{"gene":"RHOQ","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2001,"finding":"Insulin-stimulated GLUT4 translocation requires TC10 activation via a CAP/Cbl/CrkII-C3G signaling cascade at lipid rafts, operating in parallel with PI3K and independent of PI3K activity. Phosphorylated Cbl recruits the CrkII-C3G complex to lipid rafts where C3G activates TC10.","method":"Dominant-negative mutant expression, subcellular fractionation, GTP-loading assays, GLUT4 translocation assays in 3T3-L1 adipocytes","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal pathway epistasis with dominant-negative constructs and biochemical fractionation, independently replicated across multiple labs","pmids":["11309621"],"is_preprint":false},{"year":2001,"finding":"TC10 localizes to caveolin-enriched lipid raft microdomains via processing through the secretory membrane trafficking system, and lipid raft compartmentalization is required for insulin-induced TC10 activation and its inhibitory effect on GLUT4 translocation. TC10 chimeras directed to non-raft domains (via K-Ras targeting) were not activated by insulin and did not inhibit GLUT4 translocation.","method":"TC10/H-Ras and TC10/K-Ras chimeras, dominant-interfering caveolin-3 mutant (Cav3/DGV) expression, sucrose density gradient fractionation, GLUT4 translocation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple chimeric constructs plus dominant-negative caveolin, orthogonal methods in single lab with mechanistically coherent results","pmids":["11502760"],"is_preprint":false},{"year":1998,"finding":"TC10 GTPase stimulates JNK and PAK activities and interacts with a set of effectors overlapping with Cdc42 and Rac (αPAK, βPAK, γPAK, MRCKα/β, MLK2, N-WASP, MSE55) but does not interact with MLK3, WASP, or ACK-1 and interacts only weakly with ACK-1. TC10 has lower intrinsic GTPase activity than Cdc42 and greater responsiveness to p50RhoGAP.","method":"Two-hybrid screen, GST pulldown assays, in vitro GTPase activity assays, JNK and PAK kinase activity assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro enzymatic assays combined with multiple binding assays, comprehensive effector panel tested","pmids":["9799731"],"is_preprint":false},{"year":2003,"finding":"Insulin specifically induces formation of phosphatidylinositol-3-phosphate (PtdIns-3-P) through TC10 activation at lipid rafts, and exogenous PtdIns-3-P is sufficient to induce GLUT4 translocation to the plasma membrane.","method":"Lipid mass spectrometry, PtdIns-3-P detection with FYVE domain probes, dominant-active/negative TC10 mutants, exogenous lipid addition, GLUT4 translocation assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in single lab; TC10-PtdIns-3-P link established by dominant mutants and lipid quantification","pmids":["12912916"],"is_preprint":false},{"year":1999,"finding":"The Borg family of proteins (Borg1, 2, 4, 5) binds TC10 in a GTP-dependent manner via an intact CRIB domain; Borg3 does not bind TC10. No interaction was detected between Borgs and Rac1 or RhoA.","method":"Two-hybrid screen, GST pulldown assays, CRIB domain deletion mutants","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays with domain-mapping mutants, single lab","pmids":["10490598"],"is_preprint":false},{"year":2009,"finding":"TC10 interacts with the exocyst component Exo70 in neurons; IGF-1 activates TC10, which triggers translocation of Exo70 to the plasma membrane at the distal axon and growth cone. TC10 and Exo70 function are required for membrane addition and axon elongation, and for polarized insertion of the IGF-1 receptor to specify the axon.","method":"Co-immunoprecipitation, dominant-negative/constitutively active TC10 mutant expression, siRNA knockdown of TC10 and Exo70, live imaging of membrane expansion in hippocampal neurons and isolated growth cones","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, KD with defined cellular phenotype, multiple orthogonal methods in neuronal model","pmids":["19846717"],"is_preprint":false},{"year":2001,"finding":"PIST (a PDZ/coiled-coil domain protein) specifically interacts with TC10:GTP (but not GDP-bound TC10) via a leucine zipper-containing coiled-coil domain. Mutation of the TC10 effector binding domain disrupts this interaction. PIST does not interact detectably with Cdc42 and forms homodimers.","method":"Two-hybrid screen, GST pulldown assays, point and deletion mutagenesis, co-immunoprecipitation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GTP-dependence tested with nucleotide-bound forms, domain mapping by deletion mutants, single lab","pmids":["11162552"],"is_preprint":false},{"year":2002,"finding":"Constitutively active TC10 (Q75L) induces actin comet tails in Xenopus oocyte extracts and perinuclear actin polymerization in 3T3-L1 adipocytes via an N-WASP-dependent mechanism, while also disrupting cortical actin via the N-terminal extension (amino acids 1–79). TC10 directly binds Golgi COPI coat proteins through a dilysine motif in its C-terminal domain. Disruption of perinuclear actin by TC10 or N-WASP/ΔVCA reduces VSV-G trafficking to the plasma membrane.","method":"In vitro actin polymerization assay (Xenopus oocyte extracts), TC10 deletion mutants, COPI binding assay, VSV-G trafficking assay in adipocytes, fluorescence microscopy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution with Xenopus extracts plus domain-mapping mutants and vesicle trafficking assays","pmids":["12134073"],"is_preprint":false},{"year":2002,"finding":"CIP4/2 (Cdc42-interacting protein 4/2) is a TC10 effector required for insulin-stimulated GLUT4 translocation. CIP4/2 translocates from an intracellular compartment to the plasma membrane upon insulin stimulation; this translocation is prevented by dominant-negative TC10 and promoted by constitutively active TC10. N-terminal deletion mutants of CIP4/2 or reduced TC10-binding mutants inhibit insulin-stimulated Glut4 translocation.","method":"Co-immunoprecipitation, subcellular localization by fluorescence microscopy, constitutively active and dominant-negative TC10 expression, CIP4/2 mutant overexpression, GLUT4 translocation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, TC10 epistasis over CIP4/2 localization, loss-of-function with defined GLUT4 phenotype","pmids":["12242347"],"is_preprint":false},{"year":2004,"finding":"Constitutively active TC10 (Q75L) recruits PKCζ/λ to plasma membrane lipid raft microdomains through an indirect association with the Par6-Par3 complex; this recruitment is insensitive to PI3K inhibition. TC10 also promotes activation-loop phosphorylation of PKCζ. TC10-activated PKCζ/λ contributes to GSK-3β phosphorylation independently of PI3K-PKB.","method":"Subcellular fractionation, co-immunoprecipitation (TC10-Par6-Par3-PKCζ), constitutively active and dominant-negative TC10 mutants, PI3K inhibitor treatment, Clostridium difficile toxin B, cholesterol depletion, PKCζ phosphorylation assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP of multi-protein complex, genetic epistasis with dominant mutants, biochemical kinase phosphorylation measurements","pmids":["14734537"],"is_preprint":false},{"year":2003,"finding":"Lipid raft targeting of the TC10α N-terminal extension (amino acids 1–16 sufficient) is responsible for disruption of adipocyte cortical actin and inhibition of insulin-stimulated GLUT4 translocation. The N-terminal extension fused to H-Ras (raft-targeted) disrupts cortical actin; the same extension fused to K-Ras (non-raft) does not. GAG and GPG sequences within the N-terminal extension are required for these effects.","method":"TC10α/H-Ras and TC10α/K-Ras chimeric constructs with progressive truncations, point mutations of GAG/GPG motifs, cortical actin imaging, GLUT4 translocation assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic chimeric/deletion/point-mutation analysis with functional readouts, single lab with multiple orthogonal constructs","pmids":["12972548"],"is_preprint":false},{"year":2003,"finding":"TC10 localizes to caveolin-positive lipid raft microdomains via the secretory membrane system (C209S mutation excludes TC10 from both). TC10 can also traffic to the plasma membrane independently of the classical secretory pathway (brefeldin A and 19°C block do not prevent plasma membrane localization). C206S mutation does not alter raft localization.","method":"TC10 point mutants (C206S, C209S, double mutant), brefeldin A treatment, 19°C temperature block, sucrose density fractionation, fluorescence microscopy","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple point mutants and pharmacological blockers, single lab","pmids":["12529401"],"is_preprint":false},{"year":2008,"finding":"CDK5 phosphorylates TC10α on threonine 197 (T197) in lipid raft domains, dependent on Fyn-mediated CDK5 activation. T197A mutation excludes TC10α from lipid rafts and prevents its GTP-loading by insulin; T197D (phosphomimetic) is lipid-raft localized and is GTP-loaded by insulin. CDK5-dependent phosphorylation of TC10α disrupts cortical actin and inhibits insulin-stimulated GLUT4 translocation.","method":"CDK5 siRNA knockdown, CDK5 inhibitor olomoucine, phospho-specific immunoprecipitation, T197A and T197D TC10α mutants, sucrose density fractionation, GTP loading