protein kinase D (PKD/PKCmu) in vitro and in vivo controls 14-3-3 binding and RIN1 membrane localization. S351A mutation shifts RIN1 to the plasma membrane and enhances RAS transformation blockade.\",\n      \"method\": \"Surface plasmon resonance (Kd measurement), competition binding assay, focus formation/transformation assay, co-immunoprecipitation, in vitro kinase assay, subcellular fractionation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative binding measurement, in vitro kinase assay with mutagenesis, and multiple cellular assays in a single rigorous study\",\n      \"pmids\": [\"11784866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The SH2 domain of RIN1 mediates ligand-dependent binding to tyrosine-phosphorylated EGFR intracellular domain, recruits RIN1 to plasma membrane and endosomes upon EGF stimulation, and is required for EGFR internalization. Expression of the SH2 domain alone substantially impaired EGF internalization without affecting transferrin internalization.\",\n      \"method\": \"Co-immunoprecipitation, light microscopy/subcellular recruitment, dominant-negative SH2 domain expression, internalization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain-deletion mutants plus functional internalization assay, two orthogonal methods in a single study\",\n      \"pmids\": [\"12783862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RIN1 is preferentially expressed in postnatal forebrain neurons where it localizes in dendrites and is physically associated with RAS. Rin1 knockout mice show enhanced amygdala LTP and elevated amygdala-dependent aversive memory, indicating RIN1 is an inhibitory modulator of neuronal plasticity in fear memory formation.\",\n      \"method\": \"Immunolocalization in neurons, Rin1 gene knockout mice, amygdala LTP electrophysiology, fear conditioning behavioral assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined electrophysiological and behavioral phenotypes, multiple orthogonal readouts\",\n      \"pmids\": [\"12574403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RIN1 is a direct activator of ABL tyrosine kinases: it binds ABL SH3 and SH2 domains, stimulates ABL2 catalytic activity in immune complexes and in a defined-component in vitro assay with purified ABL-binding domain (ABD), leading to increased phosphorylation of CRK and CRKL. Activated RAS forms a stable RAS-RIN1-ABL2 complex and enhances ABL2 activation. Deletion of the RAS-binding domain (RBD) strongly increases ABL2 activation, suggesting RAS relieves RIN1 autoinhibition. Rin1-/- mammary epithelial cells show accelerated adhesion and increased motility.\",\n      \"method\": \"In vitro ABL2 kinase assay with purified proteins, co-immunoprecipitation, Rin1 knockout mouse cells, cell adhesion and migration assay, RNAi knockdown\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase reconstitution with purified components, mutagenesis, co-IP, and Rin1 KO cellular phenotype — multiple orthogonal methods\",\n      \"pmids\": [\"15886098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RIN1 regulates insulin receptor internalization and signaling: RIN1 expression enhances insulin receptor-mediated and fluid-phase insulin-stimulated endocytosis via its Rab5-GEF and Ras-binding domains; the SH2 domain of RIN1 associates with tyrosine-phosphorylated insulin receptor. RIN1 expression selectively blocks ERK1/2 and Akt1 activation without affecting JNK or p38.\",\n      \"method\": \"Retroviral expression of RIN1 deletion mutants, receptor internalization assay, co-immunoprecipitation, kinase activity assays, confocal microscopy co-localization\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mutants plus functional endocytosis and signaling assays, single lab\",\n      \"pmids\": [\"16457816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RIN1 interacts with STAM2 (signal-transducing adaptor molecule 2) via its proline-rich domain (PRD) and STAM2's SH3 domain. This interaction is required for RIN1-accelerated EGFR degradation following EGF stimulation; a RIN1 mutant lacking the PRD (RIN1ΔPRD) neither binds STAM2 nor accelerates EGFR degradation.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, confocal co-localization (GFP-Rin1 and HA-STAM2), domain-deletion mutagenesis, EGFR degradation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain mutants plus RNAi rescue and functional EGFR degradation assay, multiple orthogonal methods\",\n      \"pmids\": [\"17403676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RIN1 (Rin1), expressed specifically in postnatal brain excitatory neurons, interacts with EphA4 receptor tyrosine kinase in synaptosomal fractions via its SH2 domain, mediates EphA4 endocytosis in amygdala neurons following ephrinB3 engagement, and suppresses synaptic plasticity in the amygdala.