{"gene":"RND1","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1998,"finding":"Rnd1 is constitutively GTP-bound due to low affinity for GDP, rapid spontaneous nucleotide exchange, and lack of intrinsic GTPase activity. Expression of Rnd1 in fibroblasts induces disassembly of actin stress fibers, membrane ruffles, and integrin-based focal adhesions, leading to cell rounding and loss of cell-substrate adhesion.","method":"Biochemical nucleotide binding assays, GTPase activity assays, overexpression in fibroblasts with morphological readouts, subcellular fractionation/immunolocalization","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — foundational paper with multiple orthogonal methods (biochemical assays + cell biology), widely replicated","pmids":["9531558"],"is_preprint":false},{"year":1999,"finding":"Recombinant prenylated Rnd1 dose-dependently inhibits carbachol- and GTPgammaS-induced Ca2+ sensitization in smooth muscle by specifically interfering with a RhoA-dependent mechanism, without affecting basal Ca2+-tension relationships or myosin light chain phosphatase inhibition-induced tension.","method":"Permeabilized smooth muscle strip contraction assay, recombinant protein application, pharmacological dissection","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro reconstitution with recombinant protein in permeabilized muscle, multiple controls","pmids":["10200428"],"is_preprint":false},{"year":2000,"finding":"Rnd1 directly interacts with the adapter protein Grb7 via the switch II loop of Rnd1 and the SH2 domain of Grb7, as demonstrated by yeast two-hybrid, in vitro binding assays, and pull-down from SK-BR3 breast cancer cell lysate.","method":"Yeast two-hybrid, in vitro pull-down, co-immunoprecipitation from cell lysate","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 — multiple binding assays from a single lab but no functional follow-up on the interaction","pmids":["10664463"],"is_preprint":false},{"year":2000,"finding":"Expression of Rnd1 in PC12 cells induces formation of neuritic processes accompanied by disruption of cortical actin filaments; this process formation is inhibited by dominant-negative Rac1, placing Rnd1 upstream of Rac in neuritic process formation.","method":"Overexpression in PC12 cells, cytochalasin D treatment, dominant-negative Rac1 epistasis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with dominant-negative Rac1, single lab","pmids":["11095956"],"is_preprint":false},{"year":2002,"finding":"Rnd1 (and RhoD) directly binds the cytoplasmic domain of Plexin-A1; active Rnd1 is sufficient to trigger Plexin-A1 signaling and cytoskeletal collapse even without Sema3A ligand, while RhoD antagonizes Rnd1-mediated Plexin-A1 activation and blocks Sema3A-induced axon repulsion.","method":"Direct binding assays (large GTPase panel screen), overexpression/co-expression in neuronal cells, growth cone collapse assay, axon repulsion assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding assays combined with functional collapse and axon guidance assays, widely cited","pmids":["11784792"],"is_preprint":false},{"year":2003,"finding":"Rnd1 directly interacts with the cytoplasmic domain of Plexin-B1; co-expression of Rnd1 with Plexin-B1 induces Sema4D-dependent cell contraction via the PDZ-RhoGEF/RhoA/ROCK pathway. Rnd1 promotes the interaction between Plexin-B1 and PDZ-RhoGEF and potentiates Plexin-B1-mediated RhoA activation.","method":"Co-immunoprecipitation, dominant-negative RhoA, ROCK inhibitor, deletion mutants of Plexin-B1, RhoA activation assay (GST-pulldown of GTP-RhoA), COS-7 cell contraction assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including binding, RhoA activity assay, pharmacological and genetic epistasis","pmids":["12730235"],"is_preprint":false},{"year":2003,"finding":"Rnd1 is localized to synaptosomal membrane fractions in brain and promotes dendritic spine elongation when overexpressed; suppression of endogenous Rnd1 by antisense oligonucleotides reduces spine number, spine width, and increases headless protrusions in hippocampal neurons.","method":"Subcellular fractionation, Northern blot, in situ hybridization, overexpression and antisense knockdown in cultured hippocampal neurons with morphological readouts","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by fractionation with functional KD phenotype, single lab","pmids":["14657163"],"is_preprint":false},{"year":2005,"finding":"Rnd1 directly associates with FRS2alpha and FRS2beta (FGF receptor docking proteins); FRS2beta binding suppresses Rnd1's inhibitory effect on RhoA. FGF receptor 1 activation phosphorylates FRS2beta, recruits Shp2, and releases Rnd1 from FRS2beta, allowing free Rnd1 to inhibit RhoA. Knockdown of Rnd1 by siRNA suppresses FGF-induced neurite outgrowth in PC12 cells.","method":"Co-immunoprecipitation, in vitro pull-down, phosphorylation assays, RhoA activity assays, siRNA knockdown, neurite outgrowth assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (binding, activity assay, KD phenotype) establishing a regulatory mechanism","pmids":["15738000"],"is_preprint":false},{"year":2006,"finding":"Rnd1 is required for neuronal activity-dependent dendritic development in hippocampal neurons; RNAi knockdown of Rnd1 inhibits dendritic growth and branching, and this effect is rescued by inhibition of ROCK (RhoA effector), placing Rnd1 as an antagonist of the RhoA-ROCK pathway in dendritic development.","method":"RNA interference, overexpression, ROCK inhibitor epistasis, BDNF stimulation, dendritic morphology quantification","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with ROCK inhibitor plus RNAi phenotype, single lab","pmids":["16530331"],"is_preprint":false},{"year":2007,"finding":"Rac1, Rnd1, and RhoD all bind the same region (beta-strands 3-4 and a short alpha-helical segment) of the plexin-B1 Rho GTPase binding domain (RBD), which adopts a ubiquitin-like fold. GTPase binding destabilizes the RBD homodimer, suggesting a model for receptor activation by monomerization.","method":"Solution NMR spectroscopy, 2.0 Å X-ray crystallography, in vitro binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — joint NMR and X-ray crystallographic study with functional binding characterization","pmids":["17916560"],"is_preprint":false},{"year":2009,"finding":"Rnd1 physically interacts with Unc5B (a Netrin receptor) and functionally cooperates with the FLRT3-Unc5B complex to modulate cell deadhesion; Rnd1 mediates FLRT3 deadhesion activity in Xenopus embryos.","method":"Expression screen, co-immunoprecipitation, overexpression phenotype in Xenopus embryos, morpholino knockdown","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP plus morpholino phenotype in