{"gene":"RASD2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1999,"finding":"Bacterially expressed Rhes binds GTP, demonstrating GTPase functionality. Rhes is targeted to the plasma membrane by farnesylation and shares ~62% identity with Dexras1, defining a novel Ras subfamily with extended C-termini.","method":"GTP-binding assay with bacterially expressed protein; sequence analysis","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro GTP binding demonstrated in single study, farnesylation shown later in a separate study","pmids":["10467249"],"is_preprint":false},{"year":2004,"finding":"Rhes is targeted to the plasma membrane via farnesylation. Approximately 30% of native Rhes is constitutively GTP-bound, and this proportion is not altered by typical Ras nucleotide exchange factors. Rhes binds to and activates PI3K, and impairs cAMP/PKA pathway activation by G protein-coupled receptors (TSH receptor, β2-adrenergic receptor) by uncoupling receptor from its cognate heterotrimeric G protein complex. Rhes does not stimulate the ERK pathway and is not transforming in fibroblasts.","method":"GTP-loading assays, PI3K activation assay, cAMP accumulation assays, cell-based signaling in PC12 cells, membrane fractionation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical assays in single lab; farnesylation and GTP-binding confirmed, PI3K binding and cAMP pathway inhibition demonstrated","pmids":["14724584"],"is_preprint":false},{"year":2004,"finding":"Rhes knockout mice display behavioral abnormalities (gender-dependent increased anxiety, motor coordination deficits) without learning/memory impairment, establishing a role for Rhes in striatal motor function in vivo.","method":"Homologous recombination knockout, behavioral testing (rotarod, anxiety assays)","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined behavioral phenotypic readout, single lab","pmids":["15199135"],"is_preprint":false},{"year":2007,"finding":"Rhes modulates cAMP/PKA signaling in both striatopallidal and striatonigral projection neurons by increasing Golf protein levels. Rhes is required for correct dopamine-mediated GTP binding associated mainly with D2 receptor stimulation.","method":"Rhes null mutant mice, cAMP/PKA signaling measurements, GTP binding assays, dopaminergic agonist/antagonist behavioral challenges","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice with multiple biochemical and behavioral readouts, single lab","pmids":["18035555"],"is_preprint":false},{"year":2009,"finding":"Rhes binds physically and preferentially to mutant huntingtin (mHtt) over wild-type Htt. Rhes induces sumoylation of mHtt, which disaggregates mHtt inclusions and leads to cytotoxicity in cultured cells.","method":"Co-immunoprecipitation, sumoylation assays, cell viability assays, transfection in cultured cells","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding and sumoylation demonstrated biochemically, cytotoxicity established functionally, widely replicated by subsequent studies","pmids":["19498170"],"is_preprint":false},{"year":2009,"finding":"Rhes binds selectively to Gbeta1, Gbeta2, and Gbeta3 subunits of heterotrimeric G proteins via its cationic region. Rhes-AGS1 chimera studies showed that different cationic regions of Rhes and AGS1 determine their distinct Gbeta-subunit binding specificities.","method":"Yeast two-hybrid assays, Rhes-AGS1 chimera constructs","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — yeast two-hybrid with chimera validation, single lab, single study","pmids":["19255495"],"is_preprint":false},{"year":2010,"finding":"Rhes acts as a SUMO E3 ligase and is a physiologic regulator of sumoylation in the striatum; sumoylation is markedly reduced in the corpus striatum of Rhes-deleted mice. Rhes binds directly to both SUMO E1 and Ubc9 (E2), enhancing cross-sumoylation (intermolecular SUMO transfer between E1 and Ubc9) as well as thioester transfer from E1 to Ubc9.","method":"In vitro sumoylation assays, direct binding assays between Rhes and E1/Ubc9, Rhes knockout mouse striatum analysis, mass spectrometry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro biochemistry with direct binding to E1 and Ubc9, validated in Rhes KO mice with multiple orthogonal methods","pmids":["20424159"],"is_preprint":false},{"year":2011,"finding":"Rhes binds to and activates mTOR (mTORC1) in the striatum. Rhes-/- mice show reduced striatal mTOR signaling and diminished L-DOPA-induced dyskinesia while maintaining motor improvement on L-DOPA, demonstrating Rhes is a key regulator of striatal mTOR activation relevant to dyskinesia.","method":"Co-immunoprecipitation, mTOR signaling assays, Rhes-/- mice with 6-OHDA lesion and L-DOPA treatment, behavioral assessment","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus KO mouse in vivo validation, multiple readouts, published in high-impact journal","pmids":["22179112"],"is_preprint":false},{"year":2011,"finding":"Rhes decreases dopamine D1 receptor agonist-stimulated cAMP accumulation in a pertussis toxin-sensitive manner, suggesting interaction with Gαi. Rhes associates with GTP-bound Gαi in pull-down assays but does not interact with the D1 receptor directly and has no effect on D2 receptor-mediated inhibition of cAMP.","method":"cAMP accumulation assays, pertussis toxin treatment, Gαi pull-down assays, transfection in cell lines","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple assays (cAMP, PTX sensitivity, pull-down) in single lab","pmids":["21374700"],"is_preprint":false},{"year":2012,"finding":"Rhes interacts with p85, the regulatory subunit of PI3K; this interaction involves the C-terminal unique tail region of Rhes and is enhanced upon growth factor treatment. The Rhes-p85 complex facilitates AKT translocation to the membrane, indicating Rhes is a striatal regulator of the AKT pathway.","method":"Co-immunoprecipitation, domain-mapping with deletion mutants, AKT membrane translocation assays","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with domain mapping and functional translocation assay, single lab, single study","pmids":["22683505"],"is_preprint":false},{"year":2013,"finding":"Rhes binds Beclin-1 and activates autophagy in a mTOR-independent manner. Rhes decreases the inhibitory interaction between Beclin-1 and Bcl-2 independently of JNK-1 signaling. Rhes overexpression activates autophagy; deletion decreases autophagy. Co-expression of mHtt blocks Rhes-induced autophagy activation.","method":"Co-immunoprecipitation of Rhes-Beclin-1 and Beclin-1/Bcl-2, autophagy flux assays, Rhes overexpression and knockdown in PC12 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by Co-IP plus functional autophagy assays with OE and KD, single lab","pmids":["24324270"],"is_preprint":false},{"year":2013,"finding":"Rhes-/- mice are dramatically protected from neurotoxicity and motor dysfunction in the 3-nitropropionic acid (3-NP) striatal model of Huntington's disease, placing Rhes as a critical mediator of striatal selective vulnerability.","method":"Rhes knockout mice, 3-NP systemic injection, behavioral and neuropathological assessment","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined in vivo neurotoxic model and behavioral/pathological readouts, single lab","pmids":["23447628"],"is_preprint":false},{"year":2013,"finding":"Rhes co-immunoprecipitates with β-arrestins and is necessary for Akt dephosphorylation by the striatal multi-protein complex (β-arrestin2/PP2A/Akt). In Rhes-/- mice, basal Akt and GSK3β phosphorylation are increased and apomorphine treatment causes increased Akt/GSK3 phosphorylation, mimicking a lithium-treated phenotype.","method":"Co-immunoprecipitation of Rhes with β-arrestins and PP2A-C, phospho-Akt/GSK3β Western blotting in Rhes KO mice, pharmacological challenges","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo KO biochemical phenotype, single lab","pmids":["23380502"],"is_preprint":false},{"year":2013,"finding":"Rhes participates in iron uptake