assay, GLUT4 translocation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — phosphorylation site identified by mutagenesis, writer (CDK5) identified by siRNA/inhibitor, phosphomimetic and phospho-null constructs tested functionally","pmids":["18948252"],"is_preprint":false},{"year":1999,"finding":"Constitutively active TC10 (Q75L) stimulates filopodia formation, JNK activation, SRF-dependent transcription, NF-κB-dependent transcription, and synergizes with activated Raf to transform NIH3T3 cells. TC10 requires an intact effector domain and C-terminal prenylation for function. Wild-type TC10 is required for full H-Ras transforming potential. TC10 interacts with profilin in two-hybrid and in vitro binding assays.","method":"Constitutively active and dominant-negative TC10 mutant expression, luciferase reporter assays (SRF, NF-κB), JNK kinase assay, focus formation assay, two-hybrid screen, in vitro binding assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays and binding experiments in single lab","pmids":["10445846"],"is_preprint":false},{"year":2009,"finding":"Obscurin, a sarcomere-associated protein, acts as a specific GEF (guanine nucleotide exchange factor) for TC10 but not for Rac or Cdc42. TC10 binds directly to obscurin's RhoGEF motif. TC10 activity is required for myofibril assembly in human primary skeletal myoblasts; inhibition by dominant-negative TC10 or shRNA knockdown blocks myofibril formation.","method":"Direct binding assay (TC10-obscurin), GEF activity assay (nucleotide exchange), GST pulldown, dominant-negative TC10 mutant expression, shRNA knockdown, immunofluorescence of myofibril assembly","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro GEF activity assay plus direct binding plus loss-of-function in primary human cells","pmids":["19258391"],"is_preprint":false},{"year":2013,"finding":"GTP-bound TC10 binds to the pleckstrin homology (PH) domain of collybistin and activates it by relieving its autoinhibition (mediated by the SH3 domain). This TC10-collybistin interaction stimulates gephyrin clustering at inhibitory synapses and increases miniature inhibitory postsynaptic current amplitudes; dominant-negative TC10 reduces these effects. This activation does not require collybistin's GEF activity.","method":"Co-immunoprecipitation, constitutively active and dominant-negative TC10 in neurons, mIPSC recordings, immunofluorescence of gephyrin cluster density","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with PH-domain specificity, electrophysiology, and morphological readouts in neurons; multiple orthogonal methods","pmids":["24297911"],"is_preprint":false},{"year":2013,"finding":"GTP hydrolysis of TC10 (rather than GTP-bound TC10) promotes neurite outgrowth by releasing Exo70 to accelerate vesicle fusion. TC10 activity is higher on vesicles than at the plasma membrane; TC10-positive vesicles fuse to the plasma membrane in NGF-treated cells. TC10 resides on Rab11- and L1-containing vesicles, and these vesicle populations are involved in TC10-mediated exocytosis. Constitutively active TC10 cannot rescue TC10-depletion-induced reduction in neurite outgrowth.","method":"FRET-based TC10 activity biosensor in live neurons/PC12 cells, TC10 knockdown, colocalization analysis (Rab11, L1, Exo70), live imaging of vesicle fusion","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET biosensor spatiotemporal activity mapping combined with KD and vesicle tracking; single lab","pmids":["24223996"],"is_preprint":false},{"year":2014,"finding":"Local (intra-axonal) translation of TC10 mRNA is required for stimulus-induced membrane expansion and axon outgrowth in DRG axons. Axon-specific knockdown of TC10 mRNA inhibits membrane enlargement. PI3K-dependent activation of Rheb-mTOR pathway triggers simultaneous local synthesis of TC10 and Par3.","method":"Axon-specific siRNA knockdown, local translation reporters, mTOR inhibitor (rapamycin), PI3K inhibitor, mTOR pathway activation/inhibition, membrane expansion assay in DRG axons","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — axon-compartment-specific KD with functional readout, pharmacological pathway dissection, single lab but multiple orthogonal methods","pmids":["24667291"],"is_preprint":false},{"year":2007,"finding":"NGF induces an interaction between activated TC10 and Exo70 in PC12 cells (detected by FRET/FLIM). The TC10-Exo70 complex promotes membrane protrusion but locally antagonizes Cdc42-dependent activation of N-WASP, enabling a switch between Cdc42- or TC10-dominated forms of membrane outgrowth. Exo70 is responsible for targeting the TC10-Exo70 complex to sites of membrane protrusion.","method":"FRET/FLIM imaging of TC10-Exo70 interaction, N-WASP FRET activity sensor, siRNA knockdown (Cdc42, Exo70), dominant-negative and constitutively active Cdc42/TC10 constructs","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET/FLIM in live cells combined with siRNA epistasis; single lab","pmids":["17635999"],"is_preprint":false},{"year":2014,"finding":"A-to-I RNA editing of RHOQ transcripts results in an N136S amino acid substitution that increases RhoQ GTPase activity, promotes actin cytoskeletal reorganization, and enhances invasion potential in colorectal cancer cells. KRAS mutation further increases invasion in the presence of RhoQ N136S.","method":"Whole-genome/transcriptome sequencing to identify editing, expression of edited vs. unedited RHOQ in cancer cell lines, GTPase activity assay, actin cytoskeleton imaging, invasion assay","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — editing identified by sequencing, functional rescue by expression of edited protein form, GTPase activity and invasion assays; single lab","pmids":["24663214"],"is_preprint":false},{"year":2020,"finding":"RHOQ is induced by DLL4/Notch signaling and is required for Notch intracellular domain (NICD) nuclear translocation and Notch signaling. Loss of RHOQ causes Notch1 to be targeted for lysosomal/autophagy degradation, sequestering NICD from the nucleus. RHOQ forms a feed-forward loop: DLL4/Notch induces RHOQ, which in turn promotes Notch signaling.","method":"RHOQ siRNA knockdown in endothelial cells, RHOQ overexpression, in vitro sprouting assay, in vivo angiogenesis model, subcellular fractionation/NICD localization, autophagy/lysosome inhibitor experiments","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with defined signaling and cellular phenotypes, subcellular routing experiments; single lab","pmids":["32506201"],"is_preprint":false},{"year":2018,"finding":"Arhgef7 (βPix) acts upstream of TC10 to promote axon formation during cortical development. Loss of Arhgef7 causes axon loss that cannot be rescued by active Cdc42 but can be rescued by expression of active TC10. Arhgef7 interacts with TC10.","method":"In utero electroporation knockdown of Arhgef7 in cortex, rescue by active TC10, co-immunoprecipitation (Arhgef7-TC10), Cdc42 epistasis experiments","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (active TC10 rescues Arhgef7 KD) plus Co-IP; single lab","pmids":["29891904"],"is_preprint":false},{"year":2012,"finding":"Caveolin 1 interacts with TC10 specifically in its GDP-bound (inactive) state and stabilizes GDP binding, maintaining TC10 in an inactive state in unstimulated adipocytes. Knockdown of Caveolin 1 increases basal TC10 activity. TC10 intrinsically has rapid nucleotide exchange (high magnesium decreases exchange rate).","method":"Co-immunoprecipitation, GDP/GTP exchange kinetics in vitro, Caveolin 1 siRNA knockdown, GTP-loading assay in adipocytes","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with GDP/GTP state specificity, in vitro exchange kinetics, KD with activity readout; single lab","pmids":["22900022"],"is_preprint":false},{"year":2002,"finding":"TC10α and TC10β are two isoforms (∼70% identity) both activated by insulin through the CAP/Cbl pathway in 3T3-L1 adipocytes and both localize to lipid rafts. However, TC10α overexpression completely blocks glucose transport and disrupts cortical actin, whereas TC10β only partially inhibits glucose transport and has little effect on cortical actin.","method":"cDNA cloning, co-transfection with dominant-negative CAP, GTP-loading assay, sucrose density fractionation, actin imaging, glucose transport assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional comparison of isoforms with biochemical and cellular assays in single lab","pmids":["11821390"],"is_preprint":false},{"year":2002,"finding":"TC10 activation is required for osmotic shock-stimulated GLUT4 translocation and glucose transport through a Crk-II pathway, dependent on cortical actin remodeling at caveolin-enriched membrane domains, independently of PI3K and PLCγ.","method":"Dominant-interfering TC10/T31N expression, Clostridium difficile toxin B, latrunculin B, jasplakinolide, PI3K and PLCγ inhibitors, GLUT4 translocation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative epistasis plus pharmacological dissection; single lab","pmids":["12215429"],"is_preprint":false},{"year":2021,"finding":"TC10 regulates surface exposure of membrane type-1 matrix metalloproteinase (MT1-MMP) at invadopodia in breast cancer cells, controlling extracellular matrix degradation. TC10 activity at invadopodia