Xenopus, single lab","pmids":["19492039"],"is_preprint":false},{"year":2009,"finding":"Thermodynamic characterization reveals that Rnd1 and Rac1 bind the plexin-B1 RBD with similar affinities but with different thermodynamic signatures: Rac1 binding induces rigidification of the complex while Rnd1 binding is consistent with unchanged or increased flexibility, suggesting distinct downstream signaling mechanisms.","method":"Isothermal titration calorimetry at multiple temperatures/conditions, thermodynamic analysis","journal":"Protein science","confidence":"Medium","confidence_rationale":"Tier 1 — rigorous biophysical characterization, single lab","pmids":["19388051"],"is_preprint":false},{"year":2011,"finding":"Crystal structures of the plexin-A2 RBD in complex with Rnd1 and of plexin-C1 and -D1 RBDs alone reveal that the RBD beta3-beta4 loop in plexin-A2 and -B1 adjusts conformation to allow Rnd1 binding, while plexin-C1 and -D1 lack key non-polar residues at this surface; introduction of these residues by mutagenesis generates Rnd1-binding affinity in plexin-C1/-D1.","method":"X-ray crystallography, isothermal titration calorimetry, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis plus ITC, comprehensive structural study","pmids":["21610070"],"is_preprint":false},{"year":2012,"finding":"Rnd1 and Rnd3 (but not Rnd2) contain an N-terminal KERRA sequence that targets them to lipid rafts; this lipid raft targeting is required for co-recruitment and activation of p190 RhoGAP in cells, explaining the functional difference among Rnd family members in RhoA inhibition signaling.","method":"Domain swap/mutation analysis, lipid raft fractionation, p190 RhoGAP activation assay, co-localization studies","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (fractionation, activity assay, mutagenesis) establishing a novel regulatory mechanism","pmids":["22357615"],"is_preprint":false},{"year":2014,"finding":"Rnd1 suppresses Ras-MAPK signaling by activating the GAP domain of Plexin-B1, which inhibits Rap1; Rap1 inhibition derepresses p120 Ras-GAP to inhibit Ras. Rnd1 depletion in mammary epithelial cells induces EMT, and Rnd1 expression inhibits tumor metastasis in mouse models.","method":"siRNA knockdown, epistasis experiments with Rap1 and p120 Ras-GAP, RhoA/Ras activity assays, mouse xenograft models, genomic analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — multi-step epistasis with activity assays, in vivo validation, and genomic evidence; strong evidence","pmids":["25531777"],"is_preprint":false},{"year":2014,"finding":"STI1 (stress-inducible protein 1) directly interacts with Rnd1 specifically (not Rnd2 or Rnd3), and overexpression of STI1 prevents Rnd1-PlexinA1-mediated cytoskeletal collapse in COS cells and enhances neurite outgrowth initiated by Rnd1 in PC12 cells.","method":"Co-immunoprecipitation, COS collapse assay, PC12 neurite outgrowth assay, specificity controls with Rnd2/Rnd3","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP with functional cellular assays, single lab","pmids":["24690281"],"is_preprint":false},{"year":2019,"finding":"Rnd1 is induced by mechanical stretch and hypertrophic stimuli in cardiomyocytes; it interacts with Myozap (an intercalated disc protein identified by yeast two-hybrid and co-IP) and promotes RhoA-mediated SRF signaling, cardiomyocyte hypertrophy, and cell proliferation.","method":"Microarray, overexpression in NRVCMs, yeast two-hybrid, co-immunoprecipitation, Ki67/EdU proliferation assays, SRF reporter assay","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2-3 — yeast two-hybrid confirmed by co-IP, plus functional phenotypes; single lab","pmids":["30797814"],"is_preprint":false},{"year":2022,"finding":"RND1 interacts with p53, promotes p53 de-ubiquitination, and activates the p53-SLC7A11 signaling pathway to induce lipid peroxidation and ferroptosis in glioblastoma cells.","method":"Co-immunoprecipitation, ubiquitination assays, luciferase reporter assays, lipid ROS/peroxidation assays, cell viability assays, GBM xenograft model","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus ubiquitination assay plus functional readouts, single lab","pmids":["35505371"],"is_preprint":false},{"year":2022,"finding":"RND1 is a direct transcriptional target of endothelial Notch signaling (rapidly induced within 1.5-6 h of Notch activation); RND1 is required for Notch-mediated suppression of endothelial migration, sprouting angiogenesis, and Ras activity.","method":"Transcriptomic analysis (RNA-seq), ligand-specific and EGTA-induced Notch activation, RND1 knockdown with migration and sprouting assays, Ras activity assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct Notch target validation plus KD functional phenotypes in endothelial cells, single lab","pmids":["35102202"],"is_preprint":false},{"year":2022,"finding":"Rnd1 inhibits virus internalization by counteracting intracellular calcium fluctuations through inhibition of RhoA activation; Rnd1 also facilitates IL-6 and TNF-α production through Plexin-B1, providing protection against intracellular bacterial infections.","method":"Knockdown and overexpression in cell lines, viral infection assays, calcium measurements, cytokine ELISA, Plexin-B1 interaction studies","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 — functional KD/OE phenotypes with mechanistic pathway placement, single lab","pmids":["35654795"],"is_preprint":false},{"year":2021,"finding":"MD simulations show that RND1 reinforces the plexin dimerization interface (activating plexin signaling) while RhoD destabilizes it, due to differential interactions with the inner leaflet of the cell membrane; this antithetic effect is mediated by an allosteric network through the RBD, RBD linkers, and a buttress segment.","method":"Molecular dynamics simulations (computational), comparison with experimental binding data","journal":"eLife","confidence":"Low","confidence_rationale":"Tier 4 — primarily computational, though consistent with experimental data","pmids":["34114565"],"is_preprint":false},{"year":2018,"finding":"RND1 transcription is rapidly induced by camptothecin-stabilized topoisomerase I cleavage complexes (TOP1cc) via PARP-1 activity; RND1 also increases PARP-1 levels (cross-talk), and RND1 overexpression protects cells from camptothecin-induced apoptosis, promoting cellular resistance.","method":"RT-PCR, mRNA stability assays, PARP-1 inhibitor treatment, RND1 overexpression/knockdown, apoptosis assays, luciferase reporter","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple methods establishing TOP1cc-PARP-1-RND1 pathway, single lab","pmids":["30209297"],"is_preprint":false}],"current_model":"RND1 is a constitutively GTP-bound, GTPase-inactive Rho family protein that localizes to adherens junctions and lipid rafts, where it inhibits RhoA signaling (via p190 RhoGAP activation and antagonism of RhoA-ROCK-mediated Ca2+ sensitization), directly binds and activates plexin receptors (Plexin-A1, -A2, -B1) to regulate actin cytoskeletal collapse and axon guidance through PDZ-RhoGEF/RhoA/ROCK, suppresses Ras-MAPK signaling through a Plexin-B1 GAP→Rap1→p120 Ras-GAP cascade, is regulated by FRS2beta sequestration and FGF receptor-mediated release, interacts with STI1 and Grb7, and promotes dendritic spine formation and neuritic outgrowth; in non-neural contexts it is a direct Notch transcriptional target suppressing endothelial migration, promotes p53 de-ubiquitination to induce ferroptosis, and is induced by mechanical stretch to activate SRF signaling through interaction with Myozap."