{"gene":"RHOD","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1996,"finding":"Activated RhoD causes rearrangements of the actin cytoskeleton and cell surface, and governs early endosome motility and distribution, identifying RhoD as a molecular link between membrane traffic and the cytoskeleton.","method":"Expression of activated RhoD in cells with live imaging and subcellular fractionation/localization assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — foundational study with direct localization and functional consequence, widely cited and replicated","pmids":["8945468"],"is_preprint":false},{"year":1999,"finding":"Constitutively active RhoD (G26V) induces disassembly of actin stress fibers and focal adhesions, reduces cell migration, and causes multinucleation/cytokinesis arrest, antagonizing RhoA-induced stress fiber formation. Dominant-negative RhoD (T31K) had no effect on these structures, indicating GTP-dependent activity is required.","method":"Microinjection and transfection of active/dominant-negative RhoD constructs into fibroblasts; phagokinetic track migration assay; Xenopus embryo microinjection for cytokinesis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (migration assay, actin imaging, Xenopus cytokinesis) in a single study with rigorous controls","pmids":["10229194"],"is_preprint":false},{"year":2002,"finding":"RhoD and Rnd1 bind the cytoplasmic domain of Plexin-A1; Rnd1 binding activates Plexin-A1 signaling to trigger cytoskeletal collapse, while RhoD competitively blocks Plexin-A1 activation by Rnd1 and antagonizes Sema3A-induced repulsion of sympathetic axons.","method":"Co-immunoprecipitation/pulldown of GTPases with plexin cytoplasmic domain; dominant-negative and constitutively active RhoD/Rnd1 expression; axon collapse and turning assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding assays combined with functional rescue/block experiments in neurons","pmids":["11784792"],"is_preprint":false},{"year":2002,"finding":"Active RhoD acts as a molecular switch that, when expressed, shifts PAR-1/thrombin receptor signaling from a RhoA/ROCK-dependent to a Gαq/PLC/CaM-MLCK-dependent pathway to promote cellular invasion, demonstrating antagonism between RhoA and RhoD in controlling G-protein coupling and invasion.","method":"Pharmacological inhibitors (C3 exoenzyme, Y-27632, dominant-negative N19-RhoA), activated G26V-RhoD transfection, Boyden chamber invasion assays in kidney and colonic epithelial cells","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2/3 — multiple inhibitor approaches and functional readout, single lab","pmids":["11919159"],"is_preprint":false},{"year":2003,"finding":"RhoD specifically binds a novel splice variant of human Diaphanous, hDia2C, recruiting it to early endosomes. RhoD and hDia2C together align early endosomes along actin filaments and reduce endosome motility through membrane recruitment and activation of c-Src kinase, defining a RhoD→hDia2C→c-Src signaling pathway that regulates endosome motility via the actin cytoskeleton.","method":"Yeast two-hybrid screening, co-immunoprecipitation, live-cell imaging of endosome dynamics, dominant-negative and constitutively active constructs, c-Src kinase activity assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including binding assay, live imaging, kinase activity, and epistatic order of pathway; high-impact journal","pmids":["12577064"],"is_preprint":false},{"year":2007,"finding":"RhoD directly binds the cytoplasmic domain of plexin-B1 (and also Rac1 and Rnd1) through beta-strands 3 and 4 and a short alpha-helical segment of the plexin ubiquitin-like fold domain, not through the canonical CRIB motif. Binding of any one of these GTPases destabilizes the homodimer of the plexin effector domain in solution, suggesting a bidirectional signaling mechanism.","method":"Solution NMR spectroscopy, X-ray crystallography (2.0 Å structure), in vitro GTPase-binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution structure plus NMR-defined binding site with functional implications, multiple orthogonal structural methods","pmids":["17916560"],"is_preprint":false},{"year":2012,"finding":"RhoD binds the actin nucleation-promoting factor WHAMM (WASp homologue associated with actin, Golgi membranes and microtubules) and the filamin A-binding protein FILIP1. WHAMM acts downstream of RhoD to regulate cytoskeletal dynamics via the Arp2/3 complex, while FILIP1 links RhoD to filamin A. Knockdown of RhoD or WHAMM increases cell attachment and decreases cell migration, indicating RhoD coordinates Arp2/3-dependent and filamin A-dependent mechanisms.","method":"Co-immunoprecipitation, siRNA knockdown, cell migration assays, actin cytoskeleton imaging, Arp2/3 complex binding assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, siRNA phenotypes with multiple readouts, epistasis established between RhoD and WHAMM","pmids":["23087206"],"is_preprint":false}],"current_model":"RhoD is a GTP-dependent Rho family GTPase that regulates early endosome motility and distribution by recruiting the formin hDia2C to endosomes and activating c-Src kinase, aligns endosomes along actin filaments, suppresses cell migration and cytokinesis (antagonizing RhoA), regulates actin dynamics through WHAMM/Arp2/3 and FILIP1/filamin A effectors, and modulates axon guidance by competitively blocking Rnd1-induced Plexin-A1 activation and Semaphorin 3A repulsion."