is regulated by p190RhoGAP and involves downstream interaction with Exo70. Loss of TC10 reduces MT1-MMP plasma membrane exposure and ECM degradation.","method":"FRET TC10 biosensor at invadopodia, TC10 KD, p190RhoGAP overexpression/KD, Exo70 interaction, MT1-MMP surface exposure assay, ECM degradation assay","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET biosensor for spatiotemporal activity, KD with functional readout, pathway epistasis; single lab","pmids":["34531530"],"is_preprint":false},{"year":2025,"finding":"TC10 on recycling endosomes (Rab11-positive) promotes axon outgrowth by balancing microtubule stability and dynamics through a PAK2-JNK pathway. TC10 loss reduces PAK2 autophosphorylation and PAK2 localization to Rab11-positive endosomes, decreases JNK phosphorylation, and reduces phosphorylation of the microtubule-binding proteins SCG10 and MAP1B. MKK4/MKK7 mediate signaling from TC10-activated PAK to JNK on JIP1-positive endosomes.","method":"TC10 knockout neurons, phospho-proteomics, PAK2 autophosphorylation assay, subcellular fractionation of endosomal compartments, PAK inhibitor treatment, axon retraction assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TC10-KO with phosphoproteomic substrate identification and endosomal localization; single lab","pmids":["40008675"],"is_preprint":false},{"year":2017,"finding":"TC10 inactivation at the plasma membrane is mediated by a cAMP-PKA-STEF-Rac1-p190B RhoGAP pathway. cAMP treatment decreases TC10 activity locally at extending neurite tips; this inactivation requires PKA and p190B (but not p190A). TC10 depletion reduces cAMP-induced neurite outgrowth. Constitutively active TC10 cannot rescue this reduction, consistent with GTP hydrolysis being required for vesicle fusion.","method":"FRET TC10 biosensor, PKA inhibitor, p190A/B siRNA knockdown, STEF depletion, Rac1-N17 expression, neurite outgrowth assay","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET biosensor spatiotemporal mapping with siRNA epistasis; single lab","pmids":["29072354"],"is_preprint":false},{"year":2022,"finding":"TC10 (RhoQ) binds to the closed/autoinhibited form of collybistin and relieves its autoinhibition (unlike Cdc42, which only interacts with collybistin when it is forced into an open conformation by destabilizing mutations). GTP-TC10 binding to collybistin drives collybistin conformational switch from closed to open state, as measured by FRET.","method":"Time-resolved fluorescence FRET sensors of collybistin conformation, TC10 and Cdc42 binding assays with wild-type and mutant collybistin","journal":"Frontiers in synaptic neuroscience","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — FRET conformational sensor with comparative GTPase binding; single lab, mechanistically precise","pmids":["35989712"],"is_preprint":false},{"year":2024,"finding":"TC10 stimulates Exo70 mobility in HeLa cells but decreases Exo70 diffusion in the growth cone of cortical neurons; TC10 overexpression does not affect Exo70 mobility in hippocampal neuron growth cones. This indicates cell-type- and compartment-specific regulation of exocyst tethering by TC10.","method":"Super-resolution microscopy (single-particle localization and tracking), mean square displacement analysis, TC10 overexpression in HeLa and cortical/hippocampal neurons","journal":"Biophysical reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-particle tracking with OE only, single lab, no loss-of-function or interaction assay","pmids":["39521348"],"is_preprint":false},{"year":2020,"finding":"Reelin activates TC10 in DRG neurons, and this activation is mediated upstream by Cdc42 (Cdc42 controls TC10 activity). TC10 is required for axon development in DRG neurons. Reelin stimulates fusion of VAMP7-containing membrane carriers that also contain TC10 at the growth cone.","method":"TC10 activity assay (GTP-pulldown) after Reelin treatment, Cdc42 dominant-negative epistasis over TC10 activation, TC10 siRNA, VAMP7 vesicle fusion imaging","journal":"Journal of neuroscience research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/pulldown activity assay and colocalization, limited mechanistic depth; single lab","pmids":["32652719"],"is_preprint":false}],"current_model":"RHOQ (TC10) is a Rho-family GTPase that localizes to caveolin-enriched lipid raft microdomains via its unique N-terminal extension and C-terminal palmitoylation, where it is held in an inactive GDP-bound state by Caveolin 1; upon insulin stimulation, the CAP/Cbl/CrkII-C3G pathway activates TC10 in a PI3K-independent manner, leading to downstream effects including PtdIns-3-P production, CIP4/2-mediated GLUT4 translocation, cortical actin reorganization via its N-terminal domain, and Par6/Par3/PKCζ signaling; CDK5 phosphorylates TC10 at T197 to maintain its raft localization; in neurons, locally translated TC10 on Rab11-positive recycling endosomes drives membrane expansion at growth cones by recruiting Exo70 of the exocyst complex, with GTP hydrolysis required for vesicle fusion, and TC10 also promotes axon outgrowth via a PAK2-JNK-SCG10/MAP1B microtubule regulatory pathway on endosomes; TC10 activates collybistin by relieving its autoinhibition, enhancing gephyrin clustering at inhibitory synapses; obscurin acts as a muscle-specific GEF for TC10 to control myofibril assembly; and TC10 regulates MT1-MMP surface exposure at invadopodia in cancer cells via p190RhoGAP and Exo70."},"narrative":{"mechanistic_narrative":"RHOQ (TC10) is a Rho-family GTPase that couples membrane trafficking to actin and microtubule remodeling at specialized membrane microdomains, governing insulin-stimulated glucose uptake, polarized membrane expansion in neurons, myofibril assembly, and cancer cell invasion [PMID:11309621, PMID:19846717, PMID:19258391]. It localizes to caveolin-enriched lipid rafts through processing in the secretory membrane system and C-terminal cysteine modification, where Caveolin 1 binds its GDP-bound form to hold it inactive until stimulation [PMID:11502760, PMID:12529401, PMID:22900022]. In adipocytes, insulin activates TC10 in parallel with—and independent of—PI3K via a CAP/Cbl/CrkII-C3G cascade at rafts, driving PtdIns-3-P production, CIP4/2 recruitment, and Par6/Par3/PKCζ assembly to promote GLUT4 translocation, with its N-terminal extension required for cortical actin remodeling and CDK5 phosphorylation of Thr197 maintaining raft residence [PMID:11309621, PMID:12912916, PMID:12242347, PMID:14734537, PMID:12972548, PMID:18948252]. As an active GTPase TC10 engages effectors shared with Cdc42 and Rac, including PAK and JNK kinases and N-WASP, and binds the exocyst component Exo70 to tether secretory vesicles [PMID:9799731, PMID:12134073, PMID:19846717]. In neurons, locally translated TC10 on Rab11-positive recycling endosomes drives stimulus-evoked membrane expansion and axon outgrowth: GTP hydrolysis releases Exo70 to accelerate vesicle fusion, while a PAK2-JNK pathway phosphorylates the microtubule regulators SCG10 and MAP1B [PMID:24223996, PMID:24667291, PMID:40008675]. TC10 also activates the GEF collybistin by relieving its SH3-domain autoinhibition to promote gephyrin clustering at inhibitory synapses, is loaded by the muscle GEF obscurin during myofibril assembly, and at invadopodia controls MT1-MMP surface exposure and matrix degradation via p190RhoGAP and Exo70 [PMID:24297911, PMID:35989712, PMID:19258391, PMID:34531530].","teleology":[{"year":1998,"claim":"Establishing TC10 as a functional GTPase required defining its enzymatic properties and effector repertoire relative to Cdc42 and Rac.","evidence":"Two-hybrid screen, GST pulldowns, in vitro GTPase and kinase assays mapping an effector panel","pmids":["9799731"],"confidence":"High","gaps":["Cellular context of effector engagement not defined","Did not establish physiological upstream activators"]},{"year":1999,"claim":"Cellular consequences of TC10 activation were mapped to filopodia, JNK/transcriptional signaling, and oncogenic transformation, plus a GTP-dependent Borg/CRIB effector class, framing TC10 as a Cdc42-like signaling node.","evidence":"Constitutively active/dominant-negative mutants, luciferase reporters, focus formation assay, two-hybrid screen with CRIB-domain mapping","pmids":["10445846","10490598"],"confidence":"Medium","gaps":["Transformation assayed in overexpression context","Physiological relevance of Borg binding untested"]},{"year":2001,"claim":"TC10 was placed in the insulin-signaling network as a PI3K-independent driver of GLUT4 translocation activated by the CAP/Cbl/CrkII-C3G cascade specifically at lipid rafts.","evidence":"Dominant-negative epistasis, raft/non-raft chimeras, dominant-negative caveolin, subcellular fractionation and GLUT4 translocation in adipocytes","pmids":["11309621","11502760"],"confidence":"High","gaps":["Direct GEF for insulin-stimulated activation not identified here","Effectors downstream of activated TC10 not yet defined"]},{"year":2002,"claim":"Downstream effectors and isoform/stimulus specificity of TC10 in glucose transport were defined, linking TC10 to CIP4/2 recruitment, N-WASP-dependent actin, COPI/secretory trafficking, and osmotic-shock GLUT4 mobilization.","evidence":"Co-IP, TC10 epistasis over CIP4/2 localization, in