\",\n      \"method\": \"Co-immunoprecipitation from synaptosomal fractions, EphA4 endocytosis assay in amygdala neurons, Rin1 knockout mice, amygdala LTP electrophysiology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP from native synaptosomal fractions, functional endocytosis assay, and KO electrophysiology in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"18723684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RIN1 silencing decreases BCR-ABL1 kinase activity; RIN1 overexpression increases it. Rin1-/- bone marrow cells are not transformed by BCR-ABL1, ETV6-ABL1, or drug-resistant BCR-ABL1(T315I); rescue by ectopic RIN1 confirms cell-autonomous mechanism. RIN1 silencing increases imatinib sensitivity, consistent with RIN1 stabilizing an activated BCR-ABL1 conformation with reduced drug affinity.\",\n      \"method\": \"RNAi knockdown, Rin1 knockout bone marrow transformation assay, ectopic RIN1 rescue, BCR-ABL1 kinase activity assay, imatinib sensitivity assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with ectopic rescue plus RNAi and kinase activity measurements, multiple orthogonal methods confirming cell-autonomous mechanism\",\n      \"pmids\": [\"21102429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RIN1 orchestrates EGFR fate by activating RAB5 GTPases (favoring EGFR degradation over recycling) and ABL tyrosine kinases (stabilizing EGFR and inhibiting macropinocytosis). A RIN1(QM) mutant that blocks ABL activation causes EGF-stimulated membrane ruffling, actin remodeling, macropinocytosis (dextran uptake), and EGFR degradation. EGFR activation also promotes RIN1 interaction with BIN1, a membrane-bending protein.\",\n      \"method\": \"RNAi silencing and overexpression of RIN1/mutants, EGFR degradation assay, macropinocytosis (dextran uptake) assay, ABL kinase inhibitor treatment, co-immunoprecipitation (RIN1-BIN1), actin remodeling imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays with structure-function mutants and pharmacological validation in a single study\",\n      \"pmids\": [\"22976291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RIN1's RAB5-GEF activity is required for efficient Listeria monocytogenes invasion of intestinal epithelial cells (RIN1 is rapidly engaged post-infection) and subsequently facilitates phagosome-lysosome fusion to promote bacterial clearance, performing counterbalancing roles at early and late infection stages.\",\n      \"method\": \"RIN1 RNAi knockdown, L. monocytogenes invasion assay, phagosome-lysosome fusion assay in epithelial cells\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with defined invasion and phagosome fusion phenotypes, single lab, two functional readouts\",\n      \"pmids\": [\"25082076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"An engineered ABL SH3 mutant (T79Y) blocks the RIN1–BCR-ABL SH3 interaction via PxxP motifs, represses BCR-ABL autophosphorylation and downstream signaling pathways, and increases imatinib sensitivity in resistant CML cell lines in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (SH3-RIN1 interaction), BCR-ABL kinase activity assay, cell proliferation assay, xenograft mouse model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with engineered SH3 mutant plus kinase activity and in vivo tumor assay, single lab\",\n      \"pmids\": [\"26321052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A TR-FRET-based HTS identified small molecules that disrupt RIN1 binding to ABL, blocking RIN1-dependent stimulation of ABL kinase. Five confirmed compounds decrease MAPK1/3 phosphorylation (a RIN1-dependent ABL signaling indicator) in CML K562 cells and lower BCR-ABL1 kinase activity.\",\n      \"method\": \"TR-FRET binding assay, HTS of 444,743 compounds, cellular MAPK1/3 phosphorylation assay, BCR-ABL kinase activity assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical binding assay plus cellular signaling validation, single lab, two orthogonal methods\",\n      \"pmids\": [\"25811598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Smad2 forms a cytoplasmic complex with RIN1 and MFN2 (mitofusin2). Inactive cytoplasmic Smad2 recruits RIN1 to act as a GEF for MFN2-GTPase, promoting mitochondrial fusion, ATP synthesis, and suppression of superoxide production. This is distinct from TGF-β-induced nuclear Smad2/3 transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation (Smad2-RIN1-MFN2 complex), GTP exchange assay for MFN2, mitochondrial morphology imaging, ATP and ROS measurements, RNAi knockdown\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro GEF assay for MFN2, co-IP of complex, and functional mitochondrial assays with RNAi, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"27184078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PGE2-dependent PKA phosphorylation of RIN1 at Ser291 and Ser292 promotes RIN1 binding to activated RAS and abrogates TGF-β-induced RAS/RAF/ERK signaling activation and downstream cellular migration. Ser291/292Ala mutant RIN1 fails to bind activated RAS and fails to block TGF-β-induced migration.