},"narrative":{"teleology":[{"year":1996,"claim":"The discovery that activated RhoD reorganizes the actin cytoskeleton and governs early endosome motility and distribution established it as a Rho-family GTPase linking membrane traffic to the cytoskeleton.","evidence":"Expression of constitutively active RhoD in cultured cells with live imaging and subcellular fractionation","pmids":["8945468"],"confidence":"High","gaps":["Effector proteins mediating the endosome–cytoskeleton coupling were unknown","Whether the endosome phenotype required Rho effector signaling or direct membrane binding was untested"]},{"year":1999,"claim":"Demonstrating that GTP-bound RhoD disassembles stress fibers and focal adhesions, reduces migration, and blocks cytokinesis revealed a functional antagonism with RhoA and a requirement for GTPase cycling.","evidence":"Microinjection of active/dominant-negative RhoD in fibroblasts; phagokinetic track migration assay; Xenopus embryo cytokinesis assay","pmids":["10229194"],"confidence":"High","gaps":["The downstream effectors mediating stress-fiber disassembly were unidentified","Mechanism of cytokinesis inhibition was not resolved"]},{"year":2002,"claim":"Identification of competitive binding of RhoD and Rnd1 to Plexin-A1, with RhoD blocking Rnd1-driven plexin activation, extended RhoD function to axon guidance and showed it acts as a negative regulator of semaphorin signaling.","evidence":"Co-immunoprecipitation and pulldown of GTPases with plexin cytoplasmic domain; axon collapse and turning assays in sympathetic neurons","pmids":["11784792"],"confidence":"High","gaps":["Structural basis of competitive plexin binding was undefined","In vivo relevance of RhoD in axon guidance was not tested"]},{"year":2002,"claim":"Showing that RhoD switches PAR-1/thrombin signaling from a RhoA/ROCK to a Gαq/PLC/CaM-MLCK pathway to promote invasion clarified that RhoD–RhoA antagonism extends to G-protein-coupled receptor signaling.","evidence":"Pharmacological inhibitors (C3 exoenzyme, Y-27632), dominant-negative RhoA, activated RhoD transfection, Boyden chamber invasion assay","pmids":["11919159"],"confidence":"Medium","gaps":["Single-lab study without independent replication","Direct binding between RhoD and GPCR-associated signaling components was not shown"]},{"year":2003,"claim":"Discovery that RhoD recruits the formin hDia2C to early endosomes and activates c-Src kinase defined a RhoD→hDia2C→c-Src signaling axis that mechanistically explains how RhoD reduces endosome motility and aligns endosomes on actin filaments.","evidence":"Yeast two-hybrid, co-immunoprecipitation, live-cell endosome tracking, c-Src kinase activity assay","pmids":["12577064"],"confidence":"High","gaps":["Whether hDia2C actin-nucleating activity per se is required or whether c-Src is the sole downstream mediator was untested","Physiological cargo affected by slowed endosome motility was not identified"]},{"year":2007,"claim":"Atomic-resolution structural analysis revealed that RhoD binds plexin-B1 through a non-canonical interface on the ubiquitin-like fold domain, and that GTPase binding destabilizes the plexin effector-domain homodimer, providing a structural mechanism for RhoD-mediated plexin regulation.","evidence":"Solution NMR and 2.0 Å X-ray crystallography of plexin-B1 cytoplasmic domain; in vitro GTPase-binding assays","pmids":["17916560"],"confidence":"High","gaps":["Whether RhoD and Rnd1 compete for the same binding surface on plexin-B1 in cells was not directly shown","Functional consequences of dimer destabilization on downstream R-Ras GAP activity were not tested"]},{"year":2012,"claim":"Identification of WHAMM and FILIP1 as RhoD effectors connected RhoD to Arp2/3-dependent actin nucleation and filamin A scaffolding, revealing dual parallel mechanisms by which RhoD controls migration and adhesion.","evidence":"Reciprocal co-immunoprecipitation, siRNA knockdown of RhoD and WHAMM, cell migration and attachment assays","pmids":["23087206"],"confidence":"High","gaps":["Whether WHAMM and hDia2C operate on distinct or overlapping actin pools downstream of RhoD is unknown","In vivo physiological relevance of the FILIP1–filamin A axis downstream of RhoD has not been tested"]},{"year":null,"claim":"A complete in vivo model integrating RhoD's endosomal, migratory, and axon-guidance functions is