vitro actin polymerization in Xenopus extracts, COPI binding, isoform comparison and pharmacological dissection","pmids":["12242347","12134073","11821390","12215429"],"confidence":"High","gaps":["Quantitative contribution of each effector to GLUT4 vesicle docking unresolved","Direct versus indirect actin effects not fully separated"]},{"year":2003,"claim":"The lipid-raft determinants and a lipid second messenger were defined, showing the N-terminal extension targets rafts and drives cortical actin disruption while raft-localized TC10 generates GLUT4-mobilizing PtdIns-3-P.","evidence":"Chimeric/truncation/point mutants of the N-terminal extension, C206S/C209S cysteine mutants, BFA/temperature blocks, lipid mass spectrometry and FYVE probes","pmids":["12972548","11502760","12529401","12912916"],"confidence":"High","gaps":["Enzyme producing PtdIns-3-P downstream of TC10 not identified","Mechanism linking N-terminal raft targeting to actin disruption undefined"]},{"year":2004,"claim":"TC10 was shown to assemble a PI3K-independent polarity-kinase module, recruiting Par6/Par3 and activating PKCζ/λ to feed into GSK-3β regulation.","evidence":"Multi-protein Co-IP, dominant mutants, PI3K inhibitor and cholesterol depletion, PKCζ phosphorylation assays","pmids":["14734537"],"confidence":"High","gaps":["Direct versus indirect PKCζ activation mechanism unresolved","Physiological output of GSK-3β phosphorylation not quantified"]},{"year":2008,"claim":"A regulatory phosphorylation was identified showing CDK5 modifies TC10 at Thr197 to sustain raft localization and insulin-responsive GTP loading.","evidence":"CDK5 siRNA/inhibitor, phospho-specific IP, T197A/T197D mutants, fractionation, GTP-loading and GLUT4 assays","pmids":["18948252"],"confidence":"High","gaps":["Phosphatase reversing T197 not identified","Mechanism by which T197 phosphorylation maintains raft residence unclear"]},{"year":2009,"claim":"TC10's role in polarized exocytosis and tissue morphogenesis was established through its Exo70 partnership in axon growth and its dedicated muscle GEF obscurin in myofibril assembly.","evidence":"Reciprocal Co-IP, siRNA/shRNA, dominant mutants, live membrane imaging in neurons; in vitro GEF and binding assays plus loss-of-function in primary myoblasts","pmids":["19846717","19258391"],"confidence":"High","gaps":["GEFs for TC10 in non-muscle insulin signaling still unidentified","Structural basis of obscurin-TC10 specificity undefined"]},{"year":2012,"claim":"The inactive-state control of TC10 was clarified by showing Caveolin 1 binds GDP-TC10 and stabilizes it, restraining basal activity against TC10's intrinsically rapid nucleotide exchange.","evidence":"GDP/GTP-state-specific Co-IP, in vitro exchange kinetics, Caveolin 1 knockdown with activity readout","pmids":["22900022"],"confidence":"Medium","gaps":["Single-lab Co-IP without structural confirmation","How insulin displaces caveolin to permit activation unresolved"]},{"year":2013,"claim":"TC10 was defined as an upstream activator of collybistin at inhibitory synapses and shown to switch GTP-hydrolysis-dependent control of Exo70 release during neurite outgrowth.","evidence":"Co-IP with PH-domain specificity, mIPSC recordings, gephyrin cluster imaging; FRET activity biosensor with vesicle tracking and rescue tests","pmids":["24297911","24223996"],"confidence":"Medium","gaps":["GEF activating TC10 at the synapse not identified","Coupling of vesicular GTP hydrolysis to fusion machinery not structurally defined"]},{"year":2014,"claim":"TC10's spatial regulation was extended to mRNA localization (local axonal translation driving membrane expansion) and to disease via RNA editing producing a hyperactive N136S variant that enhances cancer cell invasion.","evidence":"Axon-specific knockdown, local translation reporters, mTOR/PI3K inhibitors; transcriptome sequencing, edited-protein expression, GTPase and invasion assays","pmids":["24667291","24663214"],"confidence":"High","gaps":["Trans-acting factors localizing TC10 mRNA undefined","In vivo tumor relevance of N136S editing not established"]},{"year":2017,"claim":"Spatial inactivation of TC10 at the plasma membrane was mapped to a cAMP-PKA-STEF-Rac1-p190B RhoGAP circuit required for cAMP-induced neurite outgrowth.","evidence":"FRET TC10 biosensor, PKA inhibitor, p190A/B and STEF siRNA, Rac1-N17 expression, neurite outgrowth assay","pmids":["29072354"],"confidence":"Medium","gaps":["Direct GAP-substrate engagement not biochemically reconstituted","Single-lab FRET-based epistasis"]},{"year":2018,"claim":"An upstream GEF and Cdc42-independent axon pathway were defined, with Arhgef7 (βPix) acting through TC10 to drive cortical axon formation.","evidence":"In utero electroporation knockdown, rescue by active TC10, Co-IP, Cdc42 epistasis","pmids":["29891904"],"confidence":"Medium","gaps":["Direct GEF activity of Arhgef7 toward TC10 not enzymatically demonstrated","Single Co-IP for the interaction"]},{"year":2020,"claim":"TC10's roles broadened to receptor trafficking control, stabilizing Notch1 against lysosomal degradation in a DLL4/Notch feed-forward loop during angiogenesis.","evidence":"siRNA/overexpression in endothelial cells, sprouting and in vivo angiogenesis assays, NICD fractionation, autophagy/lysosome inhibitor experiments","pmids":["32506201"],"confidence":"Medium","gaps":["Mechanism by which TC10 diverts Notch1 from degradation unknown","Direct TC10-Notch interaction not shown"]},{"year":2021,"claim":"TC10 was shown to control cancer invadopodia function by regulating MT1-MMP surface exposure and ECM degradation through p190RhoGAP and Exo70.","evidence":"FRET TC10 biosensor at invadopodia, knockdown, p190RhoGAP modulation, MT1-MMP surface and ECM degradation assays","pmids":["34531530"],"confidence":"Medium","gaps":["GEF activating TC10 at invadopodia unidentified","Single-lab biosensor study"]},{"year":2025,"claim":"The microtubule arm of TC10's outgrowth function was defined, linking endosomal TC10 to a PAK2-JNK pathway phosphorylating SCG10 and MAP1B.","evidence":"TC10-knockout neurons, phosphoproteomics, PAK2 autophosphorylation, endosomal fractionation, PAK inhibitor, axon retraction assay","pmids":["40008675"],"confidence":"Medium","gaps":["Direct PAK2 activation by TC10 versus scaffold role unresolved","Integration with the Exo70/exocytosis arm on the same endosomes undefined"]},{"year":null,"claim":"How TC10 nucleotide cycling is coordinated across distinct compartments (rafts, recycling endosomes, invadopodia) and which GEFs and GAPs act in each context remain incompletely defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking compartment-specific GEF/GAP control to effector choice","Structural basis of TC10 effector and regulator selectivity unresolved","In vivo physiological and disease roles of most pathways untested in animal models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[2,16,19,22]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5,8,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5,11]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[16,26]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[16,30]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,9,20]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[5,8,16]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated 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In active state binds to a variety of effector proteins to regulate cellular responses. Involved in epithelial cell polarization processes. May play a role in CFTR trafficking to the plasma membrane. Causes the formation of thin, actin-rich surface projections called filopodia","subcellular_location":"Cytoplasm; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P17081/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RHOQ","classification":"Common Essential","n_dependent_lines":1097,"n_total_lines":1208,"dependency_fraction":0.9081125827814569},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PACSIN2","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/RHOQ","total_profiled":1310},"omim":[{"mim_id":"613991","title":"CDC42-BINDING PROTEIN KINASE, GAMMA; CDC42BPG","url":"https://www.omim.org/entry/613991"},{"mim_id":"611432","title":"DEDICATOR OF CYTOKINESIS 8; DOCK8","url":"https://www.omim.org/entry/611432"},{"mim_id":"605857","title":"RAS HOMOLOG GENE FAMILY, MEMBER Q; RHOQ","url":"https://www.omim.org/entry/605857"},{"mim_id":"300681","title":"DEDICATOR OF CYTOKINESIS 11; DOCK11","url":"https://www.omim.org/entry/300681"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"tongue","ntpm":169.4}],"url":"https://www.proteinatlas.org/search/RHOQ"},"hgnc":{"alias_symbol":["TC10"],"prev_symbol":["RASL7A","ARHQ"]},"alphafold":{"accession":"P17081","domains":[{"cath_id":"3.40.50.300","chopping":"7-182","consensus_level":"medium","plddt":96.3198,"start":7,"end":182}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P17081","model_url":"https://alphafold.ebi.ac.uk/files/AF-P17081-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P17081-F1-predicted_aligned_error_v6.png","plddt_mean":89.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RHOQ","jax_strain_url":"https://www.jax.org/strain/search?query=RHOQ"},"sequence":{"accession":"P17081","fasta_url":"https://rest.uniprot.org/uniprotkb/P17081.