},"narrative":{"teleology":[{"year":1998,"claim":"Establishing that RND1 is constitutively GTP-bound with no intrinsic GTPase activity resolved how this atypical Rho protein is regulated and showed it acts as a potent inducer of actin stress fiber disassembly and cell rounding.","evidence":"Biochemical nucleotide binding/GTPase assays and overexpression in fibroblasts with morphological readouts","pmids":["9531558"],"confidence":"High","gaps":["Post-translational regulatory mechanisms (e.g., ubiquitination, transcriptional control) not addressed","No structural basis for constitutive GTP binding"]},{"year":1999,"claim":"Demonstrating that recombinant RND1 specifically inhibits RhoA-dependent Ca²⁺ sensitization in smooth muscle established a direct functional antagonism between RND1 and RhoA signaling.","evidence":"Permeabilized smooth muscle strip contraction assays with recombinant prenylated RND1","pmids":["10200428"],"confidence":"High","gaps":["Endogenous RND1 expression and function in smooth muscle not verified","Mechanism of RhoA inhibition (direct vs. GAP-mediated) not determined"]},{"year":2002,"claim":"Identification of RND1 as a direct binding partner and activator of Plexin-A1 revealed that RND1 operates as a co-receptor switch for semaphorin signaling, sufficient to trigger cytoskeletal collapse without ligand.","evidence":"Large-scale GTPase binding screen, growth cone collapse and axon repulsion assays in neuronal cells","pmids":["11784792"],"confidence":"High","gaps":["Stoichiometry and regulation of RND1-plexin interaction in vivo unknown","Whether RND1 is required (not just sufficient) for Sema3A signaling not demonstrated"]},{"year":2003,"claim":"Showing that RND1 binds Plexin-B1 and promotes PDZ-RhoGEF recruitment and RhoA activation extended the plexin co-activation model to class B plexins and identified the downstream effector pathway.","evidence":"Co-immunoprecipitation, RhoA-GTP pull-down, ROCK inhibitor epistasis, COS-7 cell contraction assay","pmids":["12730235"],"confidence":"High","gaps":["Whether RND1 simultaneously activates both RhoA-inhibiting (p190 GAP) and RhoA-activating (PDZ-RhoGEF) arms in the same cell was unclear"]},{"year":2003,"claim":"Localizing endogenous RND1 to synaptosomal membranes and showing that its depletion reduces dendritic spines established a physiological neuronal function for RND1 in spine morphogenesis.","evidence":"Subcellular fractionation of brain, antisense knockdown in hippocampal neurons with morphometric analysis","pmids":["14657163"],"confidence":"Medium","gaps":["Antisense approach rather than genetic knockout limits confidence","Downstream effectors in spine formation not identified"]},{"year":2005,"claim":"Discovery that FRS2β sequesters RND1 and that FGF receptor-mediated phosphorylation releases it to inhibit RhoA revealed how growth factor signaling dynamically regulates a constitutively active GTPase.","evidence":"Co-immunoprecipitation, phosphorylation assays, RhoA activity assays, siRNA knockdown with neurite outgrowth in PC12 cells","pmids":["15738000"],"confidence":"High","gaps":["In vivo validation of FRS2β-RND1 regulation not performed","Whether other RTKs similarly regulate RND1 not tested"]},{"year":2007,"claim":"Structural determination of the plexin-B1 RBD revealed the ubiquitin-like fold and mapped the shared RND1/Rac1 binding surface, providing a structural basis for how GTPases activate plexins by destabilizing RBD dimers.","evidence":"Solution NMR and 2.0 Å X-ray crystallography with in vitro binding assays","pmids":["17916560"],"confidence":"High","gaps":["Full-length plexin structure with bound RND1 not available","How RBD dimer destabilization propagates to the intracellular GAP domain unknown"]},{"year":2011,"claim":"Crystal structures of the Plexin-A2 RBD–RND1 complex and mutagenesis of plexin-C1/-D1 defined the molecular determinants of RND1 selectivity among plexin subfamilies.","evidence":"X-ray crystallography, isothermal titration calorimetry, and gain-of-function mutagenesis","pmids":["21610070"],"confidence":"High","gaps":["Functional consequences of engineering RND1 binding into plexin-C1/-D1 not tested in cells"]},{"year":2012,"claim":"Identification of the N-terminal KERRA motif as a lipid raft targeting signal that is required for p190 RhoGAP co-recruitment and activation resolved how RND1 (but not RND2) inhibits RhoA from specific membrane compartments.","evidence":"Domain swap/mutation analysis, lipid raft fractionation, p190 RhoGAP activation assay","pmids":["22357615"],"confidence":"High","gaps":["Whether lipid raft localization also affects plexin-dependent functions not tested"]},{"year":2014,"claim":"Demonstrating that RND1 suppresses Ras-MAPK signaling via Plexin-B1 GAP → Rap1 inhibition → p120 Ras-GAP derepression, and that RND1 loss drives EMT and metastasis, established RND1 as a tumor suppressor operating through a plexin-Ras signaling axis.","evidence":"siRNA epistasis with Rap1 and p120 Ras-GAP, RhoA/Ras activity assays, mouse xenograft metastasis models","pmids":["25531777"],"confidence":"High","gaps":["Whether RND1 genomic loss is a common event across cancer types beyond those tested","Relative contribution of RhoA inhibition vs. Ras inhibition to tumor suppression unclear"]},{"year":2018,"claim":"Showing that topoisomerase I cleavage complex–PARP-1 signaling rapidly induces RND1 transcription, and that RND1 in turn stabilizes PARP-1 and confers resistance to camptothecin, identified a DNA damage–RND1 regulatory loop.","evidence":"RT-PCR, mRNA stability assays, PARP-1 inhibitor treatment, overexpression/knockdown apoptosis assays","pmids":["30209297"],"confidence":"Medium","gaps":["Mechanism of RND1-mediated PARP-1 stabilization not defined","In vivo relevance for chemoresistance not demonstrated"]},{"year":2019,"claim":"Finding that RND1 is induced by