lacking; knockout or conditional deletion phenotypes in mammals have not been reported, and the GEFs and GAPs that regulate RhoD cycling remain poorly defined.","evidence":"","pmids":[],"confidence":"High","gaps":["No mammalian knockout phenotype reported","GEFs and GAPs specific to RhoD are largely unidentified","Relationship between endosome and migration phenotypes in vivo is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,5]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,4,6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,5]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,4]}],"complexes":[],"partners":["DIAPH3","WHAMM","FILIP1","PLXNA1","PLXNB1","SRC"],"other_free_text":[]},"mechanistic_narrative":"RhoD is a Rho-family small GTPase that couples actin cytoskeleton remodeling to early endosome dynamics, cell migration, cytokinesis, and axon guidance. In its GTP-bound state, RhoD recruits the formin splice variant hDia2C to early endosomes, aligning them along actin filaments and reducing their motility through activation of c-Src kinase [PMID:12577064], and independently engages the nucleation-promoting factor WHAMM to drive Arp2/3-dependent actin dynamics and FILIP1 to link to filamin A, thereby coordinating migration and adhesion [PMID:23087206]. RhoD antagonizes RhoA-mediated stress fiber formation and focal adhesion assembly, suppressing cell migration and cytokinesis [PMID:10229194], and competitively binds the cytoplasmic domains of Plexin-A1 and Plexin-B1 to block Rnd1-induced plexin activation and Semaphorin 3A-mediated axon repulsion [PMID:11784792, PMID:17916560]."},"prefetch_data":{"uniprot":{"accession":"O00212","full_name":"Rho-related GTP-binding protein RhoD","aliases":["Rho-related protein HP1","RhoHP1"],"length_aa":210,"mass_kda":23.5,"function":"Involved in endosome dynamics. May coordinate membrane transport with the function of the cytoskeleton. Involved in the internalization and trafficking of activated tyrosine kinase receptors such as PDGFRB. Participates in the reorganization of actin cytoskeleton; the function seems to involve WHAMM and includes regulation of filopodia formation and actin filament bundling. Can modulate the effect of DAPK3 in reorganization of actin cytoskeleton and focal adhesion dissolution","subcellular_location":"Cell membrane; Early endosome","url":"https://www.uniprot.org/uniprotkb/O00212/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RHOD","classification":"Not Classified","n_dependent_lines":21,"n_total_lines":1208,"dependency_fraction":0.0173841059602649},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RHOD","total_profiled":1310},"omim":[{"mim_id":"616899","title":"TBC1 DOMAIN-CONTAINING KINASE; TBCK","url":"https://www.omim.org/entry/616899"},{"mim_id":"607307","title":"FILAMIN A-INTERACTING PROTEIN 1; FILIP1","url":"https://www.omim.org/entry/607307"},{"mim_id":"606650","title":"GLUTAMATE RECEPTOR, IONOTROPIC, N-METHYL-D-ASPARTATE 3A; GRIN3A","url":"https://www.omim.org/entry/606650"},{"mim_id":"605781","title":"RAS HOMOLOG GENE FAMILY, MEMBER D; RHOD","url":"https://www.omim.org/entry/605781"},{"mim_id":"300108","title":"DIAPHANOUS-RELATED FORMIN 2; DIAPH2","url":"https://www.omim.org/entry/300108"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":185.7},{"tissue":"liver","ntpm":124.9}],"url":"https://www.proteinatlas.org/search/RHOD"},"hgnc":{"alias_symbol":["RhoHP1","Rho"],"prev_symbol":["ARHD"]},"alphafold":{"accession":"O00212","domains":[{"cath_id":"3.40.50.300","chopping":"17-201","consensus_level":"high","plddt":94.3488,"start":17,"end":201}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00212","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00212-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00212-F1-predicted_aligned_error_v6.png","plddt_mean":89.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RHOD","jax_strain_url":"https://www.jax.org/strain/search?query=RHOD"},"sequence":{"accession":"O00212","fasta_url":"https://rest.uniprot.org/uniprotkb/O00212.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00212/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00212"}},"corpus_meta":[{"pmid":"12478284","id":"PMC_12478284","title":"Rho GTPases in cell biology.","date":"2002","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12478284","citation_count":3906,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16212495","id":"PMC_16212495","title":"Rho GTPases: biochemistry and biology.","date":"2005","source":"Annual review of cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16212495","citation_count":2432,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11683406","id":"PMC_11683406","title":"Rho GTPases and cell migration.","date":"2001","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/11683406","citation_count":965,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27301673","id":"PMC_27301673","title":"Regulating Rho GTPases and their regulators.","date":"2016","source":"Nature reviews. 