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P17081/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P17081"}},"corpus_meta":[{"pmid":"11309621","id":"PMC_11309621","title":"Insulin-stimulated 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Phosphorylated Cbl recruits the CrkII-C3G complex to lipid rafts where C3G activates TC10.\",\n      \"method\": \"Dominant-negative mutant expression, subcellular fractionation, GTP-loading assays, GLUT4 translocation assays in 3T3-L1 adipocytes\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal pathway epistasis with dominant-negative constructs and biochemical fractionation, independently replicated across multiple labs\",\n      \"pmids\": [\"11309621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TC10 localizes to caveolin-enriched lipid raft microdomains via processing through the secretory membrane trafficking system, and lipid raft compartmentalization is required for insulin-induced TC10 activation and its inhibitory effect on GLUT4 translocation. TC10 chimeras directed to non-raft domains (via K-Ras targeting) were not activated by insulin and did not inhibit GLUT4 translocation.\",\n      \"method\": \"TC10/H-Ras and TC10/K-Ras chimeras, dominant-interfering caveolin-3 mutant (Cav3/DGV) expression, sucrose density gradient fractionation, GLUT4 translocation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple chimeric constructs plus dominant-negative caveolin, orthogonal methods in single lab with mechanistically coherent results\",\n      \"pmids\": [\"11502760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"TC10 GTPase stimulates JNK and PAK activities and interacts with a set of effectors overlapping with Cdc42 and Rac (αPAK, βPAK, γPAK, MRCKα/β, MLK2, N-WASP, MSE55) but does not interact with MLK3, WASP, or ACK-1 and interacts only weakly with ACK-1. TC10 has lower intrinsic GTPase activity than Cdc42 and greater responsiveness to p50RhoGAP.\",\n      \"method\": \"Two-hybrid screen, GST pulldown assays, in vitro GTPase activity assays, JNK and PAK kinase activity assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro enzymatic assays combined with multiple binding assays, comprehensive effector panel tested\",\n      \"pmids\": [\"9799731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Insulin specifically induces formation of phosphatidylinositol-3-phosphate (PtdIns-3-P) through TC10 activation at lipid rafts, and exogenous PtdIns-3-P is sufficient to induce GLUT4 translocation to the plasma membrane.\",\n      \"method\": \"Lipid mass spectrometry, PtdIns-3-P detection with FYVE domain probes, dominant-active/negative TC10 mutants, exogenous lipid addition, GLUT4 translocation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in single lab; TC10-PtdIns-3-P link established by dominant mutants and lipid quantification\",\n      \"pmids\": [\"12912916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The Borg family of proteins (Borg1, 2, 4, 5) binds TC10 in a GTP-dependent manner via an intact CRIB domain; Borg3 does not bind TC10. No interaction was detected between Borgs and Rac1 or RhoA.\",\n      \"method\": \"Two-hybrid screen, GST pulldown assays, CRIB domain deletion mutants\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays with domain-mapping mutants, single lab\",\n      \"pmids\": [\"10490598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TC10 interacts with the exocyst component Exo70 in neurons; IGF-1 activates TC10, which triggers translocation of Exo70 to the plasma membrane at the distal axon and growth cone. TC10 and Exo70 function are required for membrane addition and axon elongation, and for polarized insertion of the IGF-1 receptor to specify the axon.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative/constitutively active TC10 mutant expression, siRNA knockdown of TC10 and Exo70, live imaging of membrane expansion in hippocampal neurons and isolated growth cones\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, KD with defined cellular phenotype, multiple orthogonal methods in neuronal model\",\n      \"pmids\": [\"19846717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PIST (a PDZ/coiled-coil domain protein) specifically interacts with TC10:GTP (but not GDP-bound TC10) via a leucine zipper-containing coiled-coil domain. Mutation of the TC10 effector binding domain disrupts this interaction. PIST does not interact detectably with Cdc42 and forms homodimers.\",\n      \"method\": \"Two-hybrid screen, GST pulldown assays, point and deletion mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GTP-dependence tested with nucleotide-bound forms, domain mapping by deletion mutants, single lab\",\n      \"pmids\": [\"11162552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Constitutively active TC10 (Q75L) induces actin comet tails in Xenopus oocyte extracts and perinuclear actin polymerization in 3T3-L1 adipocytes via an N-WASP-dependent mechanism, while also disrupting cortical actin via the N-terminal extension (amino acids 1–79). TC10 directly binds Golgi COPI coat proteins through a dilysine motif in its C-terminal domain. Disruption of perinuclear actin by TC10 or N-WASP/ΔVCA reduces VSV-G trafficking to the plasma membrane.\",\n      \"method\": \"In vitro actin polymerization assay (Xenopus oocyte extracts), TC10 deletion mutants, COPI binding assay, VSV-G trafficking assay in adipocytes, fluorescence microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution with Xenopus extracts plus domain-mapping mutants and vesicle trafficking assays\",\n      \"pmids\": [\"12134073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CIP4/2 (Cdc42-interacting protein 4/2) is a TC10 effector required for insulin-stimulated GLUT4 translocation. CIP4/2 translocates from an intracellular compartment to the plasma membrane upon insulin stimulation; this translocation is prevented by dominant-negative TC10 and promoted by constitutively active TC10. N-terminal deletion mutants of CIP4/2 or reduced TC10-binding mutants inhibit insulin-stimulated Glut4 translocation.\",\n      \"method\": \"Co-immunoprecipitation, subcellular localization by fluorescence microscopy, constitutively active and dominant-negative TC10 expression, CIP4/2 mutant overexpression, GLUT4 translocation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, TC10 epistasis over CIP4/2 localization, loss-of-function with defined GLUT4 phenotype\",\n      \"pmids\": [\"12242347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Constitutively active TC10 (Q75L) recruits PKCζ/λ to plasma membrane lipid raft microdomains through an indirect association with the Par6-Par3 complex; this recruitment is insensitive to PI3K inhibition. TC10 also promotes activation-loop phosphorylation of PKCζ. TC10-activated PKCζ/λ contributes to GSK-3β phosphorylation independently of PI3K-PKB.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation (TC10-Par6-Par3-PKCζ), constitutively active and dominant-negative TC10 mutants, PI3K inhibitor treatment, Clostridium difficile toxin B, cholesterol depletion, PKCζ phosphorylation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of multi-protein complex, genetic epistasis with dominant mutants, biochemical kinase phosphorylation measurements\",\n      \"pmids\": [\"14734537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Lipid raft targeting of the TC10α N-terminal extension (amino acids 1–16 sufficient) is responsible for disruption of adipocyte cortical actin and inhibition of insulin-stimulated GLUT4 translocation. The N-terminal extension fused to H-Ras (raft-targeted) disrupts cortical actin; the same extension fused to K-Ras (non-raft) does not. GAG and GPG sequences within the N-terminal extension are required for these effects.\",\n      \"method\": \"TC10α/H-Ras and TC10α/K-Ras chimeric constructs with progressive truncations, point mutations of GAG/GPG motifs, cortical actin imaging, GLUT4 translocation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic chimeric/deletion/point-mutation analysis with functional readouts, single lab with multiple orthogonal constructs\",\n      \"pmids\": [\"12972548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TC10 localizes to caveolin-positive lipid raft microdomains via the secretory membrane system (C209S mutation excludes TC10 from both). TC10 can also traffic to the plasma membrane independently of the classical secretory pathway (brefeldin A and 19°C block do not prevent plasma membrane localization). C206S mutation does not alter raft localization.\",\n      \"method\": \"TC10 point mutants (C206S, C209S, double mutant), brefeldin A treatment, 19°C temperature block, sucrose density fractionation, fluorescence microscopy\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple point mutants and pharmacological blockers, single lab\",\n      \"pmids\": [\"12529401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CDK5 phosphorylates TC10α on threonine 197 (T197) in lipid raft domains, dependent on Fyn-mediated CDK5 activation. T197A mutation excludes TC10α from lipid rafts and prevents its GTP-loading by insulin; T197D (phosphomimetic) is lipid-raft localized and is GTP-loaded by insulin. CDK5-dependent phosphorylation of TC10α disrupts cortical actin and inhibits insulin-stimulated GLUT4 translocation.