via divalent metal transporter 1 (DMT1) by interacting with PAP7 (peripheral benzodiazepine receptor-associated protein 7), similar to Dexras1. Unlike Dexras1, Rhes is not S-nitrosylated by NO; instead, it is phosphorylated by PKA at Ser-239. Phosphomimetic (S239D) and constitutively active (A173V) Rhes mutants show increased iron uptake.","method":"Co-immunoprecipitation, iron uptake assays, site-directed mutagenesis, S-nitrosylation and phosphorylation assays","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis combined with functional iron uptake assay and binding assay, single lab","pmids":["23999124"],"is_preprint":false},{"year":2015,"finding":"Ectopic expression of Rhes in the cerebellum of HD mice (N171-82Q) during the asymptomatic period causes exacerbated motor deficits with ataxia features, cerebellar Purkinje neuron loss, caspase-3 activation, and enhanced soluble mHtt forms. Re-introducing Rhes into the striatum of Rhes-/-/Hdh150Q/150Q knock-in mice restores progressive rotarod deficits, establishing Rhes as the causative factor for selective mHtt toxicity in vivo.","method":"Adeno-associated virus (AAV)-mediated ectopic Rhes expression in cerebellum, behavioral testing, immunohistochemistry, Western blotting","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function ectopic expression with loss-of-function rescue, multiple orthogonal readouts (behavior, histology, biochemistry), independently supported by prior KO data","pmids":["26048156"],"is_preprint":false},{"year":2015,"finding":"Rhes modulates D2 receptor (D2R) signaling specifically in striatal cholinergic interneurons (ChIs); Rhes KO mice show aberrant excitatory rather than expected inhibitory D2R responses in ChIs. This abnormal D2R response requires Cav2.2 calcium channels and is rescued by selective PI3K inhibition, linking Rhes to PI3K/Akt modulation of cholinergic excitability.","method":"Electrophysiology (patch clamp) in ChIs from Rhes KO mice, pharmacological isolation, intrapipette BAPTA and GDP-β-S, Cav2.2 channel blockade, PI3K inhibition","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with multiple pharmacological validations in KO mice, single lab","pmids":["25818655"],"is_preprint":false},{"year":2016,"finding":"RasGRP1 (a guanine nucleotide exchange factor) interacts with Rhes, stabilizes Rhes protein, and increases its synaptic accumulation in the striatum. Partial Rhes deficiency (Rhes+/-) enhances the locomotor response to amphetamine, which is attenuated by coincident RasGRP1 depletion. Proteomic analysis identified the 'Rhesactome' — a set of Rhes-interacting proteins in the striatum that includes PDE2A, LRRC7, and DLG2, and whose composition is modulated by RasGRP1 and amphetamine.","method":"Co-immunoprecipitation, Western blotting (protein stabilization), Rhes+/- and Rasgrp1 KO mouse behavioral studies, LC-MS/MS proteomics of striatal lysates","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus proteomic interactome plus genetic epistasis in mice, single lab","pmids":["27902448"],"is_preprint":false},{"year":2019,"finding":"Rhes induces the biogenesis of tunneling nanotube (TNT)-like cellular protrusions ('Rhes tunnels') through which it moves between cells and transports mHtt (poly-Q expanded mutant huntingtin), but not normal HTT, mTOR, or wtTau. TNT formation requires Rhes's Ser33, C-terminal CAAX motif, and SUMO E3-like domain. Rhes tunnels carry Rab5a/Lyso20-positive vesicles. SUMOylation-defective mHtt, Rhes C263S (cannot SUMOylate mHtt), or CRISPR/Cas9 depletion of SUMO isoforms diminishes Rhes-mediated mHtt transport.","method":"Live-cell imaging, electron microscopy, CRISPR/Cas9 SUMO depletion, site-directed mutagenesis (Rhes C263S, S33A, CAAX deletion), cargo transport assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (live imaging, EM, mutagenesis, CRISPR), cargo specificity established, mechanistic dissection of required domains","pmids":["31076452"],"is_preprint":false},{"year":2019,"finding":"Rhes is a critical regulator of mitophagy. Rhes co-immunoprecipitates and co-sediments with mitochondrial and lysosomal proteins in vivo. Rhes surrounds globular mitochondria, recruits lysosomes, and degrades mitochondria in live-cell imaging. Rhes disrupts mitochondrial membrane potential and promotes mitophagy and cell death via interaction with Nix (BNIP3L) through its SUMO E3-ligase domain. Nix depletion abrogates Rhes-mediated mitophagy. Rhes KO striatum is protected from 3-NP-induced mitophagosomes and striatal lesion in vivo.","method":"Co-immunoprecipitation, density fractionation, live-cell imaging, mitochondrial membrane potential assays, Nix depletion, Rhes KO mice with 3-NP injection and ultrastructural analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, fractionation, live imaging, functional assays, in vivo KO with EM), mechanistic dissection via Nix interaction and domain mapping","pmids":["31676548"],"is_preprint":false},{"year":2022,"finding":"Rhes transports between D1R-MSNs and D2R-MSNs of intact striatum and organotypic brain slices via TNT-like protrusions. mHtt is robustly transported within the striatum and from striatum to cortical areas in the brain; Rhes deletion diminishes this transport. Rhes restricted to MSNs also moves to cortical regions in vivo.","method":"Organotypic brain slice imaging, in vivo Rhes-tagged AAV injections, Rhes KO mice, fluorescence tracking","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo and ex vivo demonstration of intercellular transport with KO validation, multiple brain circuit readouts, replicates prior cell culture findings","pmids":["35319973"],"is_preprint":false},{"year":2008,"finding":"Rhes and AGS1 trigger nearly identical modulation of N-type Ca2+ channels (CaV2.2) by selectively altering Gαi-dependent signaling: both reduce basal CaV2.2 current densities, trigger tonic voltage-dependent inhibition, and attenuate agonist-initiated Gαi-coupled receptor inhibition. These effects are blocked by pertussis toxin or Gβγ-sequestering peptide, indicating Rhes mediates tonic Gβγ signaling through PTX-sensitive G proteins.","method":"Whole-cell patch-clamp recording in HEK293 cells expressing CaV2.2, pertussis toxin treatment, Gβγ sequestration, comparison with multiple other Ras-family members","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with PTX and Gβγ-sequestration controls, comparison with multiple G-proteins, single lab","pmids":["18815223"],"is_preprint":false},{"year":2024,"finding":"RASD2 overexpression in the nucleus accumbens core (NAcc) alleviates stress-induced depression-like behaviors and activates the DRD2-cAMP-PKA-DARPP-32 signaling pathway. Rasd2 overexpression in DRD2-expressing PrL-NAcc neurons (using Drd2-cre mice) ameliorates depression-like behaviors, placing RASD2 as a modulator of DRD2-dependent signaling in NAcc circuits.","method":"AAV-mediated overexpression, Drd2-cre transgenic mice, DREADD chemogenetics, retrograde tracing, Western blotting for cAMP-PKA-DARPP-32 pathway","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific circuit manipulation with multiple behavioral readouts and pathway biochemistry, single lab","pmids":["39097664"],"is_preprint":false},{"year":2024,"finding":"Histone lactylation (H3K18la) promotes transcription of RASD2 in endometriosis. RASD2 increases the stability of CTPS1 by promoting CTPS1 SUMOylation and inhibiting its ubiquitination, thereby promoting endometriosis progression. This was established via the RASD2/CTPS1 axis.","method":"ChIP-qPCR, Co-immunoprecipitation, IP-MS, SUMOylation/ubiquitination assays, cell proliferation/invasion assays, endometriosis mouse models","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus IP-MS identification of CTPS1 interaction, functional SUMOylation/ubiquitination assays, in vivo validation, single lab","pmids":["39672102"],"is_preprint":false},{"year":2026,"finding":"Rhes directly interacts with Slc4a7 (an intracellular pH sensor/solute