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Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20630939","citation_count":36,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24706358","id":"PMC_24706358","title":"Paxillin mediates stretch-induced Rho signaling and endothelial permeability via assembly of paxillin-p42/44MAPK-GEF-H1 complex.","date":"2014","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/24706358","citation_count":34,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":34787,"output_tokens":1550,"usd":0.063806},"stage2":{"model":"claude-opus-4-6","input_tokens":4794,"output_tokens":2082,"usd":0.11403},"total_usd":0.393154,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":49165,"output_tokens":2214,"usd":0.090353},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5382,"output_tokens":2256,"usd":0.124965}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Activated RhoD causes rearrangements of the actin cytoskeleton and cell surface, and governs early endosome motility and distribution, providing a molecular link between membrane traffic and the cytoskeleton.\",\n      \"method\": \"Expression of activated RhoD in cells, microscopy of endosome dynamics and actin cytoskeleton\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean gain-of-function with defined cellular phenotype, replicated in subsequent work\",\n      \"pmids\": [\"8945468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RhoD specifically binds a novel splice variant of human Diaphanous, hDia2C, which is recruited onto early endosomes; RhoD and hDia2C together induce alignment of early endosomes along actin filaments, reduce their motility, and this requires membrane recruitment and activation of c-Src kinase, defining a RhoD→hDia2C→c-Src pathway regulating endosome motility.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, live-cell imaging, dominant-negative and overexpression constructs, kinase activity assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, functional reconstitution with multiple orthogonal methods, mechanistic pathway defined\",\n      \"pmids\": [\"12577064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RhoD binds directly to the cytoplasmic domain of Plexin-A1, and this interaction blocks Plexin-A1 activation by Rnd1, antagonizing Semaphorin 3A-induced growth cone collapse and repulsion of sympathetic axons, placing RhoD as a negative regulator of Sema3A/Plexin-A1 signaling.\",\n      \"method\": \"GST pulldown, yeast two-hybrid, microinjection of constitutively active RhoD, axon guidance assays, growth cone collapse assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding established by pulldown, functional consequence in multiple cellular assays\",\n      \"pmids\": [\"11784792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Constitutively active RhoD (G26V) induces disassembly of actin stress fibers and focal adhesions, suppresses cell migration (measured by phagokinetic track assays), and causes multinucleation by interfering with cytokinesis without affecting nuclear division; RhoD effects are antagonistic to RhoA.\",\n      \"method\": \"Microinjection and transfection of constitutively active RhoD(G26V) and dominant-negative RhoD(T31K), phagokinetic track assay, Xenopus embryo microinjection, immunofluorescence\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss- and gain-of-function with defined cytoskeletal and cytokinesis phenotypes, in vitro and in vivo (Xenopus) validation\",\n      \"pmids\": [\"10229194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RhoD directly binds the cytoplasmic domain of plexin-B1 (as well as Rac1 and Rnd1) at beta-strands 3 and 4 and a short alpha-helical segment of the plexin Rho GTPase interaction motif (not the canonical CRIB-like motif); all three GTPases interact with the same region and destabilize plexin-B1 dimerization in solution, suggesting a model for receptor regulation involving conformational change.\",\n      \"method\": \"Solution NMR spectroscopy, X-ray crystallography (2.0 Å resolution), biochemical binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure and NMR with functional validation; orthogonal methods in one study\",\n      \"pmids\": [\"17916560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RhoD acts as a molecular switch antagonizing RhoA in PAR-1-mediated cellular invasion: inhibition of endogenous RhoA by constitutively active G26V-RhoD confers invasive activity to PAR-1 via a Galphaq/PLC/Ca2+/calmodulin-MLCK/MLC phosphorylation cascade, whereas RhoA/ROCK-dependent invasion is independent of this pathway.