\",\n      \"method\": \"CDK5 siRNA knockdown, CDK5 inhibitor olomoucine, phospho-specific immunoprecipitation, T197A and T197D TC10α mutants, sucrose density fractionation, GTP loading assay, GLUT4 translocation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — phosphorylation site identified by mutagenesis, writer (CDK5) identified by siRNA/inhibitor, phosphomimetic and phospho-null constructs tested functionally\",\n      \"pmids\": [\"18948252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Constitutively active TC10 (Q75L) stimulates filopodia formation, JNK activation, SRF-dependent transcription, NF-κB-dependent transcription, and synergizes with activated Raf to transform NIH3T3 cells. TC10 requires an intact effector domain and C-terminal prenylation for function. Wild-type TC10 is required for full H-Ras transforming potential. TC10 interacts with profilin in two-hybrid and in vitro binding assays.\",\n      \"method\": \"Constitutively active and dominant-negative TC10 mutant expression, luciferase reporter assays (SRF, NF-κB), JNK kinase assay, focus formation assay, two-hybrid screen, in vitro binding assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays and binding experiments in single lab\",\n      \"pmids\": [\"10445846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Obscurin, a sarcomere-associated protein, acts as a specific GEF (guanine nucleotide exchange factor) for TC10 but not for Rac or Cdc42. TC10 binds directly to obscurin's RhoGEF motif. TC10 activity is required for myofibril assembly in human primary skeletal myoblasts; inhibition by dominant-negative TC10 or shRNA knockdown blocks myofibril formation.\",\n      \"method\": \"Direct binding assay (TC10-obscurin), GEF activity assay (nucleotide exchange), GST pulldown, dominant-negative TC10 mutant expression, shRNA knockdown, immunofluorescence of myofibril assembly\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro GEF activity assay plus direct binding plus loss-of-function in primary human cells\",\n      \"pmids\": [\"19258391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GTP-bound TC10 binds to the pleckstrin homology (PH) domain of collybistin and activates it by relieving its autoinhibition (mediated by the SH3 domain). This TC10-collybistin interaction stimulates gephyrin clustering at inhibitory synapses and increases miniature inhibitory postsynaptic current amplitudes; dominant-negative TC10 reduces these effects. This activation does not require collybistin's GEF activity.\",\n      \"method\": \"Co-immunoprecipitation, constitutively active and dominant-negative TC10 in neurons, mIPSC recordings, immunofluorescence of gephyrin cluster density\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with PH-domain specificity, electrophysiology, and morphological readouts in neurons; multiple orthogonal methods\",\n      \"pmids\": [\"24297911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"GTP hydrolysis of TC10 (rather than GTP-bound TC10) promotes neurite outgrowth by releasing Exo70 to accelerate vesicle fusion. TC10 activity is higher on vesicles than at the plasma membrane; TC10-positive vesicles fuse to the plasma membrane in NGF-treated cells. TC10 resides on Rab11- and L1-containing vesicles, and these vesicle populations are involved in TC10-mediated exocytosis. Constitutively active TC10 cannot rescue TC10-depletion-induced reduction in neurite outgrowth.\",\n      \"method\": \"FRET-based TC10 activity biosensor in live neurons/PC12 cells, TC10 knockdown, colocalization analysis (Rab11, L1, Exo70), live imaging of vesicle fusion\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET biosensor spatiotemporal activity mapping combined with KD and vesicle tracking; single lab\",\n      \"pmids\": [\"24223996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Local (intra-axonal) translation of TC10 mRNA is required for stimulus-induced membrane expansion and axon outgrowth in DRG axons. Axon-specific knockdown of TC10 mRNA inhibits membrane enlargement. PI3K-dependent activation of Rheb-mTOR pathway triggers simultaneous local synthesis of TC10 and Par3.\",\n      \"method\": \"Axon-specific siRNA knockdown, local translation reporters, mTOR inhibitor (rapamycin), PI3K inhibitor, mTOR pathway activation/inhibition, membrane expansion assay in DRG axons\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — axon-compartment-specific KD with functional readout, pharmacological pathway dissection, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24667291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NGF induces an interaction between activated TC10 and Exo70 in PC12 cells (detected by FRET/FLIM). The TC10-Exo70 complex promotes membrane protrusion but locally antagonizes Cdc42-dependent activation of N-WASP, enabling a switch between Cdc42- or TC10-dominated forms of membrane outgrowth. Exo70 is responsible for targeting the TC10-Exo70 complex to sites of membrane protrusion.\",\n      \"method\": \"FRET/FLIM imaging of TC10-Exo70 interaction, N-WASP FRET activity sensor, siRNA knockdown (Cdc42, Exo70), dominant-negative and constitutively active Cdc42/TC10 constructs\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET/FLIM in live cells combined with siRNA epistasis; single lab\",\n      \"pmids\": [\"17635999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A-to-I RNA editing of RHOQ transcripts results in an N136S amino acid substitution that increases RhoQ GTPase activity, promotes actin cytoskeletal reorganization, and enhances invasion potential in colorectal cancer cells. KRAS mutation further increases invasion in the presence of RhoQ N136S.\",\n      \"method\": \"Whole-genome/transcriptome sequencing to identify editing, expression of edited vs. unedited RHOQ in cancer cell lines, GTPase activity assay, actin cytoskeleton imaging, invasion assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — editing identified by sequencing, functional rescue by expression of edited protein form, GTPase activity and invasion assays; single lab\",\n      \"pmids\": [\"24663214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RHOQ is induced by DLL4/Notch signaling and is required for Notch intracellular domain (NICD) nuclear translocation and Notch signaling. Loss of RHOQ causes Notch1 to be targeted for lysosomal/autophagy degradation, sequestering NICD from the nucleus. RHOQ forms a feed-forward loop: DLL4/Notch induces RHOQ, which in turn promotes Notch signaling.\",\n      \"method\": \"RHOQ siRNA knockdown in endothelial cells, RHOQ overexpression, in vitro sprouting assay, in vivo angiogenesis model, subcellular fractionation/NICD localization, autophagy/lysosome inhibitor experiments\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with defined signaling and cellular phenotypes, subcellular routing experiments; single lab\",\n      \"pmids\": [\"32506201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Arhgef7 (βPix) acts upstream of TC10 to promote axon formation during cortical development. Loss of Arhgef7 causes axon loss that cannot be rescued by active Cdc42 but can be rescued by expression of active TC10. Arhgef7 interacts with TC10.\",\n      \"method\": \"In utero electroporation knockdown of Arhgef7 in cortex, rescue by active TC10, co-immunoprecipitation (Arhgef7-TC10), Cdc42 epistasis experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (active TC10 rescues Arhgef7 KD) plus Co-IP; single lab\",\n      \"pmids\": [\"29891904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Caveolin 1 interacts with TC10 specifically in its GDP-bound (inactive) state and stabilizes GDP binding, maintaining TC10 in an inactive state in unstimulated adipocytes. Knockdown of Caveolin 1 increases basal TC10 activity. TC10 intrinsically has rapid nucleotide exchange (high magnesium decreases exchange rate).\",\n      \"method\": \"Co-immunoprecipitation, GDP/GTP exchange kinetics in vitro, Caveolin 1 siRNA knockdown, GTP-loading assay in adipocytes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with GDP/GTP state specificity, in vitro exchange kinetics, KD with activity readout; single lab\",\n      \"pmids\": [\"22900022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TC10α and TC10β are two isoforms (∼70% identity) both activated by insulin through the CAP/Cbl pathway in 3T3-L1 adipocytes and both localize to lipid rafts. However, TC10α overexpression completely blocks glucose transport and disrupts cortical actin, whereas TC10β only partially inhibits glucose transport and has little effect on cortical actin.\",\n      \"method\": \"cDNA cloning, co-transfection with dominant-negative CAP, GTP-loading assay, sucrose density fractionation, actin imaging, glucose transport assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional comparison of isoforms with biochemical and cellular assays in single lab\",\n      \"pmids\": [\"11821390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TC10 activation is required for osmotic shock-stimulated GLUT4 translocation and glucose transport through a Crk-II pathway, dependent on cortical actin remodeling at caveolin-enriched membrane domains, independently of PI3K and PLCγ.