\",\n      \"method\": \"Global phosphoproteomics, in vitro PKA phosphorylation, co-immunoprecipitation/pull-down with RAS, RIN1 mutant overexpression, cell migration assay, siRNA knockdown\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics identification confirmed by mutagenesis and RAS pull-down with functional migration readout, single lab\",\n      \"pmids\": [\"27137893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RIN1 interacts with RAB25 GTPase and activates EGFR signaling in clear cell renal cell carcinoma; knockdown of RAB25 eliminates RIN1-driven increases in cell proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation (RIN1-RAB25), RIN1 gain- and loss-of-function, RAB25 knockdown rescue assay, in vitro cell growth/migration/invasion, in vivo xenograft\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with functional rescue experiments, single lab, in vitro and in vivo but mechanistic depth limited\",\n      \"pmids\": [\"28612496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Costello syndrome keratinocytes expressing HRAS(Gly12Ser), RIN1 is the quantitatively most prominent high-affinity effector of active HRAS. HRASGly12Ser strongly increases RIN1-dependent RAB5A activation and HRAS-RIN1-ABL1/2 signaling, redirects β1 integrin to RAB5/EEA1-positive early endosomes, impairs integrin recycling, and reduces β1 integrin surface distribution. RIN1 disruption reverses β1 integrin intracellular accumulation.\",\n      \"method\": \"Co-immunoprecipitation (HRAS-RIN1), RAB5A activation assay, confocal co-localization of β1 integrin with endosomal markers, RIN1 siRNA/disruption, integrin surface distribution assay, cell spreading assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with activity assay and functional integrin trafficking readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35981076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RIN1 dictates synaptic NMDAR subunit composition in spinal cord SOM+ neurons by differentially regulating synaptic trafficking of GluN2B- and GluN2A-containing NMDARs. RIN1 protein levels increase with synapse maturation and drive the developmental GluN2B-to-GluN2A switch; nerve injury-induced RIN1 increase drives a new round of this switch and alters the analgesic efficacy of NMDAR subunit antagonists.\",\n      \"method\": \"Conditional RIN1 knockout in spinal SOM+ neurons, synaptic NMDAR subunit composition analysis, immunofluorescence, behavioral nociception assays, pharmacological NMDAR antagonist sensitivity testing\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined synaptic trafficking and pharmacological phenotypes, single lab, multiple readouts\",\n      \"pmids\": [\"41329672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RIN1 in dorsal root ganglion neurons interacts with TRPV1 and promotes TRPV1 endocytosis via its Rab5-GEF activity, limiting TRPV1 plasma membrane levels and the duration/magnitude of TRPV1-dependent acute pain responses. Conditional RIN1 knockout in DRG neurons enhances TRPV1 surface accumulation and nociceptive sensitization; AAV-mediated RIN1 re-expression rescues this.\",\n      \"method\": \"Co-immunoprecipitation (RIN1-TRPV1), conditional DRG-specific RIN1 knockout, TRPV1 endocytosis assay, TRPV1 surface distribution assay, nociceptive behavioral assays, AAV rescue experiment\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus conditional KO with AAV rescue and TRPV1 surface trafficking readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42186385\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RIN1 is a multidomain RAS effector that directly competes with RAF for activated RAS binding; upon RAS activation (potentiated by growth factor receptor stimulation via its SH2 domain binding to phosphorylated receptors such as EGFR and EphA4), RIN1 activates RAB5 GTPases through its Vps9-homology GEF domain to drive receptor endocytosis and endosomal trafficking, activates ABL tyrosine kinases through its SH3/SH2-binding ABL-activation domain to remodel actin and regulate cell adhesion/migration, and can