\",\n      \"method\": \"Dominant-negative and constitutively active RhoD transfection, pharmacological inhibitors (C3 exoenzyme, Y-27632), invasion assays, biochemical pathway analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional epistasis with pharmacological and genetic tools, but single lab\",\n      \"pmids\": [\"11919159\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RhoD is an atypical Rho GTPase that, in its GTP-bound active form, regulates early endosome motility and distribution by recruiting the formin hDia2C onto endosomes and activating c-Src kinase, aligns endosomes along actin filaments, suppresses actin stress fibers and focal adhesions to inhibit cell migration, blocks cytokinesis (antagonizing RhoA), and negatively regulates Semaphorin 3A/Plexin-A1 axon guidance signaling by directly binding Plexin-A1 and blocking its activation by Rnd1.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers about the canonical RHOD protein.\n\n**Classification notes:**\n- Papers [1]-[31] from retrieved corpus: Most are about RhoA/Rac/Cdc42 family broadly, ROCK, or bacterial Rho transcription terminator → EXCLUDE unless specifically about RhoD\n- KEEP from retrieved: [32] RhoD endosome dynamics, [34] RhoD/hDia2C/Src endosome pathway, [43] RhoD/Rnd1/Plexin-A1, [53] RhoD binding to plexin-B1, [87] RhoD suppresses migration/cytokinesis, [91] RhoD regulatory switch in invasion\n- [27] from gene2pubmed: RhoD/WHAMM paper → KEEP\n- [28] in retrieved corpus: plant ROP11 → EXCLUDE (symbol collision, plant)\n- [38], [52], [83] in retrieved corpus: bacterial Rho transcription terminator → EXCLUDE\n- BioPlex papers, GWAS, cDNA collections → EXCLUDE (no mechanistic RHOD findings)\n- [17] from gene2pubmed: proximity interaction network includes RhoD data → borderline, but no specific RhoD mechanism described\n- [21] from gene2pubmed: fetal RHD (blood group gene) → EXCLUDE (alias collision)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Activated RhoD causes rearrangements of the actin cytoskeleton and cell surface, and governs early endosome motility and distribution, identifying RhoD as a molecular link between membrane traffic and the cytoskeleton.\",\n      \"method\": \"Expression of activated RhoD in cells with live imaging and subcellular fractionation/localization assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — foundational study with direct localization and functional consequence, widely cited and replicated\",\n      \"pmids\": [\"8945468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Constitutively active RhoD (G26V) induces disassembly of actin stress fibers and focal adhesions, reduces cell migration, and causes multinucleation/cytokinesis arrest, antagonizing RhoA-induced stress fiber formation. Dominant-negative RhoD (T31K) had no effect on these structures, indicating GTP-dependent activity is required.\",\n      \"method\": \"Microinjection and transfection of active/dominant-negative RhoD constructs into fibroblasts; phagokinetic track migration assay; Xenopus embryo microinjection for cytokinesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (migration assay, actin imaging, Xenopus cytokinesis) in a single study with rigorous controls\",\n      \"pmids\": [\"10229194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"RhoD and Rnd1 bind the cytoplasmic domain of Plexin-A1; Rnd1 binding activates Plexin-A1 signaling to trigger cytoskeletal collapse, while RhoD competitively blocks Plexin-A1 activation by Rnd1 and antagonizes Sema3A-induced repulsion of sympathetic axons.\",\n      \"method\": \"Co-immunoprecipitation/pulldown of GTPases with plexin cytoplasmic domain; dominant-negative and constitutively active RhoD/Rnd1 expression; axon collapse and turning assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays combined with functional rescue/block experiments in neurons\",\n      \"pmids\": [\"11784792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Active RhoD acts as a molecular switch that, when expressed, shifts PAR-1/thrombin receptor signaling from a RhoA/ROCK-dependent to a Gαq/PLC/CaM-MLCK-dependent pathway to promote cellular invasion, demonstrating antagonism between RhoA and RhoD in controlling G-protein coupling and invasion.\",\n      \"method\": \"Pharmacological inhibitors (C3 exoenzyme, Y-27632, dominant-negative N19-RhoA), activated G26V-RhoD transfection, Boyden chamber invasion assays in kidney and colonic epithelial cells\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — multiple inhibitor approaches and functional readout, single lab\",\n      \"pmids\": [\"11919159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RhoD specifically binds a novel splice variant of human Diaphanous, hDia2C, recruiting it to early endosomes. RhoD and hDia2C together align early endosomes along actin filaments and reduce endosome motility through membrane recruitment and activation of c-Src kinase, defining a RhoD→hDia2C→c-Src signaling pathway that regulates endosome motility via the actin cytoskeleton.