\",\n      \"method\": \"Dominant-interfering TC10/T31N expression, Clostridium difficile toxin B, latrunculin B, jasplakinolide, PI3K and PLCγ inhibitors, GLUT4 translocation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative epistasis plus pharmacological dissection; single lab\",\n      \"pmids\": [\"12215429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TC10 regulates surface exposure of membrane type-1 matrix metalloproteinase (MT1-MMP) at invadopodia in breast cancer cells, controlling extracellular matrix degradation. TC10 activity at invadopodia is regulated by p190RhoGAP and involves downstream interaction with Exo70. Loss of TC10 reduces MT1-MMP plasma membrane exposure and ECM degradation.\",\n      \"method\": \"FRET TC10 biosensor at invadopodia, TC10 KD, p190RhoGAP overexpression/KD, Exo70 interaction, MT1-MMP surface exposure assay, ECM degradation assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET biosensor for spatiotemporal activity, KD with functional readout, pathway epistasis; single lab\",\n      \"pmids\": [\"34531530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TC10 on recycling endosomes (Rab11-positive) promotes axon outgrowth by balancing microtubule stability and dynamics through a PAK2-JNK pathway. TC10 loss reduces PAK2 autophosphorylation and PAK2 localization to Rab11-positive endosomes, decreases JNK phosphorylation, and reduces phosphorylation of the microtubule-binding proteins SCG10 and MAP1B. MKK4/MKK7 mediate signaling from TC10-activated PAK to JNK on JIP1-positive endosomes.\",\n      \"method\": \"TC10 knockout neurons, phospho-proteomics, PAK2 autophosphorylation assay, subcellular fractionation of endosomal compartments, PAK inhibitor treatment, axon retraction assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TC10-KO with phosphoproteomic substrate identification and endosomal localization; single lab\",\n      \"pmids\": [\"40008675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TC10 inactivation at the plasma membrane is mediated by a cAMP-PKA-STEF-Rac1-p190B RhoGAP pathway. cAMP treatment decreases TC10 activity locally at extending neurite tips; this inactivation requires PKA and p190B (but not p190A). TC10 depletion reduces cAMP-induced neurite outgrowth. Constitutively active TC10 cannot rescue this reduction, consistent with GTP hydrolysis being required for vesicle fusion.\",\n      \"method\": \"FRET TC10 biosensor, PKA inhibitor, p190A/B siRNA knockdown, STEF depletion, Rac1-N17 expression, neurite outgrowth assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET biosensor spatiotemporal mapping with siRNA epistasis; single lab\",\n      \"pmids\": [\"29072354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TC10 (RhoQ) binds to the closed/autoinhibited form of collybistin and relieves its autoinhibition (unlike Cdc42, which only interacts with collybistin when it is forced into an open conformation by destabilizing mutations). GTP-TC10 binding to collybistin drives collybistin conformational switch from closed to open state, as measured by FRET.\",\n      \"method\": \"Time-resolved fluorescence FRET sensors of collybistin conformation, TC10 and Cdc42 binding assays with wild-type and mutant collybistin\",\n      \"journal\": \"Frontiers in synaptic neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — FRET conformational sensor with comparative GTPase binding; single lab, mechanistically precise\",\n      \"pmids\": [\"35989712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TC10 stimulates Exo70 mobility in HeLa cells but decreases Exo70 diffusion in the growth cone of cortical neurons; TC10 overexpression does not affect Exo70 mobility in hippocampal neuron growth cones. This indicates cell-type- and compartment-specific regulation of exocyst tethering by TC10.\",\n      \"method\": \"Super-resolution microscopy (single-particle localization and tracking), mean square displacement analysis, TC10 overexpression in HeLa and cortical/hippocampal neurons\",\n      \"journal\": \"Biophysical reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-particle tracking with OE only, single lab, no loss-of-function or interaction assay\",\n      \"pmids\": [\"39521348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Reelin activates TC10 in DRG neurons, and this activation is mediated upstream by Cdc42 (Cdc42 controls TC10 activity). TC10 is required for axon development in DRG neurons. Reelin stimulates fusion of VAMP7-containing membrane carriers that also contain TC10 at the growth cone.\",\n      \"method\": \"TC10 activity assay (GTP-pulldown) after Reelin treatment, Cdc42 dominant-negative epistasis over TC10 activation, TC10 siRNA, VAMP7 vesicle fusion imaging\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/pulldown activity assay and colocalization, limited mechanistic depth; single lab\",\n      \"pmids\": [\"32652719\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RHOQ (TC10) is a Rho-family GTPase that localizes to caveolin-enriched lipid raft microdomains via its unique N-terminal extension and C-terminal palmitoylation, where it is held in an inactive GDP-bound state by Caveolin 1; upon insulin stimulation, the CAP/Cbl/CrkII-C3G pathway activates TC10 in a PI3K-independent manner, leading to downstream effects including PtdIns-3-P production, CIP4/2-mediated GLUT4 translocation, cortical actin reorganization via its N-terminal domain, and Par6/Par3/PKCζ signaling; CDK5 phosphorylates TC10 at T197 to maintain its raft localization; in neurons, locally translated TC10 on Rab11-positive recycling endosomes drives membrane expansion at growth cones by recruiting Exo70 of the exocyst complex, with GTP hydrolysis required for vesicle fusion, and TC10 also promotes axon outgrowth via a PAK2-JNK-SCG10/MAP1B microtubule regulatory pathway on endosomes; TC10 activates collybistin by relieving its autoinhibition, enhancing gephyrin clustering at inhibitory synapses; obscurin acts as a muscle-specific GEF for TC10 to control myofibril assembly; and TC10 regulates MT1-MMP surface exposure at invadopodia in cancer cells via p190RhoGAP and Exo70.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RHOQ (TC10) is a Rho-family GTPase that couples membrane trafficking to actin and microtubule remodeling at specialized membrane microdomains, governing insulin-stimulated glucose uptake, polarized membrane expansion in neurons, myofibril assembly, and cancer cell invasion [#0, #5, #14]. It localizes to caveolin-enriched lipid rafts through processing in the secretory membrane system and C-terminal cysteine modification, where Caveolin 1 binds its GDP-bound form to hold it inactive until stimulation [#1, #11, #22]. In adipocytes, insulin activates TC10 in parallel with—and independent of—PI3K via a CAP/Cbl/CrkII-C3G cascade at rafts, driving PtdIns-3-P production, CIP4/2 recruitment, and Par6/Par3/PKCζ assembly to promote GLUT4 translocation, with its N-terminal extension required for cortical actin remodeling and CDK5 phosphorylation of Thr197 maintaining raft residence [#0, #3, #8, #9, #10, #12]. As an active GTPase TC10 engages effectors shared with Cdc42 and Rac, including PAK and JNK kinases and N-WASP, and binds the exocyst component Exo70 to tether secretory vesicles [#2, #7, #5]. In neurons, locally translated TC10 on Rab11-positive recycling endosomes drives stimulus-evoked membrane expansion and axon outgrowth: GTP hydrolysis releases Exo70 to accelerate vesicle fusion, while a PAK2-JNK pathway phosphorylates the microtubule regulators SCG10 and MAP1B [#16, #17, #26]. TC10 also activates the GEF collybistin by relieving its SH3-domain autoinhibition to promote gephyrin clustering at inhibitory synapses, is loaded by the muscle GEF obscurin during myofibril assembly, and at invadopodia controls MT1-MMP surface exposure and matrix degradation via p190RhoGAP and Exo70 [#15, #28, #14, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing TC10 as a functional GTPase required defining its enzymatic properties and effector repertoire relative to Cdc42 and Rac.\",\n      \"evidence\": \"Two-hybrid screen, GST pulldowns, in vitro GTPase and kinase assays mapping an effector panel\",\n      \"pmids\": [\"9799731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular context of effector engagement not defined\", \"Did not establish physiological upstream activators\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Cellular consequences of TC10 activation were mapped to filopodia, JNK/transcriptional signaling, and oncogenic transformation, plus a GTP-dependent Borg/CRIB effector class, framing TC10 as a Cdc42-like signaling node.\",\n      \"evidence\": \"Constitutively active/dominant-negative mutants, luciferase reporters, focus formation assay, two-hybrid screen with CRIB-domain mapping\",\n      \"pmids\": [\"10445846\", \"10490598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transformation assayed in overexpression context\", \"Physiological relevance of Borg binding untested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"TC10 was placed in the insulin-signaling network as a PI3K-independent driver of GLUT4 translocation activated by the CAP/Cbl/CrkII-C3G cascade specifically at lipid rafts.