mechanical stretch in cardiomyocytes and interacts with Myozap to activate RhoA-SRF signaling expanded RND1's role to cardiac mechano-transduction, revealing context-dependent activation rather than inhibition of RhoA.","evidence":"Yeast two-hybrid, co-immunoprecipitation, SRF reporter assay, overexpression in neonatal rat ventricular cardiomyocytes","pmids":["30797814"],"confidence":"Medium","gaps":["In vivo cardiac phenotype of RND1 loss not tested","How Myozap switches RND1 from RhoA inhibition to activation not explained"]},{"year":2022,"claim":"Three independent studies expanded RND1's biological roles: as a direct Notch target suppressing endothelial migration and angiogenesis, as a p53 stabilizer inducing ferroptosis in glioblastoma, and as an innate immune modulator inhibiting viral entry while promoting pro-inflammatory cytokine production via Plexin-B1.","evidence":"RNA-seq with Notch activation and RND1 knockdown in endothelial cells; co-IP/ubiquitination assays with p53 in GBM cells; viral infection and cytokine assays with RND1 knockdown/overexpression","pmids":["35102202","35505371","35654795"],"confidence":"Medium","gaps":["Ferroptosis mechanism is from a single lab and awaits independent confirmation","Whether Notch–RND1 axis operates in non-endothelial contexts unknown","Antiviral mechanism through calcium/RhoA inhibition needs in vivo validation"]},{"year":null,"claim":"Key unresolved questions include how RND1's opposing effects on RhoA (inhibition via p190 RhoGAP vs. activation via PDZ-RhoGEF/Myozap) are spatiotemporally partitioned, whether RND1 is regulated by ubiquitin-mediated degradation or other post-translational mechanisms in vivo, and how RND1 protein levels are controlled in tissues where it acts as a tumor suppressor.","evidence":"","pmids":[],"confidence":"Low","gaps":["No conditional knockout mouse model phenotyped","No structural model of full-length plexin with RND1 bound","Regulation of RND1 protein turnover poorly characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,13,14]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,3,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6,13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4,5,7,14,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,6,8]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,6,8]}],"complexes":[],"partners":["PLXNA1","PLXNB1","PLXNA2","FRS2","ARHGAP35","MYOZAP","UNC5B","STIP1"],"other_free_text":[]},"mechanistic_narrative":"RND1 is a constitutively GTP-bound, GTPase-inactive Rho family member that functions as a central modulator of actin cytoskeletal dynamics, RhoA signaling, and Ras-MAPK pathway activity across neuronal, vascular, and epithelial contexts. RND1 lacks intrinsic GTPase activity and disassembles actin stress fibers and focal adhesions, inducing cell rounding and loss of adhesion; it antagonizes RhoA signaling both by co-recruiting and activating p190 RhoGAP from lipid rafts via an N-terminal KERRA motif and by directly inhibiting RhoA-dependent Ca²⁺ sensitization in smooth muscle [PMID:9531558, PMID:22357615, PMID:10200428]. RND1 directly binds the cytoplasmic domains of plexin receptors (Plexin-A1, -A2, -B1), where it is sufficient to trigger cytoskeletal collapse and semaphorin-independent receptor activation; through Plexin-B1 it activates the PDZ-RhoGEF/RhoA/ROCK contraction pathway and a GAP-dependent Rap1 inhibition cascade that suppresses Ras-MAPK signaling and tumor metastasis [PMID:11784792, PMID:12730235, PMID:25531777]. In neurons, RND1 promotes dendritic spine formation and neurite outgrowth downstream of FGF receptor signaling, regulated by sequestration on FRS2β and release upon receptor-mediated FRS2β phosphorylation; in endothelial cells it is a direct Notch transcriptional target required for suppression of migration and sprouting angiogenesis [PMID:15738000, PMID:14657163, PMID:35102202]."},"prefetch_data":{"uniprot":{"accession":"Q92730","full_name":"Rho-related GTP-binding protein Rho6","aliases":["Rho family GTPase 1","Rnd1"],"length_aa":232,"mass_kda":26.1,"function":"Lacks intrinsic GTPase activity. Has a low affinity for GDP, and constitutively binds GTP. Controls rearrangements of the actin cytoskeleton. Induces the Rac-dependent neuritic process formation in part by disruption of the cortical actin filaments. Causes the formation of many neuritic processes from the cell body with disruption of the cortical actin filaments","subcellular_location":"Cell membrane; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q92730/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RND1","classification":"Not Classified","n_dependent_lines":28,"n_total_lines":1208,"dependency_fraction":0.023178807947019868},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RND1","total_profiled":1310},"omim":[{"mim_id":"610344","title":"C2 CALCIUM-DEPENDENT DOMAIN-CONTAINING PROTEIN 4B; C2CD4B","url":"https://www.omim.org/entry/610344"},{"mim_id":"610343","title":"C2 CALCIUM-DEPENDENT DOMAIN-CONTAINING PROTEIN 4A; C2CD4A","url":"https://www.omim.org/entry/610343"},{"mim_id":"609151","title":"UBX DOMAIN PROTEIN 11; UBXN11","url":"https://www.omim.org/entry/609151"},{"mim_id":"609038","title":"RHO FAMILY GTPase 1; RND1","url":"https://www.omim.org/entry/609038"},{"mim_id":"602924","title":"RHO FAMILY GTPase 3; RND3","url":"https://www.omim.org/entry/602924"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"},{"location":"Actin filaments","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":48.8},{"tissue":"liver","ntpm":119.8}],"url":"https://www.proteinatlas.org/search/RND1"},"hgnc":{"alias_symbol":["Rho6","ARHS","RHOS"],"prev_symbol":[]},"alphafold":{"accession":"Q92730","domains":[{"cath_id":"3.40.50.300","chopping":"10-187","consensus_level":"medium","plddt":96.2508,"start":10,"end":187}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92730","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92730-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92730-F1-predicted_aligned_error_v6.png","plddt_mean":85.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RND1","jax_strain_url":"https://www.jax.org/strain/search?query=RND1"},"sequence":{"accession":"Q92730","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92730.