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, live-cell imaging of endosome dynamics, dominant-negative and constitutively active constructs, c-Src kinase activity assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including binding assay, live imaging, kinase activity, and epistatic order of pathway; high-impact journal\",\n      \"pmids\": [\"12577064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RhoD directly binds the cytoplasmic domain of plexin-B1 (and also Rac1 and Rnd1) through beta-strands 3 and 4 and a short alpha-helical segment of the plexin ubiquitin-like fold domain, not through the canonical CRIB motif. Binding of any one of these GTPases destabilizes the homodimer of the plexin effector domain in solution, suggesting a bidirectional signaling mechanism.\",\n      \"method\": \"Solution NMR spectroscopy, X-ray crystallography (2.0 Å structure), in vitro GTPase-binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution structure plus NMR-defined binding site with functional implications, multiple orthogonal structural methods\",\n      \"pmids\": [\"17916560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RhoD binds the actin nucleation-promoting factor WHAMM (WASp homologue associated with actin, Golgi membranes and microtubules) and the filamin A-binding protein FILIP1. WHAMM acts downstream of RhoD to regulate cytoskeletal dynamics via the Arp2/3 complex, while FILIP1 links RhoD to filamin A. Knockdown of RhoD or WHAMM increases cell attachment and decreases cell migration, indicating RhoD coordinates Arp2/3-dependent and filamin A-dependent mechanisms.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, cell migration assays, actin cytoskeleton imaging, Arp2/3 complex binding assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, siRNA phenotypes with multiple readouts, epistasis established between RhoD and WHAMM\",\n      \"pmids\": [\"23087206\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RhoD is a GTP-dependent Rho family GTPase that regulates early endosome motility and distribution by recruiting the formin hDia2C to endosomes and activating c-Src kinase, aligns endosomes along actin filaments, suppresses cell migration and cytokinesis (antagonizing RhoA), regulates actin dynamics through WHAMM/Arp2/3 and FILIP1/filamin A effectors, and modulates axon guidance by competitively blocking Rnd1-induced Plexin-A1 activation and Semaphorin 3A repulsion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RhoD is an atypical Rho family GTPase that coordinates actin cytoskeleton remodeling with early endosome dynamics. In its GTP-bound form, RhoD recruits the formin hDia2C onto early endosomes and activates c-Src kinase, aligning endosomes along actin filaments and reducing their motility [PMID:8945468, PMID:12577064]. RhoD antagonizes RhoA signaling by disassembling actin stress fibers and focal adhesions, thereby suppressing cell migration and blocking cytokinesis, and modulates PAR-1-mediated cellular invasion through a Gαq/PLC/Ca²⁺/calmodulin pathway [PMID:10229194, PMID:11919159]. RhoD also directly binds the cytoplasmic domains of plexin-A1 and plexin-B1, where it competes with Rnd1 to negatively regulate Semaphorin/Plexin axon guidance signaling and destabilizes plexin dimerization [PMID:11784792, PMID:17916560].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"The discovery that activated RhoD rearranges the actin cytoskeleton and governs early endosome motility established the first molecular link between a Rho GTPase and membrane trafficking.\",\n      \"evidence\": \"Expression of activated RhoD in cultured cells with microscopy of endosome dynamics and actin\",\n      \"pmids\": [\"8945468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No downstream effector identified\",\n        \"Mechanism connecting actin rearrangement to endosome motility unknown\",\n        \"Endogenous RhoD activity not measured\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Gain- and loss-of-function experiments revealed that RhoD antagonizes RhoA by disassembling stress fibers and focal adhesions, suppressing migration, and blocking cytokinesis, defining it as a functional antagonist of RhoA in the cytoskeleton.\",\n      \"evidence\": \"Microinjection of constitutively active RhoD(G26V) and dominant-negative RhoD(T31K), phagokinetic track assays, Xenopus embryo injection, immunofluorescence\",\n      \"pmids\": [\"10229194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular basis of RhoA antagonism not defined\",\n        \"Cytokinesis block mechanism (contractile ring vs cleavage furrow) unresolved\",\n        \"Physiological activation context unknown\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Direct binding of RhoD to Plexin-A1 was shown to block Rnd1-mediated plexin activation, establishing RhoD as a negative regulator of Semaphorin 3A axon guidance signaling and expanding its role beyond endosome traffic to receptor-level signal modulation.