\",\n      \"evidence\": \"Dominant-negative epistasis, raft/non-raft chimeras, dominant-negative caveolin, subcellular fractionation and GLUT4 translocation in adipocytes\",\n      \"pmids\": [\"11309621\", \"11502760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct GEF for insulin-stimulated activation not identified here\", \"Effectors downstream of activated TC10 not yet defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Downstream effectors and isoform/stimulus specificity of TC10 in glucose transport were defined, linking TC10 to CIP4/2 recruitment, N-WASP-dependent actin, COPI/secretory trafficking, and osmotic-shock GLUT4 mobilization.\",\n      \"evidence\": \"Co-IP, TC10 epistasis over CIP4/2 localization, in vitro actin polymerization in Xenopus extracts, COPI binding, isoform comparison and pharmacological dissection\",\n      \"pmids\": [\"12242347\", \"12134073\", \"11821390\", \"12215429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each effector to GLUT4 vesicle docking unresolved\", \"Direct versus indirect actin effects not fully separated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The lipid-raft determinants and a lipid second messenger were defined, showing the N-terminal extension targets rafts and drives cortical actin disruption while raft-localized TC10 generates GLUT4-mobilizing PtdIns-3-P.\",\n      \"evidence\": \"Chimeric/truncation/point mutants of the N-terminal extension, C206S/C209S cysteine mutants, BFA/temperature blocks, lipid mass spectrometry and FYVE probes\",\n      \"pmids\": [\"12972548\", \"11502760\", \"12529401\", \"12912916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzyme producing PtdIns-3-P downstream of TC10 not identified\", \"Mechanism linking N-terminal raft targeting to actin disruption undefined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"TC10 was shown to assemble a PI3K-independent polarity-kinase module, recruiting Par6/Par3 and activating PKCζ/λ to feed into GSK-3β regulation.\",\n      \"evidence\": \"Multi-protein Co-IP, dominant mutants, PI3K inhibitor and cholesterol depletion, PKCζ phosphorylation assays\",\n      \"pmids\": [\"14734537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect PKCζ activation mechanism unresolved\", \"Physiological output of GSK-3β phosphorylation not quantified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"A regulatory phosphorylation was identified showing CDK5 modifies TC10 at Thr197 to sustain raft localization and insulin-responsive GTP loading.\",\n      \"evidence\": \"CDK5 siRNA/inhibitor, phospho-specific IP, T197A/T197D mutants, fractionation, GTP-loading and GLUT4 assays\",\n      \"pmids\": [\"18948252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase reversing T197 not identified\", \"Mechanism by which T197 phosphorylation maintains raft residence unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"TC10's role in polarized exocytosis and tissue morphogenesis was established through its Exo70 partnership in axon growth and its dedicated muscle GEF obscurin in myofibril assembly.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA/shRNA, dominant mutants, live membrane imaging in neurons; in vitro GEF and binding assays plus loss-of-function in primary myoblasts\",\n      \"pmids\": [\"19846717\", \"19258391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GEFs for TC10 in non-muscle insulin signaling still unidentified\", \"Structural basis of obscurin-TC10 specificity undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The inactive-state control of TC10 was clarified by showing Caveolin 1 binds GDP-TC10 and stabilizes it, restraining basal activity against TC10's intrinsically rapid nucleotide exchange.\",\n      \"evidence\": \"GDP/GTP-state-specific Co-IP, in vitro exchange kinetics, Caveolin 1 knockdown with activity readout\",\n      \"pmids\": [\"22900022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP without structural confirmation\", \"How insulin displaces caveolin to permit activation unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"TC10 was defined as an upstream activator of collybistin at inhibitory synapses and shown to switch GTP-hydrolysis-dependent control of Exo70 release during neurite outgrowth.\",\n      \"evidence\": \"Co-IP with PH-domain specificity, mIPSC recordings, gephyrin cluster imaging; FRET activity biosensor with vesicle tracking and rescue tests\",\n      \"pmids\": [\"24297911\", \"24223996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GEF activating TC10 at the synapse not identified\", \"Coupling of vesicular GTP hydrolysis to fusion machinery not structurally defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"TC10's spatial regulation was extended to mRNA localization (local axonal translation driving membrane expansion) and to disease via RNA editing producing a hyperactive N136S variant that enhances cancer cell invasion.\",\n      \"evidence\": \"Axon-specific knockdown, local translation reporters, mTOR/PI3K inhibitors; transcriptome sequencing, edited-protein expression, GTPase and invasion assays\",\n      \"pmids\": [\"24667291\", \"24663214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trans-acting factors localizing TC10 mRNA undefined\", \"In vivo tumor relevance of N136S editing not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Spatial inactivation of TC10 at the plasma membrane was mapped to a cAMP-PKA-STEF-Rac1-p190B RhoGAP circuit required for cAMP-induced neurite outgrowth.\",\n      \"evidence\": \"FRET TC10 biosensor, PKA inhibitor, p190A/B and STEF siRNA, Rac1-N17 expression, neurite outgrowth assay\",\n      \"pmids\": [\"29072354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GAP-substrate engagement not biochemically reconstituted\", \"Single-lab FRET-based epistasis\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"An upstream GEF and Cdc42-independent axon pathway were defined, with Arhgef7 (βPix) acting through TC10 to drive cortical axon formation.\",\n      \"evidence\": \"In utero electroporation knockdown, rescue by active TC10, Co-IP, Cdc42 epistasis\",\n      \"pmids\": [\"29891904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GEF activity of Arhgef7 toward TC10 not enzymatically demonstrated\", \"Single Co-IP for the interaction\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"TC10's roles broadened to receptor trafficking control, stabilizing Notch1 against lysosomal degradation in a DLL4/Notch feed-forward loop during angiogenesis.\",\n      \"evidence\": \"siRNA/overexpression in endothelial cells, sprouting and in vivo angiogenesis assays, NICD fractionation, autophagy/lysosome inhibitor experiments\",\n      \"pmids\": [\"32506201\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TC10 diverts Notch1 from degradation unknown\", \"Direct TC10-Notch interaction not shown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"TC10 was shown to control cancer invadopodia function by regulating MT1-MMP surface exposure and ECM degradation through p190RhoGAP and Exo70.\",\n      \"evidence\": \"FRET TC10 biosensor at invadopodia, knockdown, p190RhoGAP modulation, MT1-MMP surface and ECM degradation assays\",\n      \"pmids\": [\"34531530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GEF activating TC10 at invadopodia unidentified\", \"Single-lab biosensor study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The microtubule arm of TC10's outgrowth function was defined, linking endosomal TC10 to a PAK2-JNK pathway phosphorylating SCG10 and MAP1B.\",\n      \"evidence\": \"TC10-knockout neurons, phosphoproteomics, PAK2 autophosphorylation, endosomal fractionation, PAK inhibitor, axon retraction assay\",\n      \"pmids\": [\"40008675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PAK2 activation by TC10 versus scaffold role unresolved\", \"Integration with the Exo70/exocytosis arm on the same endosomes undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TC10 nucleotide cycling is coordinated across distinct compartments (rafts, recycling endosomes, invadopodia) and which GEFs and GAPs act in each context remain incompletely defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking compartment-specific GEF/GAP control to effector choice\", \"Structural basis of TC10 effector and regulator selectivity unresolved\", \"In vivo physiological and disease roles of most pathways untested in animal models\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [2, 16, 19, 22]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5, 11]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [16, 26]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [16, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 9, 20]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [5, 8, 16]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [5, 16, 25]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [17, 21, 26]}\n    ],\n    \"complexes\": [\"exocyst\"],\n    \"partners\": [\"EXOC7\", \"CAV1\", \"OBSCN\", \"ARHGEF9\", \"TRIP10\", \"GOPC\", \"PARD6A\", \"ARHGEF7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}