additionally act as a GEF for MFN2 when scaffolded by cytoplasmic Smad2 to promote mitochondrial fusion; RIN1 activity and localization are regulated by PKD-mediated phosphorylation of S351 (controlling 14-3-3 binding and membrane targeting) and by PKA-mediated phosphorylation of S291/S292, and RIN1 autoinhibition is relieved by RAS binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RIN1 is a multidomain RAS effector that couples activated RAS to membrane trafficking and tyrosine-kinase signaling, thereby controlling receptor endocytosis, cytoskeletal remodeling, and cell adhesion/migration [#3, #2, #6]. It binds activated RAS with high affinity (~22 nM) and competes directly with RAF1, and unlike canonical proliferative effectors it inhibits RAS-mediated transformation [#3]. Through its Vps9-homology domain, RIN1 acts as a guanine-nucleotide exchange factor for RAB5, stimulating Rab5-dependent endosome fusion and driving internalization of activated receptors including EGFR; activated RAS potentiates this GEF activity [#2, #4]. In parallel, RIN1 directly activates ABL tyrosine kinases by binding their SH3 and SH2 domains and stimulating catalytic activity toward CRK/CRKL, with RAS forming a stable RAS–RIN1–ABL2 complex that relieves RIN1 autoinhibition; loss of RIN1 accelerates cell adhesion and motility [#6, #0]. These two outputs are integrated at the receptor level: RIN1 dictates EGFR fate by routing it toward RAB5-driven degradation while ABL activation stabilizes the receptor and restrains macropinocytosis, with degradation requiring the RIN1 PRD–STAM2 interaction [#11, #8]. RIN1 is recruited to ligand-engaged receptors through its SH2 domain binding to phosphorylated EGFR, insulin receptor, and EphA4, and its activity and membrane localization are tuned by PKD phosphorylation of S351 (controlling 14-3-3 binding) and PKA phosphorylation of S291/S292 (promoting RAS binding and blocking TGF-β–induced migration) [#4, #7, #9, #3, #16]. Beyond receptor trafficking, RIN1 acts as a GEF for the mitofusin MFN2 when scaffolded by cytoplasmic Smad2 to promote mitochondrial fusion [#15]. In the nervous system RIN1 is an inhibitory modulator of neuronal plasticity: it is enriched in forebrain and excitatory neurons, mediates EphA4 endocytosis, and its knockout enhances amygdala LTP and aversive memory, while in sensory and spinal neurons it controls NMDAR subunit switching and TRPV1 surface levels to shape nociception [#5, #9, #19, #20]. In disease, RIN1 potentiates BCR-ABL oncogenic signaling and is required for BCR-ABL-driven leukemic transformation, with its silencing increasing imatinib sensitivity [#1, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established RIN1 as a bifunctional adaptor that physically and enzymatically links ABL tyrosine kinase to activated RAS, defining its core domain architecture.\",\n      \"evidence\": \"In vitro SH3 binding, co-IP, and tyrosine phosphorylation assays in mammalian cells\",\n      \"pmids\": [\"9144171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of ABL–RIN1 binding not yet defined\", \"Did not establish how RAS binding regulates RIN1 activity\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed RIN1 is a functional partner of oncogenic BCR-ABL, providing the first disease context by demonstrating it accelerates BCR-ABL-induced leukemia.\",\n      \"evidence\": \"Co-IP from leukemic cells, retroviral transformation, and murine leukemia model\",\n      \"pmids\": [\"9208849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which RIN1 potentiates kinase activity not resolved\", \"Whether RIN1 is required (not just sufficient) for transformation untested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified RIN1's enzymatic activity as a RAB5 GEF, explaining how a RAS effector drives receptor endocytosis and endosome fusion.\",\n      \"evidence\": \"In vitro GEF assay with domain deletions plus endosome fusion and EGFR endocytosis assays\",\n      \"pmids\": [\"11703925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAS potentiation of GEF activity is achieved structurally unknown\", \"Receptor specificity of RIN1-driven endocytosis not delineated\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Quantified RIN1–RAS binding and showed it competes with RAF and inhibits transformation, plus identified PKD/14-3-3 control of localization—distinguishing RIN1 from proliferative RAS effectors.