\",\n      \"evidence\": \"GST pulldown, yeast two-hybrid, growth cone collapse and axon guidance assays with constitutively active RhoD microinjection\",\n      \"pmids\": [\"11784792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether endogenous RhoD levels regulate Sema3A signaling in vivo not tested\",\n        \"Structural basis of competitive inhibition of Rnd1 by RhoD on plexin unknown\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"RhoD was placed in a PAR-1-dependent invasion pathway where it antagonizes RhoA and permits signaling through Gαq/PLC/Ca²⁺/calmodulin-MLCK/MLC phosphorylation, revealing a context-specific pro-invasive role distinct from its anti-migratory effects.\",\n      \"evidence\": \"Constitutively active and dominant-negative RhoD transfection, C3 exoenzyme and Y-27632 inhibitors, invasion assays\",\n      \"pmids\": [\"11919159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding not independently replicated\",\n        \"Direct interaction between RhoD and Gαq pathway components not demonstrated\",\n        \"Physiological relevance of PAR-1/RhoD axis in invasion in vivo unresolved\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of hDia2C as a direct RhoD effector recruited to early endosomes, together with c-Src kinase activation, defined a RhoD→hDia2C→c-Src signaling cascade that aligns endosomes along actin filaments and reduces their motility.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, yeast two-hybrid, live-cell imaging, dominant-negative constructs, kinase activity assays\",\n      \"pmids\": [\"12577064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How c-Src activation mechanistically reduces endosome motility not resolved\",\n        \"Other endosomal effectors of RhoD not surveyed\",\n        \"Role of formin actin polymerization activity versus scaffolding not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Structural studies showed RhoD binds plexin-B1 at the same Rho GTPase interaction motif as Rac1 and Rnd1, destabilizing plexin dimerization, providing an atomic-level explanation for how multiple Rho GTPases compete on plexin receptors to regulate signaling.\",\n      \"evidence\": \"Solution NMR, X-ray crystallography at 2.0 Å, biochemical binding assays\",\n      \"pmids\": [\"17916560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure of RhoD–plexin-A1 complex not solved\",\n        \"Whether RhoD binding alters plexin conformation in the full-length receptor in a membrane context unknown\",\n        \"Relative affinities of RhoD versus Rnd1/Rac1 for plexin in cells not quantified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The GEFs and GAPs that activate or inactivate RhoD, its full effector repertoire beyond hDia2C and plexins, and the in vivo physiological consequences of RhoD loss remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No RhoD-specific GEF or GAP identified\",\n        \"No knockout or conditional loss-of-function animal model reported\",\n        \"Relationship between endosome-regulatory and plexin-regulatory functions in the same cell type untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"DIAPH3\",\n      \"SRC\",\n      \"PLXNA1\",\n      \"PLXNB1\",\n      \"RHOA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"RhoD is a Rho-family small GTPase that couples actin cytoskeleton remodeling to early endosome dynamics, cell migration, cytokinesis, and axon guidance. In its GTP-bound state, RhoD recruits the formin splice variant hDia2C to early endosomes, aligning them along actin filaments and reducing their motility through activation of c-Src kinase [PMID:12577064], and independently engages the nucleation-promoting factor WHAMM to drive Arp2/3-dependent actin dynamics and FILIP1 to link to filamin A, thereby coordinating migration and adhesion [PMID:23087206]. RhoD antagonizes RhoA-mediated stress fiber formation and focal adhesion assembly, suppressing cell migration and cytokinesis [PMID:10229194], and competitively binds the cytoplasmic domains of Plexin-A1 and Plexin-B1 to block Rnd1-induced plexin activation and Semaphorin 3A-mediated axon repulsion [PMID:11784792, PMID:17916560].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"The discovery that activated RhoD reorganizes the actin cytoskeleton and governs early endosome motility and distribution established it as a Rho-family GTPase linking membrane traffic to the cytoskeleton.\",\n      \"evidence\": \"Expression of constitutively active RhoD in cultured cells with live imaging and subcellular fractionation\",\n      \"pmids\": [\"8945468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Effector proteins mediating the endosome–cytoskeleton coupling were unknown\",\n        \"Whether the endosome phenotype required Rho effector signaling or direct membrane binding was untested\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that GTP-bound RhoD disassembles stress fibers and focal adhesions, reduces migration, and blocks cytokinesis revealed a functional antagonism with RhoA and a requirement for GTPase cycling.