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92730/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92730"}},"corpus_meta":[{"pmid":"9531558","id":"PMC_9531558","title":"A new member of the Rho family, Rnd1, promotes disassembly of actin filament structures and loss of cell adhesion.","date":"1998","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9531558","citation_count":297,"is_preprint":false},{"pmid":"11784792","id":"PMC_11784792","title":"Antagonistic effects of Rnd1 and RhoD GTPases regulate receptor activity in Semaphorin 3A-induced cytoskeletal collapse.","date":"2002","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/11784792","citation_count":139,"is_preprint":false},{"pmid":"8592759","id":"PMC_8592759","title":"The Rho's progress: a potential role during neuritogenesis for the Rho family of GTPases.","date":"1995","source":"Trends in neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/8592759","citation_count":122,"is_preprint":false},{"pmid":"17916560","id":"PMC_17916560","title":"Binding of Rac1, Rnd1, and RhoD to a novel Rho GTPase interaction motif destabilizes dimerization of the plexin-B1 effector domain.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17916560","citation_count":113,"is_preprint":false},{"pmid":"12730235","id":"PMC_12730235","title":"Direct interaction of Rnd1 with Plexin-B1 regulates PDZ-RhoGEF-mediated Rho activation by Plexin-B1 and induces cell contraction in COS-7 cells.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12730235","citation_count":106,"is_preprint":false},{"pmid":"25531777","id":"PMC_25531777","title":"The Rho GTPase Rnd1 suppresses mammary tumorigenesis and EMT by restraining Ras-MAPK signalling.","date":"2014","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25531777","citation_count":99,"is_preprint":false},{"pmid":"10740268","id":"PMC_10740268","title":"Plant GTPases: the Rhos in bloom.","date":"2000","source":"Trends in cell 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\"finding\": \"Rnd1 is constitutively GTP-bound due to low affinity for GDP, rapid spontaneous nucleotide exchange, and lack of intrinsic GTPase activity. Expression of Rnd1 in fibroblasts induces disassembly of actin stress fibers, membrane ruffles, and integrin-based focal adhesions, leading to cell rounding and loss of cell-substrate adhesion.\",\n      \"method\": \"Biochemical nucleotide binding assays, GTPase activity assays, overexpression in fibroblasts with morphological readouts, subcellular fractionation/immunolocalization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — foundational paper with multiple orthogonal methods (biochemical assays + cell biology), widely replicated\",\n      \"pmids\": [\"9531558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Recombinant prenylated Rnd1 dose-dependently inhibits carbachol- and GTPgammaS-induced Ca2+ sensitization in smooth muscle by specifically interfering with a RhoA-dependent mechanism, without affecting basal Ca2+-tension relationships or myosin light chain phosphatase inhibition-induced tension.\",\n      \"method\": \"Permeabilized smooth muscle strip contraction assay, recombinant protein application, pharmacological dissection\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro reconstitution with recombinant protein in permeabilized muscle, multiple controls\",\n      \"pmids\": [\"10200428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Rnd1 directly interacts with the adapter protein Grb7 via the switch II loop of Rnd1 and the SH2 domain of Grb7, as demonstrated by yeast two-hybrid, in vitro binding assays, and pull-down from SK-BR3 breast cancer cell lysate.\",\n      \"method\": \"Yeast two-hybrid, in vitro pull-down, co-immunoprecipitation from cell lysate\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — multiple binding assays from a single lab but no functional follow-up on the interaction\",\n      \"pmids\": [\"10664463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Expression of Rnd1 in PC12 cells induces formation of neuritic processes accompanied by disruption of cortical actin filaments; this process formation is inhibited by dominant-negative Rac1, placing Rnd1 upstream of Rac in neuritic process formation.\",\n      \"method\": \"Overexpression in PC12 cells, cytochalasin D treatment, dominant-negative Rac1 epistasis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with dominant-negative Rac1, single lab\",\n      \"pmids\": [\"11095956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Rnd1 (and RhoD) directly binds the cytoplasmic domain of Plexin-A1; active Rnd1 is sufficient to trigger Plexin-A1 signaling and cytoskeletal collapse even without Sema3A ligand, while RhoD antagonizes Rnd1-mediated Plexin-A1 activation and blocks Sema3A-induced axon repulsion.\",\n      \"method\": \"Direct binding assays (large GTPase panel screen), overexpression/co-expression in neuronal cells, growth cone collapse assay, axon repulsion assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays combined with functional collapse and axon guidance assays, widely cited\",\n      \"pmids\": [\"11784792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Rnd1 directly interacts with the cytoplasmic domain of Plexin-B1; co-expression of Rnd1 with Plexin-B1 induces Sema4D-dependent cell contraction via the PDZ-RhoGEF/RhoA/ROCK pathway. Rnd1 promotes the interaction between Plexin-B1 and PDZ-RhoGEF and potentiates Plexin-B1-mediated RhoA activation.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative RhoA, ROCK inhibitor, deletion mutants of Plexin-B1, RhoA activation assay (GST-pulldown of GTP-RhoA), COS-7 cell contraction assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including binding, RhoA activity assay, pharmacological and genetic epistasis\",\n      \"pmids\": [\"12730235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Rnd1 is localized to synaptosomal membrane fractions in brain and promotes dendritic spine elongation when overexpressed; suppression of endogenous Rnd1 by antisense oligonucleotides reduces spine number, spine width, and increases headless protrusions in hippocampal neurons.\",\n      \"method\": \"Subcellular fractionation, Northern blot, in situ hybridization, overexpression and antisense knockdown in cultured hippocampal neurons with morphological readouts\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by fractionation with functional KD phenotype, single lab\",\n      \"pmids\": [\"14657163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Rnd1 directly associates with FRS2alpha and FRS2beta (FGF receptor docking proteins); FRS2beta binding suppresses Rnd1's inhibitory effect on RhoA. FGF receptor 1 activation phosphorylates FRS2beta, recruits Shp2, and releases Rnd1 from FRS2beta, allowing free Rnd1 to inhibit RhoA. Knockdown of Rnd1 by siRNA suppresses FGF-induced neurite outgrowth in PC12 cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro pull-down, phosphorylation assays, RhoA activity assays, siRNA knockdown, neurite outgrowth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (binding, activity assay, KD phenotype) establishing a regulatory mechanism\",\n      \"pmids\": [\"15738000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Rnd1 is required for neuronal activity-dependent dendritic development in hippocampal neurons; RNAi knockdown of Rnd1 inhibits dendritic growth and branching, and this effect is rescued by inhibition of ROCK (RhoA effector), placing Rnd1 as an antagonist of the RhoA-ROCK pathway in dendritic development.