\",\n      \"evidence\": \"Surface plasmon resonance, competition and transformation assays, in vitro PKD kinase assay, fractionation\",\n      \"pmids\": [\"11784866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling PKD-mediated S351 phosphorylation in vivo unclear\", \"Link between membrane localization and effector output not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the SH2 domain as the receptor-recruitment module, explaining how growth factor stimulation localizes RIN1 to drive EGFR internalization.\",\n      \"evidence\": \"Co-IP, recruitment microscopy, dominant-negative SH2 expression, internalization assay\",\n      \"pmids\": [\"12783862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphotyrosine specificity of the SH2 domain not mapped\", \"Whether SH2 binding feeds into GEF or ABL output untested here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed an in vivo physiological role: RIN1 restrains neuronal plasticity and fear memory, moving it beyond cell-line biochemistry.\",\n      \"evidence\": \"Neuronal immunolocalization, Rin1 knockout mice, amygdala LTP, fear conditioning\",\n      \"pmids\": [\"12574403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which RIN1 effector activity (RAB5 vs ABL) underlies the plasticity phenotype not separated\", \"Synaptic substrate/receptor unknown at this stage\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Reconstituted RIN1 as a direct ABL activator and showed RAS relieves RIN1 autoinhibition, unifying the RAS, ABL, and adhesion outputs into one regulatory logic.\",\n      \"evidence\": \"In vitro ABL2 kinase assay with purified proteins, co-IP, Rin1 KO cells, migration assays, RNAi\",\n      \"pmids\": [\"15886098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RBD-mediated autoinhibition not resolved\", \"How RAS binding allosterically opens RIN1 unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended RIN1 receptor regulation to the insulin receptor and showed it selectively dampens ERK and Akt signaling, indicating pathway-selective control.\",\n      \"evidence\": \"Retroviral expression of deletion mutants, internalization, co-IP, kinase assays, confocal\",\n      \"pmids\": [\"16457816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without independent confirmation\", \"Basis for selective ERK/Akt versus JNK/p38 effects not mechanistically explained\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified STAM2 as the PRD partner required to route EGFR to degradation, connecting RIN1 to the ESCRT/endosomal sorting machinery.\",\n      \"evidence\": \"Reciprocal co-IP, RNAi, confocal co-localization, PRD deletion, EGFR degradation assay\",\n      \"pmids\": [\"17403676\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAM2 recruitment requires concurrent RAB5 activation untested\", \"Generality across other receptors not examined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided the synaptic substrate for RIN1's plasticity role by showing SH2-mediated EphA4 binding and ephrin-triggered EphA4 endocytosis in amygdala neurons.\",\n      \"evidence\": \"Co-IP from synaptosomes, EphA4 endocytosis assay, Rin1 KO, amygdala LTP\",\n      \"pmids\": [\"18723684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling from internalized EphA4 not traced\", \"Contribution of ABL versus RAB5 activity to LTP suppression unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated RIN1 is required for BCR-ABL1 transformation and stabilizes a drug-resistant kinase conformation, establishing it as a determinant of imatinib sensitivity.\",\n      \"evidence\": \"RNAi, Rin1 KO bone marrow transformation with ectopic rescue, kinase activity and imatinib sensitivity assays\",\n      \"pmids\": [\"21102429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of the stabilized BCR-ABL1 conformation not determined\", \"Whether RIN1 targeting is therapeutically tractable not yet tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Integrated RIN1's dual outputs by showing RAB5 and ABL arms oppositely control EGFR degradation versus macropinocytosis, defining RIN1 as a switch governing receptor fate.\",\n      \"evidence\": \"RNAi/overexpression of mutants, EGFR degradation and macropinocytosis assays, ABL inhibitor, RIN1-BIN1 co-IP, actin imaging\",\n      \"pmids\": [\"22976291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the balance between the two arms is set in different cell types unclear\", \"Role of BIN1 in membrane bending mechanistically undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed RIN1's RAB5-GEF activity is exploited and used during bacterial infection, broadening its trafficking role to host–pathogen interactions.