\",\n      \"evidence\": \"Microinjection of active/dominant-negative RhoD in fibroblasts; phagokinetic track migration assay; Xenopus embryo cytokinesis assay\",\n      \"pmids\": [\"10229194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The downstream effectors mediating stress-fiber disassembly were unidentified\",\n        \"Mechanism of cytokinesis inhibition was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of competitive binding of RhoD and Rnd1 to Plexin-A1, with RhoD blocking Rnd1-driven plexin activation, extended RhoD function to axon guidance and showed it acts as a negative regulator of semaphorin signaling.\",\n      \"evidence\": \"Co-immunoprecipitation and pulldown of GTPases with plexin cytoplasmic domain; axon collapse and turning assays in sympathetic neurons\",\n      \"pmids\": [\"11784792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of competitive plexin binding was undefined\",\n        \"In vivo relevance of RhoD in axon guidance was not tested\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing that RhoD switches PAR-1/thrombin signaling from a RhoA/ROCK to a Gαq/PLC/CaM-MLCK pathway to promote invasion clarified that RhoD–RhoA antagonism extends to G-protein-coupled receptor signaling.\",\n      \"evidence\": \"Pharmacological inhibitors (C3 exoenzyme, Y-27632), dominant-negative RhoA, activated RhoD transfection, Boyden chamber invasion assay\",\n      \"pmids\": [\"11919159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study without independent replication\",\n        \"Direct binding between RhoD and GPCR-associated signaling components was not shown\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovery that RhoD recruits the formin hDia2C to early endosomes and activates c-Src kinase defined a RhoD→hDia2C→c-Src signaling axis that mechanistically explains how RhoD reduces endosome motility and aligns endosomes on actin filaments.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, live-cell endosome tracking, c-Src kinase activity assay\",\n      \"pmids\": [\"12577064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether hDia2C actin-nucleating activity per se is required or whether c-Src is the sole downstream mediator was untested\",\n        \"Physiological cargo affected by slowed endosome motility was not identified\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Atomic-resolution structural analysis revealed that RhoD binds plexin-B1 through a non-canonical interface on the ubiquitin-like fold domain, and that GTPase binding destabilizes the plexin effector-domain homodimer, providing a structural mechanism for RhoD-mediated plexin regulation.\",\n      \"evidence\": \"Solution NMR and 2.0 Å X-ray crystallography of plexin-B1 cytoplasmic domain; in vitro GTPase-binding assays\",\n      \"pmids\": [\"17916560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether RhoD and Rnd1 compete for the same binding surface on plexin-B1 in cells was not directly shown\",\n        \"Functional consequences of dimer destabilization on downstream R-Ras GAP activity were not tested\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of WHAMM and FILIP1 as RhoD effectors connected RhoD to Arp2/3-dependent actin nucleation and filamin A scaffolding, revealing dual parallel mechanisms by which RhoD controls migration and adhesion.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, siRNA knockdown of RhoD and WHAMM, cell migration and attachment assays\",\n      \"pmids\": [\"23087206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether WHAMM and hDia2C operate on distinct or overlapping actin pools downstream of RhoD is unknown\",\n        \"In vivo physiological relevance of the FILIP1–filamin A axis downstream of RhoD has not been tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A complete in vivo model integrating RhoD's endosomal, migratory, and axon-guidance functions is lacking; knockout or conditional deletion phenotypes in mammals have not been reported, and the GEFs and GAPs that regulate RhoD cycling remain poorly defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No mammalian knockout phenotype reported\",\n        \"GEFs and GAPs specific to RhoD are largely unidentified\",\n        \"Relationship between endosome and migration phenotypes in vivo is unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 4, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"DIAPH3\",\n      \"WHAMM\",\n      \"FILIP1\",\n      \"PLXNA1\",\n      \"PLXNB1\",\n      \"SRC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}