\",\n      \"method\": \"RNA interference, overexpression, ROCK inhibitor epistasis, BDNF stimulation, dendritic morphology quantification\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with ROCK inhibitor plus RNAi phenotype, single lab\",\n      \"pmids\": [\"16530331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Rac1, Rnd1, and RhoD all bind the same region (beta-strands 3-4 and a short alpha-helical segment) of the plexin-B1 Rho GTPase binding domain (RBD), which adopts a ubiquitin-like fold. GTPase binding destabilizes the RBD homodimer, suggesting a model for receptor activation by monomerization.\",\n      \"method\": \"Solution NMR spectroscopy, 2.0 Å X-ray crystallography, in vitro binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — joint NMR and X-ray crystallographic study with functional binding characterization\",\n      \"pmids\": [\"17916560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Rnd1 physically interacts with Unc5B (a Netrin receptor) and functionally cooperates with the FLRT3-Unc5B complex to modulate cell deadhesion; Rnd1 mediates FLRT3 deadhesion activity in Xenopus embryos.\",\n      \"method\": \"Expression screen, co-immunoprecipitation, overexpression phenotype in Xenopus embryos, morpholino knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP plus morpholino phenotype in Xenopus, single lab\",\n      \"pmids\": [\"19492039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Thermodynamic characterization reveals that Rnd1 and Rac1 bind the plexin-B1 RBD with similar affinities but with different thermodynamic signatures: Rac1 binding induces rigidification of the complex while Rnd1 binding is consistent with unchanged or increased flexibility, suggesting distinct downstream signaling mechanisms.\",\n      \"method\": \"Isothermal titration calorimetry at multiple temperatures/conditions, thermodynamic analysis\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — rigorous biophysical characterization, single lab\",\n      \"pmids\": [\"19388051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structures of the plexin-A2 RBD in complex with Rnd1 and of plexin-C1 and -D1 RBDs alone reveal that the RBD beta3-beta4 loop in plexin-A2 and -B1 adjusts conformation to allow Rnd1 binding, while plexin-C1 and -D1 lack key non-polar residues at this surface; introduction of these residues by mutagenesis generates Rnd1-binding affinity in plexin-C1/-D1.\",\n      \"method\": \"X-ray crystallography, isothermal titration calorimetry, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis plus ITC, comprehensive structural study\",\n      \"pmids\": [\"21610070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Rnd1 and Rnd3 (but not Rnd2) contain an N-terminal KERRA sequence that targets them to lipid rafts; this lipid raft targeting is required for co-recruitment and activation of p190 RhoGAP in cells, explaining the functional difference among Rnd family members in RhoA inhibition signaling.\",\n      \"method\": \"Domain swap/mutation analysis, lipid raft fractionation, p190 RhoGAP activation assay, co-localization studies\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (fractionation, activity assay, mutagenesis) establishing a novel regulatory mechanism\",\n      \"pmids\": [\"22357615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rnd1 suppresses Ras-MAPK signaling by activating the GAP domain of Plexin-B1, which inhibits Rap1; Rap1 inhibition derepresses p120 Ras-GAP to inhibit Ras. Rnd1 depletion in mammary epithelial cells induces EMT, and Rnd1 expression inhibits tumor metastasis in mouse models.\",\n      \"method\": \"siRNA knockdown, epistasis experiments with Rap1 and p120 Ras-GAP, RhoA/Ras activity assays, mouse xenograft models, genomic analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-step epistasis with activity assays, in vivo validation, and genomic evidence; strong evidence\",\n      \"pmids\": [\"25531777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STI1 (stress-inducible protein 1) directly interacts with Rnd1 specifically (not Rnd2 or Rnd3), and overexpression of STI1 prevents Rnd1-PlexinA1-mediated cytoskeletal collapse in COS cells and enhances neurite outgrowth initiated by Rnd1 in PC12 cells.\",\n      \"method\": \"Co-immunoprecipitation, COS collapse assay, PC12 neurite outgrowth assay, specificity controls with Rnd2/Rnd3\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP with functional cellular assays, single lab\",\n      \"pmids\": [\"24690281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rnd1 is induced by mechanical stretch and hypertrophic stimuli in cardiomyocytes; it interacts with Myozap (an intercalated disc protein identified by yeast two-hybrid and co-IP) and promotes RhoA-mediated SRF signaling, cardiomyocyte hypertrophy, and cell proliferation.\",\n      \"method\": \"Microarray, overexpression in NRVCMs, yeast two-hybrid, co-immunoprecipitation, Ki67/EdU proliferation assays, SRF reporter assay\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — yeast two-hybrid confirmed by co-IP, plus functional phenotypes; single lab\",\n      \"pmids\": [\"30797814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RND1 interacts with p53, promotes p53 de-ubiquitination, and activates the p53-SLC7A11 signaling pathway to induce lipid peroxidation and ferroptosis in glioblastoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, luciferase reporter assays, lipid ROS/peroxidation assays, cell viability assays, GBM xenograft model\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus ubiquitination assay plus functional readouts, single lab\",\n      \"pmids\": [\"35505371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RND1 is a direct transcriptional target of endothelial Notch signaling (rapidly induced within 1.5-6 h of Notch activation); RND1 is required for Notch-mediated suppression of endothelial migration, sprouting angiogenesis, and Ras activity.\",\n      \"method\": \"Transcriptomic analysis (RNA-seq), ligand-specific and EGTA-induced Notch activation, RND1 knockdown with migration and sprouting assays, Ras activity assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct Notch target validation plus KD functional phenotypes in endothelial cells, single lab\",\n      \"pmids\": [\"35102202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Rnd1 inhibits virus internalization by counteracting intracellular calcium fluctuations through inhibition of RhoA activation; Rnd1 also facilitates IL-6 and TNF-α production through Plexin-B1, providing protection against intracellular bacterial infections.\",\n      \"method\": \"Knockdown and overexpression in cell lines, viral infection assays, calcium measurements, cytokine ELISA, Plexin-B1 interaction studies\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional KD/OE phenotypes with mechanistic pathway placement, single lab\",\n      \"pmids\": [\"35654795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MD simulations show that RND1 reinforces the plexin dimerization interface (activating plexin signaling) while RhoD destabilizes it, due to differential interactions with the inner leaflet of the cell membrane; this antithetic effect is mediated by an allosteric network through the RBD, RBD linkers, and a buttress segment.\",\n      \"method\": \"Molecular dynamics simulations (computational), comparison with experimental binding data\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — primarily computational, though consistent with experimental data\",\n      \"pmids\": [\"34114565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RND1 transcription is rapidly induced by camptothecin-stabilized topoisomerase I cleavage complexes (TOP1cc) via PARP-1 activity; RND1 also increases PARP-1 levels (cross-talk), and RND1 overexpression protects cells from camptothecin-induced apoptosis, promoting cellular resistance.\",\n      \"method\": \"RT-PCR, mRNA stability assays, PARP-1 inhibitor treatment, RND1 overexpression/knockdown, apoptosis assays, luciferase reporter\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple methods establishing TOP1cc-PARP-1-RND1 pathway, single lab\",\n      \"pmids\": [\"30209297\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RND1 is a constitutively GTP-bound, GTPase-inactive Rho family protein that localizes to adherens junctions and lipid rafts, where it inhibits RhoA signaling (via p190 RhoGAP activation and antagonism of RhoA-ROCK-mediated Ca2+ sensitization), directly binds and activates plexin receptors (Plexin-A1, -A2, -B1) to regulate actin cytoskeletal collapse and axon guidance through PDZ-RhoGEF/RhoA/ROCK, suppresses Ras-MAPK signaling through a Plexin-B1 GAP→Rap1→p120 Ras-GAP cascade, is regulated by FRS2beta sequestration and FGF receptor-mediated release, interacts with STI1 and Grb7, and promotes dendritic spine formation and neuritic outgrowth; in non-neural contexts it is a direct Notch transcriptional target suppressing endothelial migration, promotes p53 de-ubiquitination to induce ferroptosis, and is induced by mechanical stretch to activate SRF signaling through interaction with Myozap.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RND1 is a constitutively GTP-bound, GTPase-inactive Rho family member that functions as a central modulator of actin cytoskeletal dynamics, RhoA signaling, and Ras-MAPK pathway activity across neuronal, vascular, and epithelial contexts. RND1 lacks intrinsic GTPase activity and disassembles actin stress fibers and focal adhesions, inducing cell rounding and loss of adhesion; it antagonizes RhoA signaling both by co-recruiting and activating p190 RhoGAP from lipid rafts via an N-terminal KERRA motif and by directly inhibiting RhoA-dependent Ca²⁺ sensitization in smooth muscle [PMID:9531558, PMID:22357615, PMID:10200428]. RND1 directly binds the cytoplasmic domains of plexin receptors (Plexin-A1, -A2, -B1), where it is sufficient to trigger cytoskeletal collapse and semaphorin-independent receptor activation; through Plexin-B1 it activates the PDZ-RhoGEF/RhoA/ROCK contraction pathway and a GAP-dependent Rap1 inhibition cascade that suppresses Ras-MAPK signaling and tumor metastasis [PMID:11784792, PMID:12730235, PMID:25531777]. In neurons, RND1 promotes dendritic spine formation and neurite outgrowth downstream of FGF receptor signaling, regulated by sequestration on FRS2β and release upon receptor-mediated FRS2β phosphorylation; in endothelial cells it is a direct Notch transcriptional target required for suppression of migration and sprouting angiogenesis [PMID:15738000, PMID:14657163, PMID:35102202].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing that RND1 is constitutively GTP-bound with no intrinsic GTPase activity resolved how this atypical Rho protein is regulated and showed it acts as a potent inducer of actin stress fiber disassembly and cell rounding.\",\n      \"evidence\": \"Biochemical nucleotide binding/GTPase assays and overexpression in fibroblasts with morphological readouts\",\n      \"pmids\": [\"9531558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-translational regulatory mechanisms (e.g., ubiquitination, transcriptional control) not addressed\", \"No structural basis for constitutive GTP binding\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that recombinant RND1 specifically inhibits RhoA-dependent Ca²⁺ sensitization in smooth muscle established a direct functional antagonism between RND1 and RhoA signaling.\",\n      \"evidence\": \"Permeabilized smooth muscle strip contraction assays with recombinant prenylated RND1\",\n      \"pmids\": [\"10200428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous RND1 expression and function in smooth muscle not verified\", \"Mechanism of RhoA inhibition (direct vs. GAP-mediated) not determined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of RND1 as a direct binding partner and activator of Plexin-A1 revealed that RND1 operates as a co-receptor switch for semaphorin signaling, sufficient to trigger cytoskeletal collapse without ligand.\",\n      \"evidence\": \"Large-scale GTPase binding screen, growth cone collapse and axon repulsion assays in neuronal cells\",\n      \"pmids\": [\"11784792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and regulation of RND1-plexin interaction in vivo unknown\", \"Whether RND1 is required (not just sufficient) for Sema3A signaling not demonstrated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showing that RND1 binds Plexin-B1 and promotes PDZ-RhoGEF recruitment and RhoA activation extended the plexin co-activation model to class B plexins and identified the downstream effector pathway.\",\n      \"evidence\": \"Co-immunoprecipitation, RhoA-GTP pull-down, ROCK inhibitor epistasis, COS-7 cell contraction assay\",\n      \"pmids\": [\"12730235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RND1 simultaneously activates both RhoA-inhibiting (p190 GAP) and RhoA-activating (PDZ-RhoGEF) arms in the same cell was unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Localizing endogenous RND1 to synaptosomal membranes and showing that its depletion reduces dendritic spines established a physiological neuronal function for RND1 in spine morphogenesis.