\",\n      \"evidence\": \"RNAi, Listeria invasion assay, phagosome-lysosome fusion assay in epithelial cells\",\n      \"pmids\": [\"25082076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study; counterbalancing early/late roles need independent confirmation\", \"Host signal triggering RIN1 engagement post-infection unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Validated the RIN1–ABL interface as a druggable node by showing both engineered and small-molecule disruption of the interaction suppress BCR-ABL signaling and restore imatinib sensitivity.\",\n      \"evidence\": \"Co-IP with engineered SH3 mutant and TR-FRET HTS, kinase activity, MAPK assays, proliferation, xenograft\",\n      \"pmids\": [\"26321052\", \"25811598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Compound selectivity and in vivo efficacy beyond initial models unestablished\", \"Single-lab validation of each approach\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered a non-trafficking role: Smad2-scaffolded RIN1 acts as a MFN2 GEF to promote mitochondrial fusion and metabolic output, expanding its GEF repertoire beyond RAB5.\",\n      \"evidence\": \"Co-IP of Smad2-RIN1-MFN2 complex, MFN2 GTP-exchange assay, mitochondrial imaging, ATP/ROS measurements, RNAi\",\n      \"pmids\": [\"27184078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RIN1 selects RAB5 versus MFN2 substrates not resolved\", \"Physiological trigger redirecting RIN1 to mitochondria unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined PKA phosphorylation of S291/S292 as a regulatory input that enhances RAS binding and blocks TGF-β-driven migration, adding a second phospho-control layer atop PKD/S351.\",\n      \"evidence\": \"Phosphoproteomics, in vitro PKA assay, RAS pull-down, mutagenesis, migration assay, siRNA\",\n      \"pmids\": [\"27137893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Interplay between S291/292 and S351 phosphorylation not examined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed a context where RIN1 promotes (rather than inhibits) oncogenic signaling, acting via RAB25 to drive EGFR signaling and tumor cell aggressiveness in renal carcinoma.\",\n      \"evidence\": \"RIN1-RAB25 co-IP, gain/loss-of-function, RAB25 knockdown rescue, growth/migration/invasion, xenograft\",\n      \"pmids\": [\"28612496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic depth limited; how RAB25 alters EGFR fate unclear\", \"Reconciliation with RIN1's transformation-inhibitory role elsewhere not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated RIN1 in RASopathy pathology by showing it is the dominant HRAS(G12S) effector in Costello syndrome keratinocytes, mislocalizing β1 integrin and impairing its recycling.\",\n      \"evidence\": \"HRAS-RIN1 co-IP, RAB5A activation assay, integrin endosomal co-localization, RIN1 disruption, surface distribution and spreading assays\",\n      \"pmids\": [\"35981076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Whether RIN1 targeting ameliorates Costello syndrome phenotypes untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established RIN1 as a regulator of nociceptive signaling by controlling NMDAR subunit composition in spinal neurons and TRPV1 surface levels in DRG neurons.\",\n      \"evidence\": \"Conditional RIN1 knockouts, synaptic NMDAR composition and TRPV1 surface trafficking assays, RIN1-TRPV1 co-IP, AAV rescue, behavioral nociception\",\n      \"pmids\": [\"41329672\", \"42186385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies\", \"Which RIN1 effector arm drives NMDAR subunit switching not separated from RAB5-GEF activity\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RIN1 partitions its GEF activity among RAB5, MFN2, and other targets, and how phosphorylation, RAS binding, and partner scaffolds combinatorially select among its receptor-degradation, ABL-activation, and metabolic outputs in a given cell, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of full-length autoinhibited versus RAS-bound RIN1\", \"Cell-type rules governing inhibitory versus oncogenic RIN1 outputs undefined\", \"Integration of S351 and S291/292 phospho-control not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005088\", \"supporting_discovery_ids\": [2, 6, 15]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 4, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15, 16]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 4, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 6, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 10, 18]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5, 9, 19, 20]}\n    ],\n    \"complexes\": [\"RAS-RIN1-ABL2 complex\", \"Smad2-RIN1-MFN2 complex\"],\n    \"partners\": [\"ABL1\", \"ABL2\", \"HRAS\", \"RAB5A\", \"EGFR\", \"STAM2\", \"MFN2\", \"SMAD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}