carrier) through both its N- and C-terminal domains. This Rhes-Slc4a7 complex is membrane-associated and modulates intracellular pH to facilitate TNT formation and mHTT intercellular transfer. Farnesylation of Rhes is required for its binding to Slc4a7 and for TNT formation. Slc4a7 KO mice show reduced cell-to-cell mHTT transmission in the striatum in vivo. The transporter activity of Slc4a7 is not required for this interaction.","method":"LC-MS/MS of membrane-associated Rhes complexes, Co-immunoprecipitation, siRNA depletion of Slc4a7, pharmacological inhibition of Slc4a7, intracellular pH measurements, Rhes farnesylation mutants, Slc4a7 KO mice with in vivo mHTT transmission assay","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — unbiased proteomics discovery followed by Co-IP, domain mapping, pharmacological and genetic validation, in vivo KO confirmation, multiple orthogonal methods","pmids":["41861004"],"is_preprint":false},{"year":2026,"finding":"RASD2 binds RAF1 and enhances RAF1 phosphorylation at Ser338, thereby activating the P38/ERK-MAPK pathway in clear cell renal cell carcinoma cells. This interaction was identified by Co-immunoprecipitation and LC-MS/MS.","method":"Co-immunoprecipitation, LC-MS/MS proteomics, phospho-RAF1 (Ser338) Western blotting, RAF1 inhibitor (BAY43-9006) experiments, xenograft models","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus LC-MS/MS identification plus functional phosphorylation assays and inhibitor validation, single lab, cancer cell line context","pmids":["42226617"],"is_preprint":false}],"current_model":"Rhes (RASD2) is a striatum-enriched, farnesylated small GTPase and SUMO E3 ligase that binds directly to mutant huntingtin (mHtt) and promotes its SUMOylation — disaggregating mHtt aggregates and increasing cytotoxicity — while also activating mTORC1, binding Beclin-1 to activate autophagy, interacting with Nix to drive mitophagy, modulating dopaminergic/cAMP/PKA and PI3K/AKT signaling by coupling to Gαi and Gβγ subunits of heterotrimeric G proteins, and inducing tunneling nanotube (TNT)-like protrusions that transport mHtt between neurons in a SUMOylation- and farnesylation-dependent manner via a membrane-associated complex with Slc4a7."},"narrative":{"mechanistic_narrative":"RASD2 (Rhes) is a striatum-enriched, farnesylated small GTPase that serves as a hub coupling G-protein signaling, protein SUMOylation, and selective neuronal vulnerability in Huntington's disease [PMID:10467249, PMID:19498170, PMID:26048156]. It binds GTP and is constitutively partly GTP-loaded, anchoring to the plasma membrane through farnesylation, and modulates GPCR signaling by uncoupling receptors from heterotrimeric G proteins and engaging Gαi and Gβ subunits to attenuate cAMP/PKA output and tonic Gβγ signaling at CaV2.2 channels [PMID:14724584, PMID:19255495, PMID:21374700, PMID:18815223]. Beyond G-protein modulation, Rhes activates PI3K/AKT through the p85 regulatory subunit and binds and activates mTORC1, a function linked in vivo to L-DOPA-induced dyskinesia [PMID:22179112, PMID:22683505]. Rhes functions as a SUMO E3 ligase that binds SUMO E1 and the E2 Ubc9 and is the principal regulator of striatal SUMOylation [PMID:20424159]. Through this activity it binds preferentially to mutant huntingtin (mHtt), promotes its SUMOylation and disaggregation, and confers cytotoxicity, and genetic loss or ectopic re-expression of Rhes establishes it as the causative factor for the striatal selectivity of mHtt toxicity in vivo [PMID:19498170, PMID:23447628, PMID:26048156]. Rhes also controls catabolic pathways, binding Beclin-1 to activate mTOR-independent autophagy and interacting with Nix (BNIP3L) through its SUMO E3-like domain to drive mitophagy and cell death [PMID:24324270, PMID:31676548]. A distinctive activity is the biogenesis of tunneling-nanotube-like \"Rhes tunnels\" that transport mHtt between neurons in a SUMOylation- and farnesylation-dependent manner, requiring a membrane-associated complex with the pH sensor Slc4a7 and validated by intercellular mHtt transfer in intact striatum [PMID:31076452, PMID:35319973, PMID:41861004]. Outside the nervous system, RASD2 promotes target-protein SUMOylation (CTPS1 in endometriosis) and activates RAF1-Ser338/MAPK signaling in renal carcinoma [PMID:39672102, PMID:42226617].","teleology":[{"year":1999,"claim":"Establishing that Rhes is a genuine GTP-binding protein defined a new membrane-targeted Ras subfamily and set the molecular starting point for all downstream signaling work.","evidence":"GTP-binding assay with bacterially expressed protein and sequence analysis","pmids":["10467249"],"confidence":"Medium","gaps":["No GTPase regulator (GEF/GAP) identified","Intrinsic hydrolysis rate not quantified"]},{"year":2004,"claim":"Biochemical dissection showed Rhes is constitutively partly GTP-bound and acts on PI3K and GPCR-cAMP signaling rather than the classical Ras-ERK/transformation axis, distinguishing it functionally from oncogenic Ras.","evidence":"GTP-loading, PI3K activation, cAMP accumulation assays and membrane fractionation in PC12/fibroblasts; plus in vivo knockout behavioral phenotyping","pmids":["14724584","15199135"],"confidence":"Medium","gaps":["Mechanism of constitutive GTP loading not resolved","Receptor-uncoupling stoichiometry undefined"]},{"year":2007,"claim":"Knockout studies tied Rhes to dopaminergic signaling, showing it raises Golf levels and is required for D2-associated dopamine-mediated GTP binding, embedding it in striatal cAMP/PKA control.","evidence":"Rhes null mice with cAMP/PKA and GTP-binding measurements plus dopaminergic pharmacological challenges","pmids":["18035555"],"confidence":"Medium","gaps":["Direct Rhes-Golf interaction not shown","Cell-type resolution within striatum limited"]},{"year":2009,"claim":"Discovery that Rhes binds preferentially to mutant huntingtin and induces its SUMOylation with disaggregation and cytotoxicity provided the first molecular link explaining striatal selectivity in Huntington's disease.","evidence":"Co-immunoprecipitation, sumoylation and cell-viability assays in cultured cells; yeast two-hybrid mapping of Gβ-subunit binding","pmids":["19498170","19255495"],"confidence":"High","gaps":["SUMO acceptor sites on mHtt not all mapped","Link between disaggregation and toxicity mechanistically incomplete"]},{"year":2010,"claim":"Reconstitution established Rhes as a bona fide SUMO E3 ligase that binds E1 and Ubc9 and is the dominant regulator of striatal SUMOylation, defining the enzymatic basis for its mHtt action.","evidence":"In vitro sumoylation and direct E1/Ubc9 binding assays plus Rhes KO striatum analysis and mass spectrometry","pmids":["20424159"],"confidence":"High","gaps":["Full striatal SUMO substrate repertoire incomplete","How GTPase state gates E3 activity unknown"]},{"year":2011,"claim":"Identification of Rhes as a direct activator of striatal mTORC1 and a modulator of Gαi/PI3K-coupled receptor signaling connected its biochemistry to L-DOPA-induced dyskinesia and cholinergic excitability.","evidence":"Co-IP with mTOR and Gαi pull-downs, cAMP/PTX-sensitivity assays, and Rhes-/- mice with 6-OHDA/L-DOPA paradigms","pmids":["22179112","21374700"],"confidence":"High","gaps":["Direct vs indirect mTORC1 activation mechanism not fully resolved","Relationship between mTOR activation and SUMO ligase activity unclear"]},{"year":2012,"claim":"Mapping the Rhes-p85 interaction to the unique C-terminal tail and showing growth-factor-enhanced AKT membrane translocation positioned Rhes as a striatal PI3K/AKT regulator.","evidence":"Co-IP with deletion-mutant domain mapping and AKT translocation assays","pmids":["22683505"],"confidence":"Medium","gaps":["Single-lab, single-study interaction","In vivo relevance of p85 binding not tested"]},{"year":2013,"claim":"A cluster of studies expanded Rhes function to catabolic and signaling control: Beclin-1-dependent mTOR-independent autophagy, β-arrestin2/PP2A-mediated Akt