\",\n      \"evidence\": \"Subcellular fractionation of brain, antisense knockdown in hippocampal neurons with morphometric analysis\",\n      \"pmids\": [\"14657163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Antisense approach rather than genetic knockout limits confidence\", \"Downstream effectors in spine formation not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that FRS2β sequesters RND1 and that FGF receptor-mediated phosphorylation releases it to inhibit RhoA revealed how growth factor signaling dynamically regulates a constitutively active GTPase.\",\n      \"evidence\": \"Co-immunoprecipitation, phosphorylation assays, RhoA activity assays, siRNA knockdown with neurite outgrowth in PC12 cells\",\n      \"pmids\": [\"15738000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo validation of FRS2β-RND1 regulation not performed\", \"Whether other RTKs similarly regulate RND1 not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Structural determination of the plexin-B1 RBD revealed the ubiquitin-like fold and mapped the shared RND1/Rac1 binding surface, providing a structural basis for how GTPases activate plexins by destabilizing RBD dimers.\",\n      \"evidence\": \"Solution NMR and 2.0 Å X-ray crystallography with in vitro binding assays\",\n      \"pmids\": [\"17916560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length plexin structure with bound RND1 not available\", \"How RBD dimer destabilization propagates to the intracellular GAP domain unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Crystal structures of the Plexin-A2 RBD–RND1 complex and mutagenesis of plexin-C1/-D1 defined the molecular determinants of RND1 selectivity among plexin subfamilies.\",\n      \"evidence\": \"X-ray crystallography, isothermal titration calorimetry, and gain-of-function mutagenesis\",\n      \"pmids\": [\"21610070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of engineering RND1 binding into plexin-C1/-D1 not tested in cells\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of the N-terminal KERRA motif as a lipid raft targeting signal that is required for p190 RhoGAP co-recruitment and activation resolved how RND1 (but not RND2) inhibits RhoA from specific membrane compartments.\",\n      \"evidence\": \"Domain swap/mutation analysis, lipid raft fractionation, p190 RhoGAP activation assay\",\n      \"pmids\": [\"22357615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether lipid raft localization also affects plexin-dependent functions not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that RND1 suppresses Ras-MAPK signaling via Plexin-B1 GAP → Rap1 inhibition → p120 Ras-GAP derepression, and that RND1 loss drives EMT and metastasis, established RND1 as a tumor suppressor operating through a plexin-Ras signaling axis.\",\n      \"evidence\": \"siRNA epistasis with Rap1 and p120 Ras-GAP, RhoA/Ras activity assays, mouse xenograft metastasis models\",\n      \"pmids\": [\"25531777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RND1 genomic loss is a common event across cancer types beyond those tested\", \"Relative contribution of RhoA inhibition vs. Ras inhibition to tumor suppression unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing that topoisomerase I cleavage complex–PARP-1 signaling rapidly induces RND1 transcription, and that RND1 in turn stabilizes PARP-1 and confers resistance to camptothecin, identified a DNA damage–RND1 regulatory loop.\",\n      \"evidence\": \"RT-PCR, mRNA stability assays, PARP-1 inhibitor treatment, overexpression/knockdown apoptosis assays\",\n      \"pmids\": [\"30209297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of RND1-mediated PARP-1 stabilization not defined\", \"In vivo relevance for chemoresistance not demonstrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Finding that RND1 is induced by mechanical stretch in cardiomyocytes and interacts with Myozap to activate RhoA-SRF signaling expanded RND1's role to cardiac mechano-transduction, revealing context-dependent activation rather than inhibition of RhoA.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, SRF reporter assay, overexpression in neonatal rat ventricular cardiomyocytes\",\n      \"pmids\": [\"30797814\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo cardiac phenotype of RND1 loss not tested\", \"How Myozap switches RND1 from RhoA inhibition to activation not explained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Three independent studies expanded RND1's biological roles: as a direct Notch target suppressing endothelial migration and angiogenesis, as a p53 stabilizer inducing ferroptosis in glioblastoma, and as an innate immune modulator inhibiting viral entry while promoting pro-inflammatory cytokine production via Plexin-B1.\",\n      \"evidence\": \"RNA-seq with Notch activation and RND1 knockdown in endothelial cells; co-IP/ubiquitination assays with p53 in GBM cells; viral infection and cytokine assays with RND1 knockdown/overexpression\",\n      \"pmids\": [\"35102202\", \"35505371\", \"35654795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ferroptosis mechanism is from a single lab and awaits independent confirmation\", \"Whether Notch–RND1 axis operates in non-endothelial contexts unknown\", \"Antiviral mechanism through calcium/RhoA inhibition needs in vivo validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how RND1's opposing effects on RhoA (inhibition via p190 RhoGAP vs. activation via PDZ-RhoGEF/Myozap) are spatiotemporally partitioned, whether RND1 is regulated by ubiquitin-mediated degradation or other post-translational mechanisms in vivo, and how RND1 protein levels are controlled in tissues where it acts as a tumor suppressor.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No conditional knockout mouse model phenotyped\", \"No structural model of full-length plexin with RND1 bound\", \"Regulation of RND1 protein turnover poorly characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 13, 14]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6, 13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4, 5, 7, 14, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 6, 8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 6, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PLXNA1\",\n      \"PLXNB1\",\n      \"PLXNA2\",\n      \"FRS2\",\n      \"ARHGAP35\",\n      \"MYOZAP\",\n      \"UNC5B\",\n      \"STIP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}