dephosphorylation, PAP7/DMT1 iron uptake regulated by PKA phosphorylation at Ser239, and protection in the 3-NP striatal HD model.","evidence":"Co-IP of Beclin-1/Bcl-2 and β-arrestin/PP2A, autophagy flux assays, iron-uptake and mutagenesis assays, and Rhes KO mice in the 3-NP toxicity model","pmids":["24324270","23380502","23999124","23447628"],"confidence":"Medium","gaps":["How one protein balances autophagy, Akt, and iron functions in vivo unclear","Tissue/cell context dependence of each interaction unresolved"]},{"year":2015,"claim":"Gain-of-function ectopic expression with loss-of-function striatal rescue formally established Rhes as the causative determinant of selective mHtt toxicity, and electrophysiology localized PI3K-dependent D2R modulation to cholinergic interneurons.","evidence":"AAV ectopic Rhes expression and striatal re-introduction in HD mouse models; patch-clamp recordings with Cav2.2/PI3K pharmacology in Rhes KO ChIs","pmids":["26048156","25818655"],"confidence":"High","gaps":["Molecular event converting Rhes presence into selective vulnerability not pinpointed","Generalizability beyond modeled HD alleles untested"]},{"year":2016,"claim":"Defining the striatal 'Rhesactome' and the RasGRP1 stabilizing interaction revealed how Rhes protein levels, synaptic localization, and interactome are dynamically regulated, including by amphetamine.","evidence":"Co-IP, protein-stabilization Westerns, LC-MS/MS striatal proteomics, and Rhes+/- / Rasgrp1 KO behavioral epistasis","pmids":["27902448"],"confidence":"Medium","gaps":["Functional roles of most Rhesactome partners (PDE2A, LRRC7, DLG2) untested","Whether RasGRP1 acts as a true GEF for Rhes unresolved"]},{"year":2019,"claim":"Discovery of Rhes-induced tunneling-nanotube biogenesis and Nix-dependent mitophagy revealed two new membrane-based functions—intercellular mHtt transport and selective mitochondrial degradation—both requiring the SUMO E3-like domain and farnesylation.","evidence":"Live-cell imaging, EM, CRISPR SUMO depletion and domain mutagenesis for TNTs; Co-IP, fractionation, mitochondrial potential and Nix-depletion assays plus 3-NP KO mice for mitophagy","pmids":["31076452","31676548"],"confidence":"High","gaps":["Structural basis of TNT membrane deformation unknown","How SUMO ligase activity mechanistically links to both processes unresolved"]},{"year":2022,"claim":"Demonstrating Rhes-driven mHtt transport between MSN subtypes and from striatum to cortex in intact and organotypic brain established intercellular spread as an in vivo mechanism of HD pathology propagation.","evidence":"Organotypic slice imaging and in vivo AAV tracking with Rhes KO validation","pmids":["35319973"],"confidence":"High","gaps":["Quantitative contribution of spread to disease progression undefined","Directionality determinants of transport unclear"]},{"year":2026,"claim":"Identification of the membrane-associated Rhes-Slc4a7 complex provided the molecular machinery for TNT formation, showing pH modulation and Rhes farnesylation—but not Slc4a7 transport activity—drive intercellular mHtt transfer in vivo.","evidence":"LC-MS/MS of membrane Rhes complexes, Co-IP, domain mapping, Slc4a7 siRNA/pharmacology, pH measurements, farnesylation mutants, and Slc4a7 KO mice with in vivo mHTT transmission","pmids":["41861004"],"confidence":"High","gaps":["How local pH change physically promotes TNT membrane biogenesis unresolved","Whether other carriers substitute for Slc4a7 untested"]},{"year":2024,"claim":"Studies outside the striatal HD context showed RASD2 modulates NAcc DRD2-cAMP-PKA-DARPP-32 circuitry to influence depression-like behavior and acts as a SUMOylation-promoting oncogenic factor (CTPS1 stabilization in endometriosis).","evidence":"AAV/Drd2-cre circuit manipulation with DREADDs and pathway Westerns; ChIP, IP-MS, SUMOylation/ubiquitination assays and mouse models in endometriosis","pmids":["39097664","39672102"],"confidence":"Medium","gaps":["Mechanistic overlap between neuronal and tumor SUMO functions untested","Whether GTPase/farnesylation are required in these contexts unknown"]},{"year":2026,"claim":"Extending RASD2 into cancer signaling, it was shown to bind RAF1 and enhance Ser338 phosphorylation to activate P38/ERK-MAPK in clear cell renal carcinoma.","evidence":"Co-IP, LC-MS/MS, phospho-RAF1 Westerns, RAF1 inhibitor and xenograft experiments","pmids":["42226617"],"confidence":"Medium","gaps":["Reconciliation with earlier finding that Rhes does not stimulate ERK/transformation unresolved","Direct vs scaffold role in RAF1 activation undefined"]},{"year":null,"claim":"How Rhes's GTP-loading state, farnesylation, and SUMO E3 activity are integrated to select among its many effectors (G proteins, mTORC1, autophagy, mitophagy, TNT transport) in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model coordinating GTPase and SUMO-ligase domains","Upstream signals switching Rhes between functions unknown","Endogenous GEF/GAP regulation of Rhes not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[6,4,18,22]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,8,20,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,23]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,8,20,7,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,4,22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,11,14,17,19]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,15,21]}],"complexes":["Rhes-Slc4a7 membrane complex","β-arrestin2/PP2A/Akt complex"],"partners":["HTT","UBE2I","MTOR","BECN1","BNIP3L","SLC4A7","RASGRP1","RAF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96D21","full_name":"GTP-binding protein Rhes","aliases":["Ras homolog enriched in striatum","Tumor endothelial marker 2"],"length_aa":266,"mass_kda":30.4,"function":"GTPase signaling protein that binds to and hydrolyzes GTP. Regulates signaling pathways involving G-proteins-coupled receptor and heterotrimeric proteins such as GNB1, GNB2 and GNB3. 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Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/39672102","citation_count":3,"is_preprint":false},{"pmid":"16945334","id":"PMC_16945334","title":"Rhes expression in pancreatic beta-cells is regulated by efaroxan in a calcium-dependent process.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16945334","citation_count":3,"is_preprint":false},{"pmid":"36959146","id":"PMC_36959146","title":"Curbing Rhes Actions: Mechanism-based Molecular Target for Huntington's Disease and Tauopathies.","date":"2024","source":"CNS & neurological disorders drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/36959146","citation_count":2,"is_preprint":false},{"pmid":"40289764","id":"PMC_40289764","title":"Modulation of RASD2 by miRNA-485-5p Drives Thyroid Cancer Progression and Metastasis.","date":"2025","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40289764","citation_count":2,"is_preprint":false},{"pmid":"8200509","id":"PMC_8200509","title":"Val-237 for Ala substitution in the TEM-2 beta-lactamase dramatically alters the catalytic efficiencies towards carbenicillin and ticarcillin.","date":"1994","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/8200509","citation_count":2,"is_preprint":false},{"pmid":"41861004","id":"PMC_41861004","title":"Membrane-associated Rhes-Slc4a7 complex orchestrates tunneling nanotube formation and mutant Huntingtin spread.","date":"2026","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/41861004","citation_count":0,"is_preprint":false},{"pmid":"37637962","id":"PMC_37637962","title":"Rhes depletion promotes striatal accumulation and aggregation of mutant huntingtin in a presymptomatic HD mouse model.","date":"2023","source":"Frontiers in aging neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37637962","citation_count":0,"is_preprint":false},{"pmid":"41537759","id":"PMC_41537759","title":"Rasd2 Knockout Exaggerates the Hearing Loss Phenotype of Tsc1-Deficient Mice.","date":"2026","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41537759","citation_count":0,"is_preprint":false},{"pmid":"42226617","id":"PMC_42226617","title":"RASD2 Drives Renal Clear Cell Carcinoma Progression via RAF1 (Ser338) Phosphorylation.","date":"2026","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/42226617","citation_count":0,"is_preprint":false},{"pmid":"8324021","id":"PMC_8324021","title":"[Oligonucleotide probes for the characterization of TEM-1 and TEM-2 beta lactamases in Salmonella strains].","date":"1993","source":"Enfermedades infecciosas y microbiologia clinica","url":"https://pubmed.ncbi.nlm.nih.gov/8324021","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":34419,"output_tokens":6674,"usd":0.101683,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15623,"output_tokens":5527,"usd":0.108145,"stage2_stop_reason":"end_turn"},"total_usd":0.209828,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Bacterially expressed Rhes binds GTP, demonstrating GTPase functionality. Rhes is targeted to the plasma membrane by farnesylation and shares ~62% identity with Dexras1, defining a novel Ras subfamily with extended C-termini.\",\n      \"method\": \"GTP-binding assay with bacterially expressed protein; sequence analysis\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro GTP binding demonstrated in single study, farnesylation shown later in a separate study\",\n      \"pmids\": [\"10467249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Rhes is targeted to the plasma membrane via farnesylation. Approximately 30% of native Rhes is constitutively GTP-bound, and this proportion is not altered by typical Ras nucleotide exchange factors. Rhes binds to and activates PI3K, and impairs cAMP/PKA pathway activation by G protein-coupled receptors (TSH receptor, β2-adrenergic receptor) by uncoupling receptor from its cognate heterotrimeric G protein complex. Rhes does not stimulate the ERK pathway and is not transforming in fibroblasts.\",\n      \"method\": \"GTP-loading assays, PI3K activation assay, cAMP accumulation assays, cell-based signaling in PC12 cells, membrane fractionation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical assays in single lab; farnesylation and GTP-binding confirmed, PI3K binding and cAMP pathway inhibition demonstrated\",\n      \"pmids\": [\"14724584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Rhes knockout mice display behavioral abnormalities (gender-dependent increased anxiety, motor coordination deficits) without learning/memory impairment, establishing a role for Rhes in striatal motor function in vivo.\",\n      \"method\": \"Homologous recombination knockout, behavioral testing (rotarod, anxiety assays)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined behavioral phenotypic readout, single lab\",\n      \"pmids\": [\"15199135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Rhes modulates cAMP/PKA signaling in both striatopallidal and striatonigral projection neurons by increasing Golf protein levels. Rhes is required for correct dopamine-mediated GTP binding associated mainly with D2 receptor stimulation.\",\n      \"method\": \"Rhes null mutant mice, cAMP/PKA signaling measurements, GTP binding assays, dopaminergic agonist/antagonist behavioral challenges\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice with multiple biochemical and behavioral readouts, single lab\",\n      \"pmids\": [\"18035555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Rhes binds physically and preferentially to mutant huntingtin (mHtt) over wild-type Htt. Rhes induces sumoylation of mHtt, which disaggregates mHtt inclusions and leads to cytotoxicity in cultured cells.\",\n      \"method\": \"Co-immunoprecipitation, sumoylation assays, cell viability assays, transfection in cultured cells\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding and sumoylation demonstrated biochemically, cytotoxicity established functionally, widely replicated by subsequent studies\",\n      \"pmids\": [\"19498170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Rhes binds selectively to Gbeta1, Gbeta2, and Gbeta3 subunits of heterotrimeric G proteins via its cationic region. Rhes-AGS1 chimera studies showed that different cationic regions of Rhes and AGS1 determine their distinct Gbeta-subunit binding specificities.\",\n      \"method\": \"Yeast two-hybrid assays, Rhes-AGS1 chimera constructs\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — yeast two-hybrid with chimera validation, single lab, single study\",\n      \"pmids\": [\"19255495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Rhes acts as a SUMO E3 ligase and is a physiologic regulator of sumoylation in the striatum; sumoylation is markedly reduced in the corpus striatum of Rhes-deleted mice. Rhes binds directly to both SUMO E1 and Ubc9 (E2), enhancing cross-sumoylation (intermolecular SUMO transfer between E1 and Ubc9) as well as thioester transfer from E1 to Ubc9.\",\n      \"method\": \"In vitro sumoylation assays, direct binding assays between Rhes and E1/Ubc9, Rhes knockout mouse striatum analysis, mass spectrometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro biochemistry with direct binding to E1 and Ubc9, validated in Rhes KO mice with multiple orthogonal methods\",\n      \"pmids\": [\"20424159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rhes binds to and activates mTOR (mTORC1) in the striatum. Rhes-/- mice show reduced striatal mTOR signaling and diminished L-DOPA-induced dyskinesia while maintaining motor improvement on L-DOPA, demonstrating Rhes is a key regulator of striatal mTOR activation relevant to dyskinesia.\",\n      \"method\": \"Co-immunoprecipitation, mTOR signaling assays, Rhes-/- mice with 6-OHDA lesion and L-DOPA treatment, behavioral assessment\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus KO mouse in vivo validation, multiple readouts, published in high-impact journal\",\n      \"pmids\": [\"22179112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Rhes decreases dopamine D1 receptor agonist-stimulated cAMP accumulation in a pertussis toxin-sensitive manner, suggesting interaction with Gαi. Rhes associates with GTP-bound Gαi in pull-down assays but does not interact with the D1 receptor directly and has no effect on D2 receptor-mediated inhibition of cAMP.\",\n      \"method\": \"cAMP accumulation assays, pertussis toxin treatment, Gαi pull-down assays, transfection in cell lines\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple assays (cAMP, PTX sensitivity, pull-down) in single lab\",\n      \"pmids\": [\"21374700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rhes interacts with p85, the regulatory subunit of PI3K; this interaction involves the C-terminal unique tail region of Rhes and is enhanced upon growth factor treatment. The Rhes-p85 complex facilitates AKT translocation to the membrane, indicating Rhes is a striatal regulator of the AKT pathway.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping with deletion mutants, AKT membrane translocation assays\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with domain mapping and functional translocation assay, single lab, single study\",\n      \"pmids\": [\"22683505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rhes binds Beclin-1 and activates autophagy in a mTOR-independent manner. Rhes decreases the inhibitory interaction between Beclin-1 and Bcl-2 independently of JNK-1 signaling. Rhes overexpression activates autophagy; deletion decreases autophagy. Co-expression of mHtt blocks Rhes-induced autophagy activation.\",\n      \"method\": \"Co-immunoprecipitation of Rhes-Beclin-1 and Beclin-1/Bcl-2, autophagy flux assays, Rhes overexpression and knockdown in PC12 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by Co-IP plus functional autophagy assays with OE and KD, single lab\",\n      \"pmids\": [\"24324270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rhes-/- mice are dramatically protected from neurotoxicity and motor dysfunction in the 3-nitropropionic acid (3-NP) striatal model of Huntington's disease, placing Rhes as a critical mediator of striatal selective vulnerability.\",\n      \"method\": \"Rhes knockout mice, 3-NP systemic injection, behavioral and neuropathological assessment\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined in vivo neurotoxic model and behavioral/pathological readouts, single lab\",\n      \"pmids\": [\"23447628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rhes co-immunoprecipitates with β-arrestins and is necessary for Akt dephosphorylation by the striatal multi-protein complex (β-arrestin2/PP2A/Akt). In Rhes-/- mice, basal Akt and GSK3β phosphorylation are increased and apomorphine treatment causes increased Akt/GSK3 phosphorylation, mimicking a lithium-treated phenotype.\",\n      \"method\": \"Co-immunoprecipitation of Rhes with β-arrestins and PP2A-C, phospho-Akt/GSK3β Western blotting in Rhes KO mice, pharmacological challenges\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo KO biochemical phenotype, single lab\",\n      \"pmids\": [\"23380502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Rhes participates in iron uptake via divalent metal transporter 1 (DMT1) by interacting with PAP7 (peripheral benzodiazepine receptor-associated protein 7), similar to Dexras1. Unlike Dexras1, Rhes is not S-nitrosylated by NO; instead, it is phosphorylated by PKA at Ser-239. Phosphomimetic (S239D) and constitutively active (A173V) Rhes mutants show increased iron uptake.\",\n      \"method\": \"Co-immunoprecipitation, iron uptake assays, site-directed mutagenesis, S-nitrosylation and phosphorylation assays\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis combined with functional iron uptake assay and binding assay, single lab\",\n      \"pmids\": [\"23999124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ectopic expression of Rhes in the cerebellum of HD mice (N171-82Q) during the asymptomatic period causes exacerbated motor deficits with ataxia features, cerebellar Purkinje neuron loss, caspase-3 activation, and enhanced soluble mHtt forms. Re-introducing Rhes into the striatum of Rhes-/-/Hdh150Q/150Q knock-in mice restores progressive rotarod deficits, establishing Rhes as the causative factor for selective mHtt toxicity in vivo.\",\n      \"method\": \"Adeno-associated virus (AAV)-mediated ectopic Rhes expression in cerebellum, behavioral testing, immunohistochemistry, Western blotting\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function ectopic expression with loss-of-function rescue, multiple orthogonal readouts (behavior, histology, biochemistry), independently supported by prior KO data\",\n      \"pmids\": [\"26048156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rhes modulates D2 receptor (D2R) signaling specifically in striatal cholinergic interneurons (ChIs); Rhes KO mice show aberrant excitatory rather than expected inhibitory D2R responses in ChIs. This abnormal D2R response requires Cav2.2 calcium channels and is rescued by selective PI3K inhibition, linking Rhes to PI3K/Akt modulation of cholinergic excitability.\",\n      \"method\": \"Electrophysiology (patch clamp) in ChIs from Rhes KO mice, pharmacological isolation, intrapipette BAPTA and GDP-β-S, Cav2.2 channel blockade, PI3K inhibition\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with multiple pharmacological validations in KO mice, single lab\",\n      \"pmids\": [\"25818655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RasGRP1 (a guanine nucleotide exchange factor) interacts with Rhes, stabilizes Rhes protein, and increases its synaptic accumulation in the striatum. Partial Rhes deficiency (Rhes+/-) enhances the locomotor response to amphetamine, which is attenuated by coincident RasGRP1 depletion. Proteomic analysis identified the 'Rhesactome' — a set of Rhes-interacting proteins in the striatum that includes PDE2A, LRRC7, and DLG2, and whose composition is modulated by RasGRP1 and amphetamine.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting (protein stabilization), Rhes+/- and Rasgrp1 KO mouse behavioral studies, LC-MS/MS proteomics of striatal lysates\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus proteomic interactome plus genetic epistasis in mice, single lab\",\n      \"pmids\": [\"27902448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rhes induces the biogenesis of tunneling nanotube (TNT)-like cellular protrusions ('Rhes tunnels') through which it moves between cells and transports mHtt (poly-Q expanded mutant huntingtin), but not normal HTT, mTOR, or wtTau. TNT formation requires Rhes's Ser33, C-terminal CAAX motif, and SUMO E3-like domain. Rhes tunnels carry Rab5a/Lyso20-positive vesicles. SUMOylation-defective mHtt, Rhes C263S (cannot SUMOylate mHtt), or CRISPR/Cas9 depletion of SUMO isoforms diminishes Rhes-mediated mHtt transport.\",\n      \"method\": \"Live-cell imaging, electron microscopy, CRISPR/Cas9 SUMO depletion, site-directed mutagenesis (Rhes C263S, S33A, CAAX deletion), cargo transport assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (live imaging, EM, mutagenesis, CRISPR), cargo specificity established, mechanistic dissection of required domains\",\n      \"pmids\": [\"31076452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rhes is a critical regulator of mitophagy. Rhes co-immunoprecipitates and co-sediments with mitochondrial and lysosomal proteins in vivo. Rhes surrounds globular mitochondria, recruits lysosomes, and degrades mitochondria in live-cell imaging. Rhes disrupts mitochondrial membrane potential and promotes mitophagy and cell death via interaction with Nix (BNIP3L) through its SUMO E3-ligase domain. Nix depletion abrogates Rhes-mediated mitophagy. Rhes KO striatum is protected from 3-NP-induced mitophagosomes and striatal lesion in vivo.\",\n      \"method\": \"Co-immunoprecipitation, density fractionation, live-cell imaging, mitochondrial membrane potential assays, Nix depletion, Rhes KO mice with 3-NP injection and ultrastructural analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, fractionation, live imaging, functional assays, in vivo KO with EM), mechanistic dissection via Nix interaction and domain mapping\",\n      \"pmids\": [\"31676548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Rhes transports between D1R-MSNs and D2R-MSNs of intact striatum and organotypic brain slices via TNT-like protrusions. mHtt is robustly transported within the striatum and from striatum to cortical areas in the brain; Rhes deletion diminishes this transport. Rhes restricted to MSNs also moves to cortical regions in vivo.\",\n      \"method\": \"Organotypic brain slice imaging, in vivo Rhes-tagged AAV injections, Rhes KO mice, fluorescence tracking\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo and ex vivo demonstration of intercellular transport with KO validation, multiple brain circuit readouts, replicates prior cell culture findings\",\n      \"pmids\": [\"35319973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Rhes and AGS1 trigger nearly identical modulation of N-type Ca2+ channels (CaV2.2) by selectively altering Gαi-dependent signaling: both reduce basal CaV2.2 current densities, trigger tonic voltage-dependent inhibition, and attenuate agonist-initiated Gαi-coupled receptor inhibition. These effects are blocked by pertussis toxin or Gβγ-sequestering peptide, indicating Rhes mediates tonic Gβγ signaling through PTX-sensitive G proteins.\",\n      \"method\": \"Whole-cell patch-clamp recording in HEK293 cells expressing CaV2.2, pertussis toxin treatment, Gβγ sequestration, comparison with multiple other Ras-family members\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with PTX and Gβγ-sequestration controls, comparison with multiple G-proteins, single lab\",\n      \"pmids\": [\"18815223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RASD2 overexpression in the nucleus accumbens core (NAcc) alleviates stress-induced depression-like behaviors and activates the DRD2-cAMP-PKA-DARPP-32 signaling pathway. Rasd2 overexpression in DRD2-expressing PrL-NAcc neurons (using Drd2-cre mice) ameliorates depression-like behaviors, placing RASD2 as a modulator of DRD2-dependent signaling in NAcc circuits.\",\n      \"method\": \"AAV-mediated overexpression, Drd2-cre transgenic mice, DREADD chemogenetics, retrograde tracing, Western blotting for cAMP-PKA-DARPP-32 pathway\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific circuit manipulation with multiple behavioral readouts and pathway biochemistry, single lab\",\n      \"pmids\": [\"39097664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Histone lactylation (H3K18la) promotes transcription of RASD2 in endometriosis. RASD2 increases the stability of CTPS1 by promoting CTPS1 SUMOylation and inhibiting its ubiquitination, thereby promoting endometriosis progression. This was established via the RASD2/CTPS1 axis.\",\n      \"method\": \"ChIP-qPCR, Co-immunoprecipitation, IP-MS, SUMOylation/ubiquitination assays, cell proliferation/invasion assays, endometriosis mouse models\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus IP-MS identification of CTPS1 interaction, functional SUMOylation/ubiquitination assays, in vivo validation, single lab\",\n      \"pmids\": [\"39672102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Rhes directly interacts with Slc4a7 (an intracellular pH sensor/solute carrier) through both its N- and C-terminal domains. This Rhes-Slc4a7 complex is membrane-associated and modulates intracellular pH to facilitate TNT formation and mHTT intercellular transfer. Farnesylation of Rhes is required for its binding to Slc4a7 and for TNT formation. Slc4a7 KO mice show reduced cell-to-cell mHTT transmission in the striatum in vivo. The transporter activity of Slc4a7 is not required for this interaction.\",\n      \"method\": \"LC-MS/MS of membrane-associated Rhes complexes, Co-immunoprecipitation, siRNA depletion of Slc4a7, pharmacological inhibition of Slc4a7, intracellular pH measurements, Rhes farnesylation mutants, Slc4a7 KO mice with in vivo mHTT transmission assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — unbiased proteomics discovery followed by Co-IP, domain mapping, pharmacological and genetic validation, in vivo KO confirmation, multiple orthogonal methods\",\n      \"pmids\": [\"41861004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RASD2 binds RAF1 and enhances RAF1 phosphorylation at Ser338, thereby activating the P38/ERK-MAPK pathway in clear cell renal cell carcinoma cells. This interaction was identified by Co-immunoprecipitation and LC-MS/MS.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS/MS proteomics, phospho-RAF1 (Ser338) Western blotting, RAF1 inhibitor (BAY43-9006) experiments, xenograft models\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus LC-MS/MS identification plus functional phosphorylation assays and inhibitor validation, single lab, cancer cell line context\",\n      \"pmids\": [\"42226617\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Rhes (RASD2) is a striatum-enriched, farnesylated small GTPase and SUMO E3 ligase that binds directly to mutant huntingtin (mHtt) and promotes its SUMOylation — disaggregating mHtt aggregates and increasing cytotoxicity — while also activating mTORC1, binding Beclin-1 to activate autophagy, interacting with Nix to drive mitophagy, modulating dopaminergic/cAMP/PKA and PI3K/AKT signaling by coupling to Gαi and Gβγ subunits of heterotrimeric G proteins, and inducing tunneling nanotube (TNT)-like protrusions that transport mHtt between neurons in a SUMOylation- and farnesylation-dependent manner via a membrane-associated complex with Slc4a7.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RASD2 (Rhes) is a striatum-enriched, farnesylated small GTPase that serves as a hub coupling G-protein signaling, protein SUMOylation, and selective neuronal vulnerability in Huntington's disease [#0, #4, #14]. It binds GTP and is constitutively partly GTP-loaded, anchoring to the plasma membrane through farnesylation, and modulates GPCR signaling by uncoupling receptors from heterotrimeric G proteins and engaging Gαi and Gβ subunits to attenuate cAMP/PKA output and tonic Gβγ signaling at CaV2.2 channels [#1, #5, #8, #20]. Beyond G-protein modulation, Rhes activates PI3K/AKT through the p85 regulatory subunit and binds and activates mTORC1, a function linked in vivo to L-DOPA-induced dyskinesia [#7, #9]. Rhes functions as a SUMO E3 ligase that binds SUMO E1 and the E2 Ubc9 and is the principal regulator of striatal SUMOylation [#6]. Through this activity it binds preferentially to mutant huntingtin (mHtt), promotes its SUMOylation and disaggregation, and confers cytotoxicity, and genetic loss or ectopic re-expression of Rhes establishes it as the causative factor for the striatal selectivity of mHtt toxicity in vivo [#4, #11, #14]. Rhes also controls catabolic pathways, binding Beclin-1 to activate mTOR-independent autophagy and interacting with Nix (BNIP3L) through its SUMO E3-like domain to drive mitophagy and cell death [#10, #18]. A distinctive activity is the biogenesis of tunneling-nanotube-like \\\"Rhes tunnels\\\" that transport mHtt between neurons in a SUMOylation- and farnesylation-dependent manner, requiring a membrane-associated complex with the pH sensor Slc4a7 and validated by intercellular mHtt transfer in intact striatum [#17, #19, #23]. Outside the nervous system, RASD2 promotes target-protein SUMOylation (CTPS1 in endometriosis) and activates RAF1-Ser338/MAPK signaling in renal carcinoma [#22, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that Rhes is a genuine GTP-binding protein defined a new membrane-targeted Ras subfamily and set the molecular starting point for all downstream signaling work.\",\n      \"evidence\": \"GTP-binding assay with bacterially expressed protein and sequence analysis\",\n      \"pmids\": [\"10467249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No GTPase regulator (GEF/GAP) identified\", \"Intrinsic hydrolysis rate not quantified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Biochemical dissection showed Rhes is constitutively partly GTP-bound and acts on PI3K and GPCR-cAMP signaling rather than the classical Ras-ERK/transformation axis, distinguishing it functionally from oncogenic Ras.\",\n      \"evidence\": \"GTP-loading, PI3K activation, cAMP accumulation assays and membrane fractionation in PC12/fibroblasts; plus in vivo knockout behavioral phenotyping\",\n      \"pmids\": [\"14724584\", \"15199135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of constitutive GTP loading not resolved\", \"Receptor-uncoupling stoichiometry undefined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Knockout studies tied Rhes to dopaminergic signaling, showing it raises Golf levels and is required for D2-associated dopamine-mediated GTP binding, embedding it in striatal cAMP/PKA control.\",\n      \"evidence\": \"Rhes null mice with cAMP/PKA and GTP-binding measurements plus dopaminergic pharmacological challenges\",\n      \"pmids\": [\"18035555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Rhes-Golf interaction not shown\", \"Cell-type resolution within striatum limited\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery that Rhes binds preferentially to mutant huntingtin and induces its SUMOylation with disaggregation and cytotoxicity provided the first molecular link explaining striatal selectivity in Huntington's disease.\",\n      \"evidence\": \"Co-immunoprecipitation, sumoylation and cell-viability assays in cultured cells; yeast two-hybrid mapping of Gβ-subunit binding\",\n      \"pmids\": [\"19498170\", \"19255495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO acceptor sites on mHtt not all mapped\", \"Link between disaggregation and toxicity mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Reconstitution established Rhes as a bona fide SUMO E3 ligase that binds E1 and Ubc9 and is the dominant regulator of striatal SUMOylation, defining the enzymatic basis for its mHtt action.\",\n      \"evidence\": \"In vitro sumoylation and direct E1/Ubc9 binding assays plus Rhes KO striatum analysis and mass spectrometry\",\n      \"pmids\": [\"20424159\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full striatal SUMO substrate repertoire incomplete\", \"How GTPase state gates E3 activity unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of Rhes as a direct activator of striatal mTORC1 and a modulator of Gαi/PI3K-coupled receptor signaling connected its biochemistry to L-DOPA-induced dyskinesia and cholinergic excitability.\",\n      \"evidence\": \"Co-IP with mTOR and Gαi pull-downs, cAMP/PTX-sensitivity assays, and Rhes-/- mice with 6-OHDA/L-DOPA paradigms\",\n      \"pmids\": [\"22179112\", \"21374700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect mTORC1 activation mechanism not fully resolved\", \"Relationship between mTOR activation and SUMO ligase activity unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapping the Rhes-p85 interaction to the unique C-terminal tail and showing growth-factor-enhanced AKT membrane translocation positioned Rhes as a striatal PI3K/AKT regulator.\",\n      \"evidence\": \"Co-IP with deletion-mutant domain mapping and AKT translocation assays\",\n      \"pmids\": [\"22683505\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab, single-study interaction\", \"In vivo relevance of p85 binding not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"A cluster of studies expanded Rhes function to catabolic and signaling control: Beclin-1-dependent mTOR-independent autophagy, β-arrestin2/PP2A-mediated Akt dephosphorylation, PAP7/DMT1 iron uptake regulated by PKA phosphorylation at Ser239, and protection in the 3-NP striatal HD model.\",\n      \"evidence\": \"Co-IP of Beclin-1/Bcl-2 and β-arrestin/PP2A, autophagy flux assays, iron-uptake and mutagenesis assays, and Rhes KO mice in the 3-NP toxicity model\",\n      \"pmids\": [\"24324270\", \"23380502\", \"23999124\", \"23447628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How one protein balances autophagy, Akt, and iron functions in vivo unclear\", \"Tissue/cell context dependence of each interaction unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Gain-of-function ectopic expression with loss-of-function striatal rescue formally established Rhes as the causative determinant of selective mHtt toxicity, and electrophysiology localized PI3K-dependent D2R modulation to cholinergic interneurons.\",\n      \"evidence\": \"AAV ectopic Rhes expression and striatal re-introduction in HD mouse models; patch-clamp recordings with Cav2.2/PI3K pharmacology in Rhes KO ChIs\",\n      \"pmids\": [\"26048156\", \"25818655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular event converting Rhes presence into selective vulnerability not pinpointed\", \"Generalizability beyond modeled HD alleles untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining the striatal 'Rhesactome' and the RasGRP1 stabilizing interaction revealed how Rhes protein levels, synaptic localization, and interactome are dynamically regulated, including by amphetamine.\",\n      \"evidence\": \"Co-IP, protein-stabilization Westerns, LC-MS/MS striatal proteomics, and Rhes+/- / Rasgrp1 KO behavioral epistasis\",\n      \"pmids\": [\"27902448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional roles of most Rhesactome partners (PDE2A, LRRC7, DLG2) untested\", \"Whether RasGRP1 acts as a true GEF for Rhes unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery of Rhes-induced tunneling-nanotube biogenesis and Nix-dependent mitophagy revealed two new membrane-based functions—intercellular mHtt transport and selective mitochondrial degradation—both requiring the SUMO E3-like domain and farnesylation.\",\n      \"evidence\": \"Live-cell imaging, EM, CRISPR SUMO depletion and domain mutagenesis for TNTs; Co-IP, fractionation, mitochondrial potential and Nix-depletion assays plus 3-NP KO mice for mitophagy\",\n      \"pmids\": [\"31076452\", \"31676548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TNT membrane deformation unknown\", \"How SUMO ligase activity mechanistically links to both processes unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating Rhes-driven mHtt transport between MSN subtypes and from striatum to cortex in intact and organotypic brain established intercellular spread as an in vivo mechanism of HD pathology propagation.\",\n      \"evidence\": \"Organotypic slice imaging and in vivo AAV tracking with Rhes KO validation\",\n      \"pmids\": [\"35319973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of spread to disease progression undefined\", \"Directionality determinants of transport unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of the membrane-associated Rhes-Slc4a7 complex provided the molecular machinery for TNT formation, showing pH modulation and Rhes farnesylation—but not Slc4a7 transport activity—drive intercellular mHtt transfer in vivo.\",\n      \"evidence\": \"LC-MS/MS of membrane Rhes complexes, Co-IP, domain mapping, Slc4a7 siRNA/pharmacology, pH measurements, farnesylation mutants, and Slc4a7 KO mice with in vivo mHTT transmission\",\n      \"pmids\": [\"41861004\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How local pH change physically promotes TNT membrane biogenesis unresolved\", \"Whether other carriers substitute for Slc4a7 untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Studies outside the striatal HD context showed RASD2 modulates NAcc DRD2-cAMP-PKA-DARPP-32 circuitry to influence depression-like behavior and acts as a SUMOylation-promoting oncogenic factor (CTPS1 stabilization in endometriosis).\",\n      \"evidence\": \"AAV/Drd2-cre circuit manipulation with DREADDs and pathway Westerns; ChIP, IP-MS, SUMOylation/ubiquitination assays and mouse models in endometriosis\",\n      \"pmids\": [\"39097664\", \"39672102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic overlap between neuronal and tumor SUMO functions untested\", \"Whether GTPase/farnesylation are required in these contexts unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extending RASD2 into cancer signaling, it was shown to bind RAF1 and enhance Ser338 phosphorylation to activate P38/ERK-MAPK in clear cell renal carcinoma.\",\n      \"evidence\": \"Co-IP, LC-MS/MS, phospho-RAF1 Westerns, RAF1 inhibitor and xenograft experiments\",\n      \"pmids\": [\"42226617\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with earlier finding that Rhes does not stimulate ERK/transformation unresolved\", \"Direct vs scaffold role in RAF1 activation undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Rhes's GTP-loading state, farnesylation, and SUMO E3 activity are integrated to select among its many effectors (G proteins, mTORC1, autophagy, mitophagy, TNT transport) in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model coordinating GTPase and SUMO-ligase domains\", \"Upstream signals switching Rhes between functions unknown\", \"Endogenous GEF/GAP regulation of Rhes not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [6, 4, 18, 22]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 8, 20, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 23]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 8, 20, 7, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 4, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 11, 14, 17, 19]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 15, 21]}\n    ],\n    \"complexes\": [\n      \"Rhes-Slc4a7 membrane complex\",\n      \"β-arrestin2/PP2A/Akt complex\"\n    ],\n    \"partners\": [\n      \"HTT\",\n      \"UBE2I\",\n      \"MTOR\",\n      \"BECN1\",\n      \"BNIP3L\",\n      \"SLC4A7\",\n      \"RASGRP